ASP8273 ISN 8273-CL-0101 CONFIDENTIAL Astellas Pharma Inc

ASP8273 ISN 8273-CL-0101Non-small Cell Lung Cancer (NSCLC)CONFIDENTIAL

Name of Sponsor/Company: Astellas Pharma Inc.

Name of Finished Product: Not applicable

Name of Active Ingredient: ASP8273

May 2018 Astellas Synopsis Page 1 of 45

SYNOPSIS

Title of Study: An open-label study of the oral administration of ASP8273 in patients with non-small cell lung

cancer harboring epidermal growth factor receptor (EGFR) mutations

Investigators/Coordinating Investigator: ,

Study Center(s):

Phase 1: 4 study sites in Japan

Phase 2: 9 study sites in Japan, 3 study sites in Korea and 2 study sites in Taiwan

Publication Based on the Study: None

Study Period: Ongoing study.

Study Initiation Date (Date of First Evaluation):

Phase 1: 23 Jan 2014

Phase 2: 25 Dec 2014

Study Completion Date (Date of Last Evaluation):

Phase 1: 29 May 2017

Phase 2: 14 Jun 2017

Phase of Development: 1 and 2

Objectives:

Phase 1

To determine the following in patients with non-small cell lung cancer (NSCLC) harboring EGFR activating

mutations.

Primary objectives:

● To determine the safety and tolerability of ASP8273

● To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of ASP8273

based on the dose limiting toxicity (DLT) profile

Secondary objectives:



● To determine the pharmacokinetics of ASP8273

● To determine the antitumor activity of ASP8273

Phase 2

To determine the following at the RP2D of ASP8273 in patients with NSCLC harboring an EGFR activating

mutation and the EGFR-T790M mutation.

Primary objective:

● To determine the efficacy of ASP8273

Secondary objectives:

● To determine the safety of ASP8273

● To determine the pharmacokinetics of ASP8273

Methodology: This study consisted of phase 1 and phase 2.

Phase 1

Phase 1 was divided into 3 parts: a dose-escalation part, an additional EGFR-T790M part and a re-enrollment

part.

Dose-escalation and Additional EGFR-T790M Parts:

Phase 1 of this study was aimed to evaluate the safety, tolerability, pharmacokinetics and efficacy of ASP8273

administered as a single oral dose or as multiple oral doses once daily in patients with NSCLC that had been

confirmed to harbor an EGFR activating mutation.

The dose-escalation and additional EGFR-T790M parts consisted of 2 periods: a single-dose period (cycle 0

lasting 2 days) and a multiple-dose period (from cycle 1 onwards, each cycle lasting 21 days). In the

single-dose period, enrolled patients received ASP8273 as the single oral dose assigned to each patient on day 1

of cycle 0 and patients were then observed for 2 days (including the day of dosing). In the multiple-dose period,

ASP8273 was administered as multiple oral doses during each cycle lasting 21 days. Patients continued to

receive treatment with ASP8273 until they met the discontinuation criteria.

The study was designed to assess DLTs of ASP8273 using the Bayesian continual reassessment method

(Bayesian-CRM) with sequential dose escalation or de-escalation (change of dose level) of ASP8273. After the

assessment of DLTs in cycles 0 and 1, patients continued to receive treatment with ASP8273 until they met the

discontinuation criteria.

In the dose-escalation part, at least 3 patients were enrolled at each dose level depending on the occurrence of

DLTs in cycles 0 and 1. Patients enrolled at one dose level were not enrolled at other dose levels. ASP8273

was administered at an initial dose of 25 mg, which was to be escalated to higher dose levels set at 50, 100, 200,

400, 600 and 800 mg. Among these dose levels, the next recommended dose level was in principle selected

according to the posterior mean incidence of DLTs calculated based on the Bayesian-CRM. Proceeding to the

next dose level (including enrollment of additional patients to the current dose level) was discussed by the

investigator and the sponsor (called “dose escalation meeting”) in reference to the recommended dose level

calculated by the Bayesian-CRM in consideration of safety data, etc. Whether to proceed to the next dose level

was finally decided in consultation with the sponsor’s responsible person. Depending on the result of the



meeting, an intermediate dose level, whose dose was calculated by multiplying the percent dose increment listed

in the table below by 50%, could be added. Since dose escalation continued until MTD was reached or RP2D

was decided, an additional dose level that was higher than 800 mg could also be used. Other treatment

schedules, such as twice daily treatment, could also be assessed depending on the obtained safety and

pharmacokinetic data, etc. The next dose level was determined after the end of cycle 1 assessments in all

patients enrolled in the last dose-escalation part.

At dose levels equal to or higher than the level at which patients showed a tumor response (partial response

[PR] or complete response [CR]) in the dose-escalation part, patients with NSCLC harboring both an EGFR

activating mutation and the EGFR-T790M mutation could be enrolled in another part than the dose-escalation

part (additional EGFR-T790M part). Only dose levels from which dose escalation to the next dose level had

been approved in the dose-escalation part could be included in this additional part.

Once patients were enrolled in the additional EGFR-T790M part, the incidence of DLTs (posterior mean) at

each dose level was calculated using all DLT data obtained up to that time, not only that obtained in the

dose-escalation part, but also that obtained in the additional EGFR-T790M part.

Dose level

Daily dose ofASP8273

Percentincrement

Number of patients in thedose-escalation part

Number of patients in theadditional EGFR-T790M part †

1 25 mg - ≥ 3 ≤ 10 at each dose level, includingpatients in the dose-escalation part2 50 mg 100% ≥ 3

3 100 mg 100% ≥ 34 200 mg 100% ≥ 35 400 mg 100% ≥ 36 600 mg 50% ≥ 37 800 mg 33% ≥ 3

† Patients could be enrolled at dose levels equal to or higher than the level at which patients had shown a tumor response inthe dose-escalation part.

The MTD was defined as the highest dose of ASP8273 at which the incidence of DLTs was estimated to be the

closest to 33%. In this study, the dose-escalation and additional EGFR-T790M parts could be terminated when

at least 6 patients had already been enrolled at the next recommended dose level calculated by the

Bayesian-CRM. Patient enrollment and DLT assessment continued until this requirement for study termination

was met.

The sponsor decided the RP2D of ASP8273 to be used in phase 2, taking the MTD, safety, pharmacokinetics

and efficacy of ASP8273 into consideration.

Re-enrollment Part:

In the re-enrollment part, a patient who discontinued the study due to progressive disease (PD) in the 25 mg

cohort in the dose-escalation part could be re-enrolled if the patient wished to reintroduce ASP8273 and the

investigator considered that reintroduction was appropriate. The part was designed to assess the safety and

efficacy of ASP8273 in the re-enrolled patient. In each cycle lasting 21 days, ASP8273 was administered as

multiple oral doses at the RP2D decided in the dose-escalation and additional EGFR-T790M parts. Patients

continued to receive treatment with ASP8273 until they met the discontinuation criteria. The safety and

efficacy of ASP8273 in the re-enrollment part were evaluated separately from the evaluation in the

dose-escalation and additional EGFR-T790M parts.



Phase 2

Phase 2 of this study was aimed to evaluate the efficacy, safety and pharmacokinetics of ASP8273 administered

as multiple oral doses to patients with NSCLC harboring an EGFR activating mutation and the EGFR-T790M

mutation.

In each cycle lasting 21 days, ASP8273 was administered as multiple oral doses at the RP2D decided in the

dose-escalation and additional EGFR-T790M parts of phase 1. Patients continued to receive treatment with

ASP8273 until they met the discontinuation criteria.

The efficacy was evaluated as a 2-stage study according to Simon’s 2-stage design (optimal design). In the first

stage, the efficacy was assessed when efficacy data had been collected from 24 patients.

The efficacy was evaluated at each stage as follows:

First stage (to be performed in 24 patients):

● When at least 9 of 24 patients were assessed to have a tumor response, the study was to enter the second

stage.

● When equal or less than 8 of 24 patients were assessed to have a tumor response, it was to be considered

unlikely from a statistical point of view that the observed response rate to ASP8273 was higher than the

threshold response rate of 0.3.

When study continuation was to be approved based on the results of the first stage, an additional 39 patients

were to be enrolled in the second stage.

At the final assessments (to be performed in 63 patients [24 patients in the first stage + 39 patients in the second

stage]):

● When at least 25 of 63 patients were assessed to have a tumor response, it was to be determined that

ASP8273 has antitumor effects, based on an observed response rate of equal to or higher than the threshold

response rate of 0.3.

● When equal or less than 24 of 63 patients were assessed to have a tumor response, it was to be considered

unlikely that the observed response rate to ASP8273 was higher than the threshold response rate of 0.3.

From safety and efficacy perspectives, the final decision on proceeding to the second stage, and on making a

necessary change to the RP2D during phase 2, had to be made by the sponsor, in consultation with the Data and

Safety Monitoring Board and the medical expert, as needed.

There were no efficacy data that could be used for direct comparison with the treatment of patients with NSCLC

harboring the EGFR-T790M mutation who have become resistant to EGFR tyrosine-kinase inhibitors (TKIs).

The response rate to platinum-based therapy as the first-line treatment for NSCLC harboring EGFR activating

mutations is reported to be approximately 30%.

Response rates of higher than 30% could therefore be considered to indicate high clinical benefit. Based on this

assumption, the expected and threshold response rates to ASP8273 were estimated to be 0.5 and 0.3,

respectively, with a 1-sided 0.05 level of significance and a 90% power of test.

Number of Patients (Planned, Enrolled and Analyzed):

Planned:



Phase 1

Dose-escalation part: 42 patients (To be adjusted depending on the number of patients showing toxicities; at

least 3 patients were enrolled at each dose level.)

Additional EGFR-T790M part: 12 patients (To be adjusted depending on the number of patients showing a

tumor response; enrollment was allowed at dose levels equal to or higher than the level at which patients

showed a tumor response in the dose-escalation part; a total of up to 10 patients were to be enrolled at each dose

level in the dose-escalation and additional EGFR-T790M parts combined.)

Re-enrollment part: Up to 3 patients

Phase 2

70 patients

Enrolled and Analyzed:

Phase 1

Dose-escalation and additional EGFR-T790M parts: A total of 47 patients were enrolled and 45 were included

in the safety analysis set (SAF), full analysis set (FAS), dose-determine analysis set (DDAS) and

pharmacokinetic analysis set (PKAS).

Re-enrollment part: 1 patient

Phase 2

A total of 76 patients were enrolled and were included in the SAF, FAS and PKAS.

Diagnosis and Main Criteria for Inclusion: Patients were eligible for inclusion in the study if they were

≥ 20 years of age at the time of obtaining informed consent (in Korea and Taiwan, adult patients [defined

according to local regulations]), had Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1, had

histologically or cytologically confirmed diagnosis of NSCLC, and were confirmed to have the deletion of exon

19 (del ex19), L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study

site who were documented to have any of the above-stated EGFR activating mutations could be enrolled in the

study).

Patients also had to meet the following criteria:

● For prior treatment for NSCLC, in phase 1, patients had to have previously been treated with

EGFR-TKIs †, and had not been expected to show a therapeutic response to existing treatments in the

investigator’s/subinvestigator’s opinion; in phase 2, patients had to be confirmed to have PD after previous

treatment with EGFR-TKIs † (for those who had received 2 or more regimens of previous treatment, the

last regimen before enrollment had to have included EGFR-TKIs and PD had to have been confirmed).

† Erlotinib, gefitinib, afatinib and EGFR-TKIs under clinical investigation (e.g., neratinib, dacomitinib)

● In the additional EGFR-T790M part of phase 1, patients had to be confirmed to have the EGFR-T790M

mutation (patients at the study site who were documented to have the EGFR-T790M mutation could be

enrolled in the study).



● In phase 2, patients had to have expression of the EGFR-T790M mutation as confirmed by a tumor biopsy

of the primary or metastatic lesions after confirmation of PD following treatment with EGFR-TKIs as the

last regimen before enrollment, or by a tumor tissue sample that had been collected and archived after

confirmation of PD following treatment with EGFR-TKIs as the last regimen before enrollment; and had

to have at least 1 measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST)

Version 1.1.

● In the re-enrollment part of phase 1, patients had to have discontinued the study due to PD in the 25 mg

cohort in the dose-escalation part.

Patients were not eligible for enrollment if they had clinical evidence of previous antitumor treatment-related

toxicity ≥ grade 2 using the National Cancer Institute Common Terminology Criteria for Adverse Events

(NCI-CTCAE) v4.0 – Japan Clinical Oncology Group (JCOG) (except alopecia and skin toxicities considered

irrelevant in study enrollment by the investigator/subinvestigator), received treatment with gefitinib within

8 days or with erlotinib within 5 days before the start of the study treatment, received previous treatment (except

reversible EGFR-TKIs) intended to have antitumor effects or treatment with another investigational drug or an

investigational device within 14 days before the start of the study treatment, previously received treatment with

EGFR-TKIs (e.g., CO-1686, AZD9291) that can inhibit EGFR with the T790M mutation (this did not apply to

the re-enrollment part) or used strong cytochrome P450 (CYP) 3A inhibitors within 9 days prior to the start of

the study treatment (for itraconazole, within 14 days prior to the start of the study treatment).

Test Product, Dose and Mode of Administration, Batch Numbers: ASP8273 was provided as capsules in 5,

25 and 100 mg strengths in bottles containing 30 capsules each.

Phase 1

The dose-escalation and additional EGFR-T790M parts of phase 1 consisted of 2 periods: a single-dose period

(cycle 0 lasting 2 days) and a multiple-dose period (cycle 1 onwards, each cycle lasting 21 days).

In the single-dose period, ASP8273 was administered as a single oral dose on day 1 of cycle 0, followed by

1-day cessation of treatment on the day after dosing (day 2 of cycle 0). In the multiple-dose period, ASP8273

was administered as multiple oral doses once daily in each cycle lasting 21 days. Patients continued to receive

treatment with ASP8273 until they met the discontinuation criteria.

The Re-enrollment Part of Phase 1 and Phase 2

ASP8273 was administered as multiple oral doses once daily in each cycle lasting 21 days at the RP2D

(300 mg) decided in the dose-escalation and additional EGFR-T790M parts of phase 1. Patients continued to

receive treatment with ASP8273 until they met the discontinuation criteria.

Lot numbers for study drugs were and , , , , ,

and .

Duration of Treatment (or Duration of Study, if applicable): In phase 1, the duration of study drug

administration ranged from 23 to 660 days. In phase 2, the duration of study drug administration ranged from 7

to 361 days.

Reference Product, Dose and Mode of Administration, Batch Numbers: Not applicable.



Criteria for Evaluation:

Efficacy:

Primary Variables

Phase 1:

Not applicable.

Phase 2:

● Overall response rate (ORR) (CR + PR) †

† Best overall response at week 24 which met RECIST Version 1.1 best overall response confirmation criteria

was categorized into ORR (CR + PR).

In phase 2, ORR (CR + PR) based on central review was regarded as primary. ORR (CR + PR) based on local

review was regarded as secondary. In phase 2, to confirm the best overall response rated as CR or PR, the

response had to continue to meet the criteria for CR or PR, respectively, for at least 4 weeks.

Secondary Variables

Phase 1 (Dose-escalation and Additional EGFR-T790M Parts):

● Best overall response †

● Best overall response without confirmation ‡

● ORR (CR + PR) †

● ORR (CR + PR) without confirmation ‡

● Disease control rate (DCR) (CR + PR + stable disease [SD]) †

● DCR (CR + PR + SD) without confirmation ‡

† In accordance with RECIST Version 1.1 “Best overall response when confirmation of CR and PR required.”

‡ Regardless of RECIST Version 1.1 “Best overall response when confirmation of CR and PR required.”

● Progression-free survival (PFS)

PFS was defined as the time from the start of the study treatment until death from any cause or radiographical

disease progression assessed according to RECIST Version 1.1, whichever occurred first during study period.

● Duration of response (DOR)

DOR was defined as the time from the date of the first confirmed response CR/PR (whichever was first

recorded) assessed according to RECIST Version 1.1 to the date of radiographical progression or date of

censoring. If a patient had not progressed, the patient was censored at the date of last radiological assessment or

at the date of first confirmed CR/PR if no subsequent radiological assessment was available. DOR was derived

for patients with best overall response as CR or PR (with confirmation).

Phase 1 (Re-enrollment Part):

● Best overall response †




Phase 2:

● Best overall response at week 24 †

● Best overall response without confirmation at week 24 ‡

● ORR (CR + PR) without confirmation at week 24 ‡

● DCR (CR + PR + SD) at week 24 †

● DCR (CR + PR + SD) at week 24 without confirmation ‡

● Best overall response over the entire exposure period †

● Best overall response over the entire exposure period without confirmation ‡

● ORR (CR + PR) over the entire exposure period without confirmation ‡

● DCR (CR + PR + SD) over the entire exposure period †

● DCR (CR + PR + SD) over the entire exposure period without confirmation ‡


Central review and local review were applied.

‡ Regardless of RECIST Version 1.1 “Best overall response when confirmation of CR and PR required.”


● PFS during study period † (not including additional follow-up period)

† Study period was defined as first dose of study drug up to the end of follow-up period, and not including

additional follow-up period.

PFS was applied to central review and local review.

● PFS including additional follow-up period

PFS including additional follow-up period was applied to local review only.

● Overall survival (OS) including additional follow-up period

● DOR during study period † (not including additional follow-up period)

† Study period was defined as first dose of study drug up to the end of follow-up period, and not including

additional follow-up period.


● DOR during study period (including additional follow-up period)

DOR including additional follow-up period was applied to local review only.

Pharmacokinetics:

Pharmacokinetics were evaluated as secondary variables.

Phase 1 (Dose-escalation and Additional EGFR-T790M Parts)

● Plasma concentrations of unchanged ASP8273

● Urine concentrations of unchanged ASP8273

Phase 2

● Plasma concentrations of unchanged ASP8273



Safety:

In phase 1, as primary variable, the safety was assessed based on the DLTs (excluding the re-enrollment part),

adverse events (AEs), clinical laboratory tests, bone turnover markers, vital signs, percutaneous oxygen

saturation (SpO2), body weight, 12-lead electrocardiogram (ECG) (including the assessment of the QT interval),

ophthalmologic examination, chest X-ray examination, chest computed tomography (CT) examination and

ECOG performance status.

In phase 2, as secondary variable, the safety was assessed based on AEs, clinical laboratory tests, bone turnover

markers, vital signs, SpO2, body weight, 12-lead ECG (including the assessment of the QT interval),

ophthalmologic examination, chest X-ray examination, chest CT examination and ECOG performance status.

Statistical Methods:

The data cut-off date was 15 Jan 2016 for all analyses summarized in this report unless otherwise specified.

For phase 1, all the analysis was conducted for combined data of dose-escalation part and additional

EGFR-T790M part, and for re-enrollment part independently.

For continuous variables, descriptive statistics included the number of patients (n), mean, standard deviation

(SD), median, minimum and maximum. Frequencies and percentages were displayed for categorical data.

Percentages by categories were based on the number of patients with no missing data, i.e., would add up to

100%. Kaplan-Meier survival curves were displayed for time-to-event variables and median survival time was

estimated with 2-sided 95% confidence interval (CI).

All analysis was presented by dose level taken at the first time, unless specifically stated otherwise.

All data processing, summarization and analyses were performed with SAS® Drug Development (ver. 4.5) and

PC-SAS (ver. 9.4) or higher versions.

Efficacy: The FAS, defined as all patients who received at least 1 dose of ASP8273 and were evaluated for at

least 1 efficacy endpoint after the start of the study treatment, was used for summaries and the analyses of

efficacy data. In phase 2, the FAS was the primary analysis set for efficacy analyses. Following variables were

analyzed in each phase. Patients without acceptable imaging data for baseline assessment of tumor lesions in

the FAS were excluded from the analyses described in “Analysis of the Primary Endpoint” and “Antitumor

Effect.” Image assessment data in phase 2 were primarily based on central review. Image assessment data

based on local review in phase 2 was secondary. In phase 1, ORR was presented by initial dose level and by

onset dose level respectively, unless specified otherwise. In the re-enrollment part of phase 1, no specific

planned analysis was conducted and the results of the efficacy variables, that is, best overall response was listed

only. In the first stage of phase 2, an analysis of the primary endpoint was performed on the first 24 patients in

the FAS at the first stage data cut-off.

Analysis of the Primary Endpoint

ORR (Primary Analysis):

Not applicable for phase 1.

In phase 2, the antitumor effects of ASP8273 based on RECIST Version 1.1 were evaluated as a 2-stage study

according to Simon’s 2-stage design (optimal design). In this analysis, the ORR to ASP8273 at week 24, which

was defined as the proportion of patients whose best overall response at week 24 was rated as CR or PR, was



expressed as “p,” and the expected and threshold response rates to ASP8273 were estimated to be 0.5 and 0.3,

respectively, with a 1-sided 0.05 level of significance and a 90% power of test. The null and alternative

hypotheses (H0 and H1, respectively) tested in this analysis are shown below. The ORR at week 24 was

presented with 95% CI (Clopper-Pearson).

H0: p ≤ 0.3, H1: p ≥ 0.5 (p: The ORR to ASP8273 at week 24)

● First stage (to be performed on first-enrolled 24 patients):

o When at least 9 of 24 patients were assessed to have a tumor response, the study was to enter the

second stage.

o When equal or less than 8 of 24 patients were assessed to have a tumor response, it was considered

unlikely from a statistical point of view that the observed response rate to ASP8273 was higher than

the threshold response rate of 0.3.

● At the final assessments (to be performed in 63 patients [24 in the first stage + 39 in the second stage]):

o When at least 25 of 63 patients were assessed to have a tumor response, the null hypothesis was to be

rejected, and it was to be determined that ASP8273 has antitumor effects based on the observed

response rate equal to or more than the threshold response rate of 0.3.

o When equal or less than 24 of 63 patients were assessed to have a tumor response, the null hypothesis

could not be rejected; and it was considered unlikely that the observed response rate to ASP8273 was

more than the threshold response rate of 0.3.

ORR (Secondary Analysis):

The antitumor effects of ASP8273 based on RECIST Version 1.1 were analyzed as described below.

In phase 1, the ORR, which was defined as the proportion of patients whose best overall response over the

entire exposure period was rated as CR or PR, was calculated by dose in each part and its 95% CI

(Clopper-Pearson) was presented. The ORR without confirmation was conducted, similarly as above.

In phase 2, data of all patients who were enrolled in phase 2 (i.e., not only 24 or 63 patients) were analyzed as

described below.

● The ORR at week 24, which was defined as the proportion of patients whose best overall response at week

24 was rated as CR or PR, and its 95% CI (Clopper-Pearson) were calculated. The same analysis was

conducted with unconfirmed CR or PR. This analysis was conducted by central review and local review.

● As a sensitivity analysis, the ORR at week 24 for central review excluding the patients who did not have

any target lesion at baseline was summarized as well as the above analysis.

● As a sensitivity analysis, the ORR at week 24 for central review excluding the patients who discontinued

from the study due to the reason other than progressive disease was summarized as well as the above

analysis.

● The ORR for the entire treatment, which was defined as the proportion of patients whose best overall

response over the entire exposure period was rated as CR or PR, and its 95% CI (Clopper-Pearson) were

calculated. The same analysis was conducted with unconfirmed CR or PR. This analysis was conducted

by central review only.

● As a sensitivity analysis, the ORR for the entire treatment in central review excluding the patients who did

not have any target lesion at baseline was summarized as well as the above analysis.



Analysis of Secondary Endpoints

Antitumor Effect (DCR):

In phase 1, the DCR, which was defined as the proportion of patients whose best overall response over the

entire exposure period was rated as CR, PR or SD, was calculated in the analysis population by dose in each

part and its 95% CI (Clopper-Pearson) was presented. The DCR without confirmation was conducted, similarly

as above.

In phase 2, the DCR at week 24 and for entire period were analyzed same as ORR at week 24 and for entire

period, but rated as confirmed CR, PR or SD. This analysis was conducted by central review and local review.

Antitumor Effect (Waterfall Plot):

In phase 1 (excluding the re-enrollment part), the maximum shrinkage of sum of diameter from baseline in

target lesion was plotted as a waterfall plot.

In phase 2, same as phase 1, but calculated for central review and local review. Target lesion was applicable

during study period (not including additional follow-up period). If there was no target lesion at baseline or no

postbaseline target lesion evaluation for central review, then these patients were not included in the denominator.

Antitumor Effect (Maximum Shrinkage in Target Lesion):

In phase 1 (excluding the re-enrollment part), the proportion of patients whose maximum shrinkage from

baseline in target lesion was equal to or more than 30%.

In phase 2, same as phase 1, but calculated for central review and local review. Target lesion was applicable

during study period (not including additional follow-up period). If there was no target lesion at baseline or no

postbaseline target lesion evaluation for central review, then these patients were not included in the denominator.

Antitumor Effect (Other Analysis):

In phase 1, the number and percentage of patients with each overall time point response, with CR or PR, and

with CR or PR or SD were presented at each visit.

In phase 2, the number and percentage of patients with each overall time point response, with CR or PR, and

with CR or PR or SD were presented at each visit. In addition, the summary statistics for the time to first PD

and the concordance rate for best overall response at week 24 between central review and local review were

presented.

PFS:

In phase 1, the median follow-up time for PFS was estimated according to the Kaplan-Meier estimate of

potential follow-up also termed as “Reverse Kaplan-Meier.” The number of patients who already experienced

death or radiographic disease progression, the number of patients still at risk and Kaplan-Meier estimate with

95% CI of PFS rate using Greenwood’s formula with log-log transformation were presented at given time

points. Additionally, median PFS and the associated 95% CI using the method of Brookmeyer and Crowley

with log-log transformation were presented. Kaplan-Meier plot was also presented.

In phase 2, same as phase 1. PFS was applied to central review and local review. For local review, PFS

including additional follow-up period was also created.



OS:

Not applicable for phase 1.

In phase 2, OS was defined as the time from the start of the study treatment until death from any cause

including additional follow-up period. The OS was censored in the following scenarios; if a patient had no

death, the OS was censored at last known alive date. OS (in days) was calculated as: (Date of death) – (Date of

the first treatment) + 1. The number of patients who experienced death, the number of patients still at risk and

Kaplan-Meier estimate with 95% CI of cumulative incidence using Greenwood’s formula with log-log

transformation were presented at given time points. Kaplan-Meier plot and median survival time and its 95%

CI with log-log transformation were presented in phase 2.

DOR:

In phase 1, median DOR and the associated 95% CI using the method of Brookmeyer and Crowley with log-log

transformation were presented. Additionally, Kaplan-Meier plot of DOR was presented.

In phase 2, same as phase 1. DOR was applied to central review and local review. For local review, DOR

including additional follow-up period was also created.

Analysis of Efficacy by Subgroup:

Some select efficacy variables were summarized by dose level and the subgroups defined on the basis of the

categorized variables below.

● Phase 1 (excluding the re-enrollment part): sex (female, male), age (< 75, ≥ 75 years), number of previous

EGFR-TKI treatment (0, 1, 2, 3), immediate cancer treatment (EGFR-TKI, not EGFR-TKI), patients with

evidence of an EGFR-T790M mutation (local) (yes, no, unknown), tobacco history (never used tobacco,

current tobacco user, former tobacco user) and existence of brain metastasis at baseline (yes, no)

● Phase 2: sex (female, male), age (< 75, ≥ 75 years), race in Asian (Japanese, Korean, Taiwanese, other

Asian), number of previous EGFR-TKI treatment (0, 1, 2, 3), immediate cancer treatment (EGFR-TKI, not

EGFR-TKI), patients with evidence of an EGFR-T790M mutation with blood sample at central EGFR

gene testing laboratory (+, -, unable to be analyzed), del ex19 tested with tissue sample at central EGFR

gene testing laboratory (+, -, unable to be analyzed), L858R tested with tissue sample at central EGFR

gene testing laboratory (+, -, unable to be analyzed), tobacco history (never used tobacco, current tobacco

user, former tobacco user), existence of brain metastasis at baseline (yes, no) and existence of liver

metastasis at baseline (yes, no)

Pharmacokinetics: The PKAS, defined as all patients who received at least 1 dose of ASP8273 and in whom

drug concentration was measured at least 1 time point after the start of the study treatment, was used for

pharmacokinetic analyses; while, patients whose blood sampling was conducted within 30 minutes after ECG

monitoring were used in the concentration-QT interval corrected for heart rate according to Fridericia’s formula

(QTcF) analysis.

Estimation of Pharmacokinetic Parameters

The noncompartmental methods were employed to calculate pharmacokinetic parameters.

The following plasma pharmacokinetic parameters were estimated using plasma concentrations of ASP8273

and actual elapsed times from dosing, provided enough data were available for accurate estimations.



Phase 1 (Excluding the Re-enrollment Part)

● Single-dose pharmacokinetics (cycle 0 day 1): AUCinf, AUClast, AUC24h, AUC48h, Cmax, C24h, CL/F, λz,

MRTinf, tmax, t1/2, Vz/F

● Multiple-dose pharmacokinetics (cycle 1 day 21): AUCtau, Cmax, C24h, CL/F, tmax, PTR, Rac (AUC),

Rac (Cmax)

● Trough concentration: Ctrough on cycle 1 day 8, day 15, day 18, day 21 and cycle 3 day 1

Phase 2

● Single-dose pharmacokinetics (cycle 1 day 1): AUClast, AUC24h, Cmax, C24h, CL/F, λz, tmax, t1/2, Vz/F

● Multiple-dose pharmacokinetics (cycle 1 day 21): AUCtau, Cmax, C24h, CL/F, tmax, PTR, Rac (AUC),

Rac (Cmax)

● Trough concentration: Ctrough on cycle 1 day 8, day 15, day 21 and cycle 3 day 1

The following urinary pharmacokinetic parameters were estimated using urinary concentrations of ASP8273

and planned elapsed time from dosing if sufficient data for accurate estimation were available.


● Cycle 0 day 1 to 2: Ae24h, Ae48h, Ae24h%, Ae48h%, CLR

● Cycle 1 day 21: Aetau, Aetau%, CLR

Summary Statistics

Concentrations and pharmacokinetic parameters were summarized using the following summary statistics:

number of observation (n), arithmetic mean, SD, coefficient of variation (%CV), minimum, median, maximum,

geometric mean (GM) and %CV of GM (Geo %CV). Mean, SD, %CV, GM and Geo %CV were not

summarized for tmax. GM and Geo %CV were not calculated if at least 1 value was below the quantification

limit (BQL). If more than 50% of values were BQL at a given time point, SD and %CV were not calculated,

and error bars were not shown in concentration-time plots at that specific time point.

Statistical Analysis

Analysis of dose proportionality (phase 1 only): Dose proportionality of ASP8273 was assessed using the

power model with the SAS MIXED procedure. The log-transformed dose and pharmacokinetic parameters

(AUCinf, AUClast, AUCtau and Cmax) were used for the analysis: log(pharmacokinetic parameter) = α +

β∙log(dose), where α and β represent the intercept and the slope of the regression line, respectively. The

estimates of β and its 95% CI were shown in a table. No dose proportionality was to be declared if the 95% CI

did not contain 1.

Confirmation of steady-state concentrations: Steady-state was assessed by visual inspection. For phase 1, mean

(SD) Ctrough from cycle 1 day 8 to cycle 1 day 21 was presented. For phase 2, mean (SD) Ctrough from cycle 1

day 8 to cycle 1 day 21 was presented.

Confirmation of accumulation: Accumulation was assessed using the analysis of variance (ANOVA) with the

SAS MIXED procedure with day as a fixed effect and patients as a random effect. Geometric least square mean

ratios (GMRs) and their 90% CIs of Cmax and AUCtau of cycle 1 day 21 to cycle 0 day 1 (phase 1) or cycle 1

day 1 (phase 2) were shown in a table.



Confirmation of ethnic differences (phase 2 only): For visual inspection, the box plots of plasma ASP8273

pharmacokinetic parameters for Cmax, AUClast and AUC24h for cycle 1 day 1, and Cmax, AUClast and AUCtau for

cycle 1 day 21against ethnic (Japanese, Korean, Taiwanese) were to be presented. For ANOVA between ethnic,

analysis was to be performed for Cmax, AUClast and AUC24h for cycle 1 day 1, and Cmax, AUClast and AUCtau for

cycle 1 day 21. The natural log-transformed Cmax, AUClast, AUC24h and AUCtau were used for the ANOVA by

the SAS MIXED procedure with ethnic as fixed effects. The GMR (Korean/Japanese and Taiwanese/Japanese)

and its 95% CI were to be calculated by exponentially transforming the geometric least square mean difference

and CI. They were presented in table.

Concentration-response Relationship Analysis (Concentration-QTcF Analysis)

The relationship between plasma ASP8273 concentrations and changes in QTcF was analyzed in an exploratory

manner. Single delta QTcF (ΔQTcF), defined as the mean change from baseline in QTcF, was used for the

analysis. The baseline QTcF was collected on cycle 0 day 1 predose (phase 1) or cycle 1 day 1 predose

(phase 2). Effects of plasma concentrations of ASP8273 on ΔQTcF were assessed using the linear mixed model

with the SAS MIXED procedure with concentrations as a fixed effect and patients as a random effect: ΔQTcF

= α + β∙(concentration), where α and β represent the intercept and the slope of the regression line, respectively.

The significant effect of plasma concentrations of ASP8273 on ΔQTcF was to be declared if the slope estimate

was statistically significant (p < 0.05). The regression plots of ΔQTcF versus plasma concentrations of

ASP8273 were presented. BQL concentrations were included in the analysis with imputing 0 value.

Other Analyses:

EGFR Mutation Test Using Histological or Cytological Samples

In phase 1 (excluding the re-enrollment part), for the following status (presence or absence) of EGFR mutations,

the frequencies were tabulated by dose: EGFR-T790M mutation and EGFR activating mutations (del ex19,

L858R, L861Q, S768I, G719A, G719S, G719C, exon20 insertion mutation).

In phase 2, for the following status (presence or absence) of EGFR mutations, the frequencies were tabulated:

EGFR activating mutations (del ex19, L858R, L861Q, S768I, G719A, G719S, G719C, exon20 insertion

mutation).

EGFR Mutation Test Using Blood Samples

In phase 1 (excluding the re-enrollment part), for the following status (presence or absence) of EGFR mutations,

the frequencies were tabulated by dose: EGFR-T790M mutation and EGFR activating mutations (del ex19,

L858R, L861Q, S768I, G719A, G719S, G719C, exon20 insertion mutation).

In phase 2, for the following status (presence or absence) of EGFR mutations, the frequencies were tabulated:

EGFR-T790M mutation and EGFR activating mutations.

Safety: The DDAS, defined as all patients in SAF who did not meet any of the following criteria, was used for

the analysis of DLT incidence (only in phase 1): ASP8273 treatment was interrupted for ≥ 5 days in cycle 1 for

other reasons than interruption of the study treatment due to AEs related to the study drug; considered that

safety could not be appropriately evaluated during cycle 0 or 1 because of inadequate safety assessments or

protocol deviations related to concomitant medications; or found not to meet the inclusion criteria or to meet

any exclusion criteria after enrollment. The SAF, defined as all patients who received at least 1 dose of



ASP8273, was used for summaries of demographic and baseline characteristics and all safety and tolerability

related variables.

For DLT incidence (phase 1), the following data were summarized by dose level in the dose-escalation part:

For DLT incidence, the number and percentage of patients were summarized by dose. All DLT data were

displayed in a listing. The posterior mean incidence of DLTs was calculated by dose based on the

Bayesian-CRM.

In phase 1 (dose-escalation and additional EGFR-T790M parts) and phase 2, the number and percentage of

patients with AEs, as classified by system organ class (SOC) and preferred term (PT) using the Medical

Dictionary for Regulatory Activities (MedDRA) version 16.1, were summarized. Summaries were provided for

AEs, drug-related AEs, serious AEs (SAEs), drug-related SAEs, AEs leading to permanent discontinuation of

study drug, drug-related AEs leading to permanent discontinuation of study drug, AEs leading to death,

drug-related AEs leading to death, AEs which equaled to or exceeded a threshold of 10%, SAEs which equaled

to or exceeded a threshold of 10%, and AEs leading to dose reduction. The number and percentage of patients

with AEs, drug-related AEs, SAEs and drug-related SAEs classified by SOC and PT were summarized by

NCI-CTCAE grade (all grade) and NCI-CTCAE grade (< grade 3, ≥ grade 3). In addition, in phase 2, the

number of death, which was defined as all reported deaths after the first study drug administration (including

additional follow-up period), was presented. Summary statistics were calculated and frequency was tabulated

according to the data characteristics of the following parameters: laboratory values, bone turnover markers,

vital signs, SpO2, body weight, 12-lead ECG, ophthalmologic examination, chest X-ray examination, chest CT

examination, ECOG performance status. For laboratory assessments, summary shifts in laboratory test results

(from baseline to postbaseline, shift to low, shift to high) were summarized; sodium values were also graded as

hyponatremia, using NCI-CTCAE grade (v4.03); and shift tables of NCI-CTCAE grade change from baseline to

worst postbaseline grade were presented.

In the re-enrollment part of phase 1, the results of the safety variables were merely listed.

AEs and SAEs were summarized by dose level and the subgroups defined on the basis of the categorized

variables below.

● Phase 1 (excluding the re-enrollment part): sex (female, male), age (< 75, ≥ 75 years), number of previous

EGFR-TKI treatment (0, 1, 2, 3), immediate cancer treatment (EGFR-TKI, not EGFR-TKI), tobacco

history (never used tobacco, current tobacco user, former tobacco user) and existence of brain metastasis at

baseline (yes, no)

● Phase 2: sex (female, male), age (< 75, ≥ 75 years), race in Asian (Japanese, Korean, Taiwanese, other

Asian), number of previous EGFR-TKI treatment (0, 1, 2, 3), immediate cancer treatment (EGFR-TKI, not

EGFR-TKI), tobacco history (never used tobacco, current tobacco user, former tobacco user) and existence

of brain metastasis at baseline (yes, no)

Summary of Results/Conclusions:

Population:


All 47 patients who were enrolled into the study received study drug. Of 47 patients who were enrolled into the

study, 45 patients were included in the SAF, FAS, DDAS and PKAS, and 2 patients in the 25 mg dose group



were excluded from all analysis sets [Table 1] for the reason “There are some problems when informed consent

is given by patient.”

Overall, all enrolled patients (100%, 47/47) discontinued treatment. The primary reasons for discontinuation

were PD (83.0%, 39/47), withdrawal by patient (8.5%, 4/47) and AE (6.4%, 3/47) [Table 2].

The majority of patients in the study were female (73.3%, 33/45) and < 75 years of age (93.3%, 42/45). All

were Japanese (100%, 45/45) [Table 3].

Overall, all patients (100%, 45/45) had Stage IV NSCLC and had pathologic diagnosis of adenocarcinoma.

Based on local testing, positive EGFR status in the total population at baseline was found for the following:

T790M (51.1%, 23/45), del ex19 (66.7%, 30/45), L858R (31.1%, 14/45) and other EGFR activating mutations

(6.7%, 3/45).

EGFR status was reported for 14 patients with central-tissue testing and 37 patients with central-blood testing.

No EGFR status was reported with central-cell testing. Based on central-tissue testing, positive EGFR status in

the total population at baseline was reported for the following: T790M (57.1%, 8/14), del ex19 (64.3%, 9/14),

L858R (28.6%, 4/14) and G719X (7.1%, 1/14). Based on central-blood testing, positive EGFR status in the

total population at baseline was reported for the following: T790M (37.8%, 14/37), del ex19 (37.8%, 14/37)

and L858R (24.3%, 9/37).

Overall, a median duration of study drug exposure was 170.0 days. Dose increases were experienced by 40.0%

(18/45) of patients, dose decreases by 33.3% (15/45) of patients and dose interruptions by 62.2% (28/45) of

patients. In the 600 mg dose group, all patients (100%, 4/4) experienced a dose decrease and a dose interruption.

The mean compliance rate was 92.39%.

Phase 1 (Re-enrollment Part)

In the re-enrollment part of phase 1, 1 patient was re-enrolled. The patient discontinued treatment due to PD.

The patient was female, 54 years old and Asian.

The patient had Stage IV NSCLC and had pathologic diagnosis of adenocarcinoma. Based on local testing,

positive EGFR status for the patient at baseline was found for T790M.

Duration of study drug exposure for the patient was 467 days and compliance rate was 96.8%.

Phase 2

All 76 patients who were enrolled into the study received study drug and were included in the SAF, FAS and

PKAS [Table 4].

All enrolled patients (100%, 76/76) discontinued treatment. The primary reasons for discontinuation were PD

(72.4%, 55/76), study terminated by sponsor (10.5%, 8/76), AE (7.9%, 6/76), withdrawal by patient (6.6%,

5/76), and death and other (1.3%, 1/76, each) [Table 5].

All enrolled patients (100%, 76/76) ended additional follow-up. The primary reasons for end of additional

follow-up were death (48.7%, 37/76), study terminated by sponsor (32.9%, 25/76), withdrawal by patient

(15.8%, 12/76) and lost to follow-up (2.6%, 2/76).



The majority of patients in the study were female (63.2%, 48/76), Japanese (59.2%, 45/76) and < 75 years of

age (88.2%, 67/76) [Table 6].

A total of 89.5% (68/76) of patients had Stage IV NSCLC and all patients (100%, 76/76) had pathologic

diagnosis of adenocarcinoma.

Based on local testing, positive EGFR status in the total population at baseline was found for the following: del

ex19 (68.4%, 52/76), L858R (28.9%, 22/76), L861Q (2.6%, 2/76), G719C (1.3%, 1/76) and other EGFR

activating mutations (7.9%, 6/76).

EGFR status was reported for 76 patients with central-tissue testing and 61 patients with central-blood testing.

Based on central-tissue testing, positive EGFR status in the total population at baseline was reported for the

following: T790M (100%, 76/76), del ex19 (64.5%, 49/76), L858R (30.3%, 23/76), L861Q (1.3%, 1/76) and

G719X (2.6%, 2/76). Based on central-blood testing, positive EGFR status in the total population at baseline

was reported for the following: T790M (45.9%, 28/76), del ex19 (45.9%, 28/76) and L858R (24.6%, 15/76).

Overall, a median duration of study drug exposure was 240.0 days. Dose increases were experienced by 3.9%

(3/76) of patients, dose decreases by 21.1% (16/76) of patients and dose interruptions by 64.5% (49/76) of

patients. The mean compliance rate was 94.10%.

Efficacy/Pharmacokinetic Results:

Efficacy Results:


Primary Endpoint (Secondary Analysis):

ORR over the entire exposure period (local review) was 48.9% (22/45; 95% CI: 33.7, 64.2) in the total

population. By each initial dose level, ORR over the entire exposure period (local review) was 0% (0/1; 95%

CI: 0.0, 97.5) in the 25 mg dose group, 0% (0/4; 95% CI: 0.0, 60.2) in the 50 mg dose group, 33.3% (2/6; 95%

CI: 4.3, 77.7) in the 100 mg dose group, 50.0% (5/10; 95% CI: 18.7, 81.3) in the 200 mg dose group, 50.0%

(5/10; 95% CI: 18.7, 81.3) in the 300 mg dose group, 70.0% (7/10; 95% CI: 34.8, 93.3) in the 400 mg dose

group and 75.0% (3/4; 95% CI: 19.4, 99.4) in the 600 mg dose group [Table 7].

Secondary Endpoints:

DCR over the entire exposure period (local review) was 88.9% (40/45; 95% CI: 75.9, 96.3) in the total

population. By each initial dose level, DCR over the entire exposure period (local review) was 100% (1/1; 95%

CI: 2.5, 100.0) in the 25 mg dose group, 75.0% (3/4; 95% CI: 19.4, 99.4) in the 50 mg dose group, 100% (6/6;

95% CI: 54.1, 100.0) in the 100 mg dose group, 90.0% (9/10; 95% CI: 55.5, 99.7) in the 200 mg dose group,

80.0% (8/10; 95% CI: 44.4, 97.5) in the 300 mg dose group, 100% (10/10; 95% CI: 69.2, 100.0) in the 400 mg

dose group and 75.0% (3/4; 95% CI: 19.4, 99.4) in the 600 mg dose group.

Waterfall plot of maximum percent change from baseline in target lesion (local review) showed most patients in

50 mg and higher dose groups had shrinkage in target lesion; and the degree of percent change from baseline

tended to be larger in the 100 to 600 mg dose groups than the 50 mg dose group, with no clear relation between

the degree of percent change from baseline in target lesion and the dose level for doses 100 to 600 mg.

The proportion of patients with maximum shrinkage from baseline in target lesion ≥ 30% (local review) was

54.5% (24/44) in the total population. By each initial dose level, the proportion of patients with maximum



shrinkage from baseline in target lesion ≥ 30% (local review) was 0% (0/1) in the 25 mg dose group, 0% (0/4)

in the 50 mg dose group, 33.3% (2/6) in the 100 mg dose group, 70.0% (7/10) in the 200 mg dose group, 55.6%

(5/9) in the 300 mg dose group, 70.0% (7/10) in the 400 mg dose group and 75.0% (3/4) in the 600 mg dose

group.

The median duration of PFS (local review) was 5.6 months (95% CI: 3.6, 11.1) in the total population. PFS rate

at 6 months (local review) was 46.1% (95% CI: 30.4, 60.5) and PFS rate at 12 months (local review) was 26.6%

(95% CI: 13.8, 41.3).

The median DOR (local review) was 8.4 months (95% CI: 4.2, 11.0) in the total population.

Subgroup analyses suggested higher efficacy (difference of ≥ 20% for ORR, DCR or the proportion of patients

with maximum shrinkage from baseline in target lesion ≥ 30%; or of ≥ 2 months for the median duration of

PFS) (local review) in patients whose immediate cancer treatment was EGFR-TKI than patients whose

immediate cancer treatment was not EGFR-TKI. Although grouping variables of age (< 75, ≥ 75 years),

number of previous EGFR-TKI treatment (0, 1, 2, 3) and patients with evidence of an EGFR-T790M mutation

(local) (yes, no, unknown) also suggested difference in efficacy between subgroups, it should be interpreted

with caution due to a small number of patients for some subgroups; in addition, patients ≥ 75 years (3 patients)

received 400 or 600 mg doses and no difference was suggested for this grouping variable in phase 2.


In the re-enrollment part of phase 1, 1 patient was re-enrolled. Best overall response for the patient was PR.

The maximum shrinkage of sum of diameter from baseline in target lesion for the patient was more than 30%

(from 77 mm to 39 mm). Time point response for the patient was PR from cycle 3 day 1 to cycle 13 day 1 and

PD from cycle 15 day 1 to withdrawal.

Phase 2

Primary Endpoint (Primary Analysis):

For patients in the first stage, 9 out of 24 patients (37.5%) had CR or PR at week 24 (central review). Therefore,

the criteria to continue to second stage were met. For patients in the first and second stages combined, 27 out of

63 patients (42.9%; 95% CI: 30.5, 56.0) had CR or PR response at week 24 (central review) based on

independent radiographic reviewer [Table 8]; therefore, it was determined that ASP8273 has antitumor effects

in patients with NSCLC harboring an EGFR activating mutation and the EGFR-T790M mutation.

Primary Endpoint (Secondary Analysis):

ORR at week 24 (central review) was 43.4% (33/76; 95% CI: 32.1, 55.3) [Table 9].

ORR over the entire exposure period (central review) was 43.4% (33/76; 95% CI: 32.1, 55.3).

Secondary Endpoints:

DCR at week 24 (central review) was 80.3% (61/76; 95% CI: 69.5, 88.5).

DCR over the entire exposure period (central review) was 80.3% (61/76; 95% CI: 69.5, 88.5).

Waterfall plot of maximum percent change from baseline in target lesion (central review) showed almost all

patients had shrinkage in target lesion.



The proportion of patients with maximum shrinkage from baseline in target lesion ≥ 30% (central review) was

69.6% (48/69).

The mean time to first PD (not including additional follow-up period) (central review) was 189.4 days.

The concordance rate for ORR at week 24 between central review and local review was 65.8% (50/76).

The median duration of PFS during study period (not including additional follow-up period) (central review)

was 8.5 months (95% CI: 5.6, 11.2). PFS rate at 6 months (central review) was 58.0% (95% CI: 44.8, 69.1);

PFS rate at 12 months (central review) was 36.8% (95% CI: 23.9, 49.6).

The median survival time including additional follow-up period (central review) was 21.8 months (95% CI:

11.8, not estimated). OS rate at 6 months (central review) was 84.8% (95% CI: 74.2, 91.3); OS rate at

12 months (central review) was 60.9% (95% CI: 48.3, 71.3).

The median DOR during study period (not including additional follow-up period) (central review) was

9.9 months (95% CI: 5.4, not estimated).

Subgroup analyses suggested higher efficacy (difference of ≥ 20% for ORR, DCR, the proportion of patients

with maximum shrinkage from baseline in target lesion ≥ 30%, PFS rate or OS rate; or of ≥ 2 months for the

median duration of PFS or the median survival time) (central review) in patients who received 2 or 3 previous

EGFR-TKI treatments than patients who received 1 previous EGFR-TKI treatment, in patients who never used

tobacco than patients who were former tobacco user, in patients without brain metastasis at baseline than

patients with brain metastasis at baseline, in Korean patients than Japanese patients, in patients without evidence

of an EGFR-T790M mutation based on central-blood testing than patients with evidence of an EGFR-T790M

mutation based on central-blood testing, in patients with del ex19 based on central-tissue testing than patients

without del ex19 based on central-tissue testing, and in patients without L858R based on central-tissue testing

than patients with L858R based on central-tissue testing. Although a grouping variable of immediate cancer

treatment (EGFR-TKI, not EGFR-TKI) also suggested difference in efficacy between subgroups, it should be

interpreted with caution due to a small number of patients whose immediate cancer treatment was not

EGFR-TKI (2 patients); in phase 1, subgroup analyses suggested higher efficacy in patients whose immediate

cancer treatment was EGFR-TKI than patients whose immediate cancer treatment was not EGFR-TKI.

Pharmacokinetic Results:


After single-dose ASP8273 on cycle 0 day 1 (dose levels 50 to 600 mg), median AUCinf ranged from 1150 to

103000 ng•h/mL, median Cmax ranged from 185 to 4840 ng/mL, median tmax ranged from 1.01 to 5.92 hours and

median t1/2 ranged from 10.9 to 14.3 hours [Table 10]. After multiple-dose ASP8273 on cycle 1 day 21 (dose

levels 50 to 400 mg), median AUCtau ranged from 1330 to 42300 ng•h/mL, median Cmax ranged from 173 to

2950 ng/mL and median tmax ranged from 1.48 to 5.90 hours [Table 11]. ASP8273 showed linear

pharmacokinetics and dose proportionality over the dose range of 100 to 400 mg. Steady-state ASP8273 was

achieved by cycle 1 day 8 after once-daily dosing. After 21 days of daily dosing, about 30% to 60%

accumulation as AUC was observed.

After single-dose ASP8273 on cycle 0 day 1 (dose levels 50 to 600 mg), median Ae48h% ranged from 0.673 to

2.21%. After multiple-dose ASP8273 on cycle 1 day 21 (dose levels 50 to 400 mg), median Aetau% ranged

from 1.45 to 1.95%.



Phase 2

After single-dose ASP8273 300 mg on cycle 1 day 1, AUClast was 20800 ng•h/mL, median Cmax was

1890 ng/mL, median tmax was 3.94 hours and median t1/2 was 8.40 hours. After multiple-dose ASP8273 300 mg

on cycle 1 day 21, median AUCtau was 22500 ng•h/mL, median Cmax was 1830 ng/mL and median tmax was

3.92 hours [Table 12]. Steady-state ASP8273 was achieved by cycle 1 day 8 after once-daily dosing. After

21 days of daily dosing, about 20% accumulation as AUC was observed. The exposures of ASP8273 were

comparable among each population (Japanese, Korean and Taiwanese).

Safety Results:


A total of 20.0% (9/45) of patients experienced a DLT during the study including 50.0% (5/10) of patients in the

400 mg dose group and 100% (4/4) of patients in the 600 mg dose group. All the DLTs were ≥ grade 3

nonhematologic toxicity [Table 13]. Overall, the most common DLT was diarrhoea (6.7%, 3/45), followed by

colitis, nausea (4.4%, 2/45, each), malaise, biliary tract infection and hyponatraemia (2.2%, 1/45, each) [Table

14].

The posterior means of the DLT rate at 300 mg and 400 mg estimated by Bayesian-CRM were 0.21 and 0.38,

respectively.

Based on comprehensive evaluation of the above DLT profile as well as safety, efficacy and pharmacokinetic

data, the MTD and RP2D were determined to be 400 mg and 300 mg, respectively. The antitumor effects were

confirmed in the 100 mg and higher dose groups, and the minimum dose for dose reduction was therefore

determined to be 100 mg.

Overall, all patients (100%, 45/45) reported at least 1 treatment-emergent adverse event (TEAE) [Table 15].

The most common (≥ 30% of all patients) TEAEs were diarrhoea (75.6%, 34/45), nausea (53.3%, 24/45),

vomiting (48.9%, 22/45), alanine aminotransferase increased (46.7%, 21/45), decreased appetite, peripheral

sensory neuropathy (37.8%, 17/45, each), aspartate aminotransferase increased (35.6%,16/45), blood creatinine

increased, constipation (33.3%, 15/45, each), hyponatraemia and platelet count decreased (31.1%, 14/45, each)

[Table 16].

Drug-related TEAEs were reported in all patients (100%, 45/45). The most common (≥ 30% of all patients)

drug-related TEAEs were diarrhoea (75.6%, 34/45), alanine aminotransferase increased, vomiting (44.4%,

20/45, each), nausea (42.2%, 19/45), peripheral sensory neuropathy (35.6%, 16/45), aspartate aminotransferase

increased, blood creatinine increased and platelet count decreased (31.1%, 14/45, each).

A TEAE leading to death (lung infection) was reported in 25.0% (1/4) of patients in the 600 mg dose group and

the event was not attributed to ASP8273 administration.

Serious TEAEs were reported in 0% (0/1) of patients in the 25 mg dose group, 25.0% (1/4) of patients in the

50 mg dose group, 50.0% (3/6) of patients in the 100 mg dose group, 30.0% (3/10) of patients in the 200 mg

dose group, 50.0% (5/10) of patients in the 300 mg dose group, 60.0% (6/10) of patients in the 400 mg dose

group and 75.0% (3/4) of patients in the 600 mg dose group. The most common (≥ 2 patients) serious TEAEs



were lung infection, metastases to meninges (6.7%, 3/45, each), diarrhoea, dehydration, hyponatraemia, cancer

pain, tumour pain and anxiety (4.4%, 2/45, each) [Table 17].

Drug-related serious TEAEs were reported in 0% (0/1) of patients in the 25 mg dose group, 0% (0/4) of patients

in the 50 mg dose group, 0% (0/6) of patients in the 100 mg dose group, 10.0% (1/10) of patients in the 200 mg

dose group, 10.0% (1/10) of patients in the 300 mg dose group, 40.0% (4/10) of patients in the 400 mg dose

group and 75.0% (3/4) of patients in the 600 mg dose group. The most common (≥ 2 patients) drug-related

serious TEAEs were diarrhoea, dehydration and hyponatraemia (4.4%, 2/45, each).

TEAEs leading to permanent discontinuation of study drug were reported in 0% (0/1) of patients in the 25 mg

dose group, 0% (0/4) of patients in the 50 mg dose group, 16.7% (1/6) of patients in the 100 mg dose group, 0%

(0/10) of patients in the 200 mg dose group, 10.0% (1/10) of patients in the 300 mg dose group, 0% (0/10) of

patients in the 400 mg dose group and 50.0% (2/4) of patients in the 600 mg dose group. The most common (≥

2 patients) TEAE leading to permanent discontinuation of study drug was metastases to meninges (4.4%, 2/45).

A drug-related TEAE leading to permanent discontinuation of study drug was reported in 1 patient (interstitial

lung disease) (2.2%, 1/45), which was in the 600 mg dose group (25.0%, 1/4).

TEAEs leading to dose reduction were reported in 0% (0/1) of patients in the 25 mg dose group, 0% (0/4) of

patients in the 50 mg dose group, 0% (0/6) of patients in the 100 mg dose group, 10.0% (1/10) of patients in the

200 mg dose group, 10.0% (1/10) of patients in the 300 mg dose group, 90.0% (9/10) of patients in the 400 mg

dose group and 100% (4/4) of patients in the 600 mg dose group. The most common (≥ 2 patients) TEAEs

leading to dose reduction were diarrhoea (11.1%, 5/45), colitis, haematuria, hyponatraemia, nausea and

peripheral sensory neuropathy (4.4%, 2/45, each). All of the TEAEs leading to dose reduction were considered

study drug related with the exception of 1 (oesophageal stenosis) in the 200 mg dose group.

Maximum NCI-CTCAE grade 3 or higher TEAEs were reported in 0% (0/1) of patients in the 25 mg dose group,

50.0% (2/4) of patients in the 50 mg dose group, 66.7% (4/6) of patients in the 100 mg dose group, 60.0%

(6/10) of patients in the 200 mg dose group, 60.0% (6/10) of patients in the 300 mg dose group, 100% (10/10)

of patients in the 400 mg dose group and 100% (4/4) of patients in the 600 mg dose group. The most common

(≥ 3 patients) maximum NCI-CTCAE grade 3 or higher TEAEs were hyponatraemia (24.4%, 11/45), diarrhoea

(17.8%, 8/45), anaemia, hypoalbuminaemia (11.1%, 5/45, each), lung infection, alanine aminotransferase

increased, hypokalaemia and hypophosphataemia (6.7%, 3/45, each).

Maximum NCI-CTCAE grade 3 or higher drug-related TEAEs were reported in 0% (0/1) of patients in the

25 mg dose group, 0% (0/4) of patients in the 50 mg dose group, 50.0% (3/6) of patients in the 100 mg dose

group, 40.0% (4/10) of patients in the 200 mg dose group, 40.0% (4/10) of patients in the 300 mg dose group,

90.0% (9/10) of patients in the 400 mg dose group and 100% (4/4) of patients in the 600 mg dose group. The

most common (≥ 3 patients) maximum NCI-CTCAE grade 3 or higher drug-related TEAEs were hyponatraemia

(20.0%, 9/45), diarrhoea (17.8%, 8/45), alanine aminotransferase increased and anaemia (6.7%, 3/45, each).

For sodium (hyponatremia), patients who had baseline values < grade 3 that shifted to worst postbaseline values

≥ grade 3 were observed as follows: shifts from grade 0 to grade 3, 1 patient (25.0%) in the 50 mg dose group,

1 patient (16.7%) in the 100 mg dose group, 1 patient (20.0%) in the 200 mg dose group, 1 patient (11.1%) in

the 300 mg dose group, 3 patients (42.9%) in the 400 mg dose group and 2 patients (50.0%) in the 600 mg dose

group; shifts from grade 0 to grade 4, 1 patient (16.7%) in the 100 mg dose group and 1 patient (14.3%) in the



400 mg dose group; shifts from grade 1 to grade 3, 2 patients (50.0%) in the 200 mg dose group; and shifts from

grade 1 to grade 4, 1 patient (100%) in the 300 mg dose group and 1 patient (33.3%) in the 400 mg dose group.

Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN)

and total bilirubin (TBL) > 2 x ULN was reported in 1 patient (10.0%, 1/10) in the 400 mg dose group and

1 patient (25.0%, 1/4) in the 600 mg dose group.

No patient in the study had absolute QTcF values > 480 msec or changes from baseline QTcF > 60 msec.

Clinically significant abnormal results for the ophthalmologic examination were reported in 1 to 2 patients at

several time points across dose groups. A TEAE of punctate keratitis was reported in 1 patient (2.2% of all

patients, 1/45; initial dose/onset dose, 300 mg/200 mg).

Clinically significant abnormal results for the chest X-ray examination were reported in 1 to 3 patients at several

time points across dose groups.

Clinically significant abnormal results for the chest CT examination were reported in 1 patient (2.4%) on

cycle 3 day 1 and in 5 patients (29.4%) at discontinuation across dose groups.

ECOG performance status of 2 or 3 was reported in a few patients at a few time points across dose groups

(observed in the 50, 100, 200, 300, 400 and 600 mg groups). ECOG performance status of 4 was reported in

2 patients (7.7%) across dose groups at discontinuation including 1 (20.0%) in the 100 mg dose group and 1

(14.3%) in the 300 mg dose group; and in 2 patients (11.8%) across dose groups at follow-up including 2

(40.0%) in the 300 mg dose group. No ECOG performance status of grade 5 was reported for any patient

during the study.

Subgroup analyses showed higher incidence (difference of ≥ 20%) of serious TEAEs in female patients than

male patients; this difference can be considered due to higher incidence of serious TEAEs in the 400 and

600 mg dose groups in female patients (75.0% [6/8] and 100% [3/3] in female patients vs 0% [0/2] and 0% [0/1]

in male patients, respectively). Although a grouping variable of age (< 75, ≥ 75 years) also showed difference

in incidence of serious TEAEs between subgroups, it should be interpreted with caution due to a small number

of patients; in addition, different result was shown for this grouping variable in phase 2.


For the 1 patient enrolled in re-enrollment part, TEAEs including drug-related TEAEs were reported. No

NCI-CTCAE grade 3 or higher TEAE, death, serious TEAE or TEAE leading to permanent discontinuation of

study drug was reported.

Phase 2

Overall, all patients (100%, 76/76) reported at least 1 TEAE [Table 18]. The most common (≥ 30% of patients)

TEAEs were diarrhoea (67.1%, 51/76), nausea (43.4%, 33/76), alanine aminotransferase increased (39.5%,

30/76), vomiting (36.8%, 28/76), decreased appetite (35.5%, 27/76) and hyponatraemia (32.9%, 25/76) [Table

19].

Drug-related TEAEs were reported in 94.7% (72/76) of patients. The most common (≥ 30% of patients)

drug-related TEAE was diarrhoea (56.6%, 43/76) and alanine aminotransferase increased (31.6%, 24/76).



A total of 37 patients died in the study. TEAEs leading to deaths were reported in 2.6% (2/76) of patients

including dyspnoea (2.6%, 2/76), pneumonia, metastases to meninges and cough (1.3%, 1/76, each); none of the

TEAEs leading to deaths were attributed to ASP8273 administration.

Serious TEAEs were reported in 50.0% (38/76) of patients. The most common (≥ 2 patients) serious TEAEs

were hyponatraemia (6.6%, 5/76), convulsion (5.3%, 4/76), alanine aminotransferase increased, nausea, pleural

effusion, pneumonia (3.9%, 3/76, each), aspartate aminotransferase increased, decreased appetite, dehydration,

dyspnoea, femoral neck fracture, headache, hepatic function abnormal, metastases to meninges, pyrexia, sepsis

and urinary tract infection (2.6%, 2/76, each) [Table 20].

Drug-related serious TEAEs were reported in 23.7% (18/76) of patients. The most common (≥ 2 patients) drug-

related serious TEAEs were hyponatraemia (6.6%, 5/76), alanine aminotransferase increased, decreased appetite,

dehydration, hepatic function abnormal and nausea (2.6%, 2/76, each).

TEAEs leading to permanent discontinuation of study drug were reported in 7.9% (6/76) of patients. No TEAE

leading to permanent discontinuation of study drug was reported in 2 or more patients. Drug-related TEAEs

leading to permanent discontinuation of study drug were reported in 3 patients (3.9%, 3/76) including infectious

pleural effusion, sepsis, hyponatraemia and organising pneumonia (1.3%, 1/76, each).

TEAEs leading to dose reduction were reported in 19.7% (15/76) of patients. The most common (≥ 2 patients)

TEAEs leading to dose reduction were hyponatraemia (5.3%, 4/76), alanine aminotransferase increased,

decreased appetite and peripheral sensory neuropathy (2.6%, 2/76, each). All of the TEAEs leading to dose

reduction were considered study drug related.

Maximum NCI-CTCAE grade 3 or higher TEAEs were reported in 59.2% (45/76) of patients. The most

common (≥ 3 patients) maximum NCI-CTCAE grade 3 or higher TEAEs were hyponatraemia (25.0%, 19/76),

anaemia (9.2%, 7/76), alanine aminotransferase increased, decreased appetite (6.6%, 5/76, each), urinary tract

infection, aspartate aminotransferase increased (5.3%, 4/76, each), hepatic function abnormal and pneumonia

(3.9%, 3/76, each).

Maximum NCI-CTCAE grade 3 or higher drug-related TEAEs were reported in 43.4% (33/76) of patients. The

most common (≥ 3 patients) maximum NCI-CTCAE grade 3 or higher drug-related TEAEs were hyponatraemia

(21.1%, 16/76), alanine aminotransferase increased, anaemia and decreased appetite (3.9%, 3/76, each).

For sodium (hyponatremia), patients who had baseline values < grade 3 that shifted to worst postbaseline values

≥ grade 3 were observed as follows: shifts from grade 0 to grade 3, 15 patients (23.1%); shifts from grade 0 to

grade 4, 5 patients (7.7%); shifts from grade 1 to grade 3, 2 patients (22.2%); and shifts from grade 1 to grade 4,

2 patients (22.2%).

No patient had an ALT and/or AST > 3 x ULN and TBL > 2 x ULN.

Categorized absolute QTcF values > 480 to ≤ 500 msec were observed in 1 patient (1.4%) on cycle 1 day 2 and

in 1 patient (1.9%) on cycle 1 day 15. No patient in the study had absolute QTcF values > 500 msec. Changes

from baseline QTcF > 60 msec were observed in 1 patient (1.8%) at 2 h postdose on cycle 1 day 21 and in

1 patient (1.8%) at 4 h postdose on cycle 1 day 21.

From concentration-QTcF analysis based on the linear mixed model in phase 1 and phase 2, the slope estimate

was -0.00116 (P < 0.001) for overall; indicating no significant effect of plasma concentrations of ASP8273 on

ΔQTcF prolongation.



Post dose, clinically significant abnormal results for the ophthalmologic examination were reported in 1 to 4

patients at several time points. TEAEs of punctate keratitis were reported in 2 patients (2.6%, 2/76; initial

dose/onset dose, 300 mg/300 mg).

Post dose, clinically significant abnormal results for the chest X-ray examination were reported in 1 to 8

patients at several time points.

Post dose, clinically significant abnormal results for the chest CT examination were reported in 3 patients

(4.1%) on cycle 1 day 21, in 2 patients (2.9%) on cycle 3 day 1 and in 8 patients (21.6%) at discontinuation.

ECOG performance status of 2 or 3 was reported in a few patients at several time points. ECOG performance

status of 4 was reported in 1 patient (1.5%) on cycle 4 day 1, in 1 patient (2.0%) on cycle 7 day 1, in 5 patients

(7.9%) at discontinuation and in 2 patients (14.3%) at follow-up. No ECOG performance status of grade 5 was

reported for any patient during the study.

Subgroup analyses showed higher incidence (difference of ≥ 20%) of serious TEAEs in patients who received 3

previous EGFR-TKI treatments than patients who received 1 or 2 previous EGFR-TKI treatments.

CONCLUSIONS:

Phase 1

Based on comprehensive evaluation of the DLT profile as well as safety, efficacy and pharmacokinetic data, the

MTD and RP2D were determined to be 400 mg and 300 mg, respectively. The antitumor effects were

confirmed in the 100 mg and higher dose groups, and the minimum dose for dose reduction was therefore

determined to be 100 mg.

Tumor response was observed in patients enrolled in the 100 mg and higher dose groups.

The percentage of patients with serious TEAEs tended to be higher in higher dose groups than lower dose

groups. There was no clear tendency for the percentage of patients with TEAEs leading to permanent

discontinuation of study drug to be increased with increasing doses.

ASP8273 showed linear pharmacokinetics and dose proportionality over the dose range of 100 to 400 mg.

Steady-state ASP8273 was achieved by cycle 1 day 8 after once-daily dosing. After 21 days of daily dosing,

about 30% to 60% accumulation as AUC was observed.

Phase 2

In the primary analysis of primary endpoint, ORR at week 24 (central review) was 42.9%; therefore, it was

determined that ASP8273 has antitumor effects in patients with NSCLC harboring an EGFR activating mutation

and the EGFR-T790M mutation. The secondary analysis of primary endpoint and the secondary endpoints

support this result.

After 21 days of daily dosing, about 20% accumulation as AUC was observed. The exposures of ASP8273

were comparable among each population (Japanese, Korean and Taiwanese).

ASP8273 at 300 mg was well tolerated in patients with NSCLC harboring an EGFR activating mutation and the

EGFR-T790M mutation. No significant effect of plasma concentrations of ASP8273 on ΔQTcF prolongation

was indicated.

Date of Report: 08 May 2018



Table 1 Analysis Sets in Phase 1 (All Enrolled Patients)

Analysis Set, n (%)25 mg(N=3)

50 mg(N=4)

100 mg(N=6)

200 mg(N=10)

300 mg(N=10)

400 mg(N=10)

600 mg(N=4)

Total(N=47)

Drug Taken 3 (100) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 47 (100)SAF † 1 (33.3) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 45 (95.7)FAS ‡ 1 (33.3) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 45 (95.7)DDAS § 1 (33.3) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 45 (95.7)PKAS ¶ 1 (33.3) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 45 (95.7)

DDAS: dose-determine analysis set; FAS: full analysis set; PKAS: pharmacokinetic analysis set; SAF: safety analysis set.

† All patients who received at least 1 dose of ASP8273.

‡ All patients who received at least 1 dose of ASP8273 and were evaluated for at least 1 efficacy endpoint after the start of the study treatment.

§ All patients in SAF who did not meet any of the following criteria: ASP8273 treatment was interrupted for ≥ 5 days in cycle 1 for other reasons than interruption of the study treatment due to AEs related to the study drug; considered that safety could not be appropriately evaluated during cycle 0 or 1 because of inadequate safety assessments or protocol violations related to concomitant medications; or found not to meet the inclusion criteria or to meet any exclusion criteria after enrollment.

¶ All patients who received at least 1 dose of ASP8273 and in whom drug concentration was measured at least1 time point after the start of the study treatment.

Source: Table A.12.1.1.2

Table 2 Study Discontinuation in Phase 1 (All Enrolled Patients)

n (%)25 mg(N=3)

50 mg(N=4)

100 mg(N=6)

200 mg(N=10)

300 mg(N=10)

400 mg(N=10)

600 mg(N=4)

Total(N=47)

Treatment DiscontinuationYes 3 (100) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 47 (100)No 0 0 0 0 0 0 0 0

Primary Reason for Discontinuation †PD 3 (100) 3 (75.0) 5 (83.3) 9 (90.0) 9 (90.0) 9 (90.0) 1 (25.0) 39 (83.0)Adverse Event 0 0 1 (16.7) 0 0 0 2 (50.0) 3 (6.4)Protocol Violation 0 0 0 0 0 0 0 0Lost to Follow-up 0 0 0 0 0 0 0 0Withdrawal by Patient

0 1 (25.0) 0 1 (10.0) 1 (10.0) 0 1 (25.0) 4 (8.5)

Randomized/Enrolled but Never Received/Dispensed Study Drug

0 0 0 0 0 0 0 0

Death 0 0 0 0 0 0 0 0Lack of Efficacy 0 0 0 0 0 0 0 0Study Terminated by Sponsor

0 0 0 0 0 1 (10.0) 0 1 (2.1)

Pregnancy 0 0 0 0 0 0 0 0Other 0 0 0 0 0 0 0 0

PD: progressive disease.

† Only the primary reason for discontinuation was collected.

Source: Table A.12.1.1.3.2



Table 3 Demographic Characteristics in Phase 1 (SAF)

ParameterCategory/Statistic

25 mg(N=1)

50 mg(N=4)

100 mg(N=6)

200 mg(N=10)

300 mg(N=10)

400 mg(N=10)

600 mg(N=4)

Total(N=45)

Sex, n (%) Male 0 1 (25.0) 4 (66.7) 1 (10.0) 3 (30.0) 2 (20.0) 1 (25.0) 12 (26.7)Female 1 (100) 3 (75.0) 2 (33.3) 9 (90.0) 7 (70.0) 8 (80.0) 3 (75.0) 33 (73.3)

Race in Asian, n (%)

Japanese 1 (100) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 45 (100)

Race , n (%) Asian 1 (100) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 45 (100)Age (Years) Mean

(SD)70.0 (-) 70.8 (3.8) 62.7 (10.4) 64.3 (8.3) 55.9 (17.3) 65.1 (10.6) 67.3 (8.1) 63.4 (11.7)

Median 70.0 71.0 65.0 64.5 60.0 67.0 65.5 65.0Min - Max 70-70 67-74 43-74 47-74 28-74 42-78 60-78 28-78

Age Group(Years), n (%)

<75 1 (100) 4 (100) 6 (100) 10 (100) 10 (100) 8 (80.0) 3 (75.0) 42 (93.3)≥75 0 0 0 0 0 2 (20.0) 1 (25.0) 3 (6.7)

Weight (kg) Mean (SD)

44.70 (-) 56.90 (5.88)

58.75 (12.53)

49.59 (12.53)

55.16 (10.63)

50.27 (10.51)

58.28 (22.95)

53.51 (12.21)

Median 44.70 58.65 60.20 47.60 56.85 47.85 50.70 52.30Min - Max 44.7-44.7 48.5-61.8 44.0-75.6 36.8-77.0 35.6-71.1 34.0-67.9 40.1-91.6 34.0-91.6

Height (cm) Mean (SD)

147.80 (-)

156.68 (7.29)

163.97 (9.04)

158.62 (9.20)

161.48 (12.77)

155.58 (9.31)

155.73 (9.45)

158.62 (9.95)

Median 147.80 154.65 163.35 159.50 164.15 151.75 153.85 157.40Min - Max 147.8-

147.8150.4-167.0

154.5-179.3

143.2-177.5

138.6-177.2

146.2-171.3

146.4-168.8

138.6-179.3

ECOG Performance Status

Grade 0 0 1 (25.0) 1 (16.7) 5 (50.0) 3 (30.0) 3 (30.0) 3 (75.0) 16 (35.6)Grade 1 1 (100) 3 (75.0) 5 (83.3) 5 (50.0) 7 (70.0) 7 (70.0) 1 (25.0) 29 (64.4)Grade 2 to 4

0 0 0 0 0 0 0 0

Tobacco History , n (%)

Never Used Tobacco

1 (100) 3 (75.0) 2 (33.3) 8 (80.0) 8 (80.0) 8 (80.0) 3 (75.0) 33 (73.3)

Current Tobacco User

0 0 0 0 0 0 0 0

Former Tobacco User

0 1 (25.0) 4 (66.7) 2 (20.0) 2 (20.0) 2 (20.0) 1 (25.0) 12 (26.7)

Number of Previous Treatment With EGFR-TKI , n (%)

0 0 0 0 0 0 0 0 01 0 3 (75.0) 1 (16.7) 6 (60.0) 6 (60.0) 6 (60.0) 3 (75.0) 25 (55.6)2 1 (100) 1 (25.0) 5 (83.3) 4 (40.0) 1 (10.0) 4 (40.0) 1 (25.0) 17 (37.8)3 0 0 0 0 3 (30.0) 0 0 3 (6.7)

The Immediate Prior Cancer Drug Therapy is EGFR-TKI , n (%)

Yes 0 2 (50.0) 2 (33.3) 5 (50.0) 6 (60.0) 7 (70.0) 2 (50.0) 24 (53.3)No 1 (100) 2 (50.0) 4 (66.7) 5 (50.0) 4 (40.0) 3 (30.0) 2 (50.0) 21 (46.7)

ECOG: Eastern Cooperative Oncology Group; EGFR-TKI: EGFR tyrosine-kinase inhibitor.




Table 4 Analysis Sets in Phase 2 (All Enrolled Patients)

Analysis Set, n (%)300 mg(N=76)

Drug Taken 76 (100)SAF † 76 (100)FAS ‡ 76 (100)PKAS § 76 (100)

FAS: full analysis set; PKAS: pharmacokinetic analysis set; SAF: safety analysis set.

† All patients who received at least 1 dose of ASP8273.

‡ All patients who received at least 1 dose of ASP8273 and were evaluated for at least 1 efficacy endpoint after the start of the study treatment.

§ All patients who received at least 1 dose of ASP8273 and in whom drug concentration was measured at least 1 time point after the start of the study treatment.

Source: Table B.12.1.1.2

Table 5 Study Discontinuation in Phase 2 (All Enrolled Patients)

n (%)300 mg(N=76)

Treatment DiscontinuationYes 76 (100)No 0

Primary Reason for Discontinuation †PD 55 (72.4)Adverse Event 6 (7.9)Protocol Violation 0Lost to Follow-up 0Withdrawal by Patient 5 (6.6)Randomized/Enrolled but Never Received/Dispensed Study Drug 0Death 1 (1.3)Lack of Efficacy 0Study Terminated by Sponsor 8 (10.5)Pregnancy 0Other 1 (1.3)

PD: progressive disease.

† Only the primary reason for discontinuation was collected.

Source: Table B.12.1.1.3.2



Table 6 Demographic Characteristics in Phase 2 (FAS)

ParameterCategory/Statistic

300 mg(N=76)

Sex, n (%) Male 28 (36.8)Female 48 (63.2)

Race in Asian, n (%) Japanese 45 (59.2)Korean 17 (22.4)Taiwanese 14 (18.4)Other Asian 0

Race, n (%) Asian 76 (100)Age (Years) Mean (SD) 62.8 (11.1)

Median 63.0Min-Max 39-83

Age Group (Years) <75 67 (88.2)≥75 9 (11.8)

Weight (kg) † Mean (SD) 54.18 (10.43)Median 52.30Min-Max 35.8-91.3

Height (cm) Mean (SD) 158.44 (9.88)Median 156.60Min-Max 138.7-182.8

ECOG Performance Status, n (%) Grade 0 20 (26.3)Grade 1 56 (73.7)Grade 2 to 4 0

Tobacco History, n (%) Never Used Tobacco 51 (67.1)Current Tobacco User 0Former Tobacco User 25 (32.9)

Number of Previous Treatment With EGFR-TKI, n (%)

0 01 45 (59.2)2 21 (27.6)3 10 (13.2)

The Immediate Prior Cancer Drug Therapy is EGFR-TKI, n (%)

Yes 74 (97.4)No 2 (2.6)

ECOG: Eastern Cooperative Oncology Group; EGFR-TKI: EGFR tyrosine-kinase inhibitor.

† n=75




Table 7 Best Overall Response Rate Over the Entire Exposure Period (Local Review) in Phase 1 (Initial Dose Level) (FAS)

Parameter25 mg(N=1)

50 mg(N=4)

100 mg(N=6)

200 mg(N=10)

300 mg(N=10)

400 mg(N=10)

600 mg(N=4)

Total(N=45)

Best Overall Response ‡, n (%)

CR 0 0 0 0 0 0 0 0PR 0 0 2 (33.3) 5 (50.0) 5 (50.0) 7 (70.0) 3 (75.0) 22 (48.9)SD 1 (100) 3 (75.0) 4 (66.7) 4 (40.0) 3 (30.0) 3 (30.0) 0 18 (40.0)PD 0 1 (25.0) 0 1 (10.0) 2 (20.0) 0 1 (25.0) 5 (11.1)NE 0 0 0 0 0 0 0 0Total 1 4 6 10 10 10 4 45

Analysis ‡ ORR (CR + PR), n (%)

0 0 2 (33.3) 5 (50.0) 5 (50.0) 7 (70.0) 3 (75.0) 22 (48.9)

95% CI †(%)

0.0, 97.5 0.0, 60.2 4.3, 77.7 18.7, 81.3

18.7, 81.3

34.8, 93.3

19.4, 99.4

33.7, 64.2

DCR (CR + PR + SD), n (%)

1 (100) 3 (75.0) 6 (100) 9 (90.0) 8 (80.0) 10 (100) 3 (75.0) 40 (88.9)

95% CI †(%)

2.5, 100.0

19.4, 99.4

54.1, 100.0

55.5, 99.7

44.4, 97.5

69.2, 100.0

19.4, 99.4

75.9, 96.3

CR: complete response; DCR: disease control rate; NE: not evaluated; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease.

† Based on exact binomial confidence interval (Clopper-Pearson)

‡ The denominator for percentage calculation is number of patients who have best overall response.

Source: Table A.12.3.1.2.1.1

Table 8 Best Overall Response Rate at Week 24 in First and Second Stages for Simon’s 2-stage Design (Central Review) in Phase 2 (FAS)

Parameter

Patients in First Stage of Simon’s 2-stage Design

(N=24)

Patients in First and Second Stages of Simon’s

2-stage Design(N=63)

Best Overall Response ‡, n (%)

CR 0 0PR 9 (37.5) 27 (42.9)SD 8 (33.3) 24 (38.1)NN 1 (4.2) 3 (4.8)PD 6 (25.0) 8 (12.7)NE 0 1 (1.6)Total 24 63

Analysis ‡ ORR (CR + PR), n (%) 9 (37.5) 27 (42.9)95% CI † (%) 18.8, 59.4 30.5, 56.0DCR (CR + PR + SD), n (%) 17 (70.8) 51 (81.0)95% CI † (%) 48.9, 87.4 69.1, 89.8

CR: complete response; DCR: disease control rate; NE: not evaluated; NN: Non-CR/Non-PD; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease.



Source: Table B.12.3.1.1A and Table B.12.3.1.1B



Table 9 Best Overall Response Rate at Week 24 (Central Review) in Phase 2 (FAS)

Parameter300 mg(N=76)

Best Overall Response ‡, n (%) CR 0PR 33 (43.4)SD 28 (36.8)NN 4 (5.3)PD 9 (11.8)NE 2 (2.6)Total 76

Analysis ‡ ORR (CR + PR), n (%) 33 (43.4)95% CI † (%) 32.1, 55.3DCR (CR + PR + SD), n (%) 61 (80.3)95% CI † (%) 69.5, 88.5

CR: complete response; DCR: disease control rate; NE: not evaluated; NN: Non-CR/Non-PD; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease.



Source: Table B.12.3.1.1.1.1



Table 10 Summary of Plasma Pharmacokinetic Parameters of ASP8273 on Cycle 0 Day 1 in Phase 1 (PKAS)

ParameterStatistic

25 mg 50 mg 100 mg 200 mg 300 mg 400 mg 600 mg

AUCinf (ng•h/mL)n 1 3 5 10 9 9 4Mean (SD)

1300 (NA) 1390 (802) 8620 (7030)

17800 (13400)

24600 (14200)

41100 (21700)

90200 (49800)

%CV NA 57.6 81.6 75.5 57.5 52.8 55.1Median NA 1150 6970 14500 19700 35700 103000Min -Max

NA - NA 741 - 2290 1490 -16500

3910 -47200

11200 -51900

20100 -82800

19100 -135000

AUClast (ng•h/mL)n 1 4 6 10 10 10 4Mean (SD)

1190 (NA) 1290 (612) 7070 (5580)

16700 (12500)

22700 (12600)

42800 (24300)

82900 (46000)


NA - NA 671 - 2120 1310 -14500

3730 -43600

10900 -49400

18800 -85400

18400 -127000

AUC24h (ng•h/mL)n 1 4 6 10 10 10 4Mean (SD)

1010 (NA) 1090 (527) 5610 (4230)

13800 (9640)

19300 (10400)

34600 (18800)

66100 (37200)


NA - NA 542 - 1800 1050 -11600

3280 -31600

9450 -41800

15500 -64600

15700 -105000

Cmax (ng/mL)n 1 4 6 10 10 10 4Mean (SD)

138 (NA) 183 (92.7) 629 (502) 1350 (835) 1870 (796) 2790 (1490)

4430 (2390)


NA - NA 69.6 - 290 148 - 1490 561 - 3030 922 - 3220 1130 -4990

1270 -6790

CL/F (L/h)n 1 3 5 10 9 9 4Mean (SD)

19.3 (NA) 44.3 (22.8) 26.3 (26.1) 19.2 (14.6) 15.7 (7.55) 12.1 (5.37) 11.9 (13.1)

%CV NA 51.6 99.4 76.3 48.1 44.4 110.0Median NA 43.5 14.3 15.1 15.2 11.2 5.80Min -Max

NA - NA 21.9 - 67.5 6.08 - 67.0 4.24 - 51.1 5.78 - 26.9 4.83 - 19.9 4.44 - 31.5

tmax (h)n 1 4 6 10 10 10 4Mean (SD)

NC (NC) NC (NC) NC (NC) NC (NC) NC (NC) NC (NC) NC (NC)

%CV NC NC NC NC NC NC NCMedian NA 1.01 1.48 1.89 3.88 4.94 5.92Min -Max

NA - NA 0.967 -1.92

0.983 -3.88

1.00 - 9.97 1.03 - 6.00 1.93 - 6.00 3.98 - 6.00

Table continued on next page



ParameterStatistic

25 mg 50 mg 100 mg 200 mg 300 mg 400 mg 600 mg

t1/2 (h)n 1 3 5 10 9 9 4Mean (SD)

15.6 (NA) 13.3 (0.667)

14.5 (1.70) 11.6 (1.87) 11.6 (2.36) 12.3 (2.22) 11.6 (2.51)

%CV NA 5.0 11.7 16.2 20.4 18.1 21.6Median NA 13.6 14.3 11.6 11.6 12.9 10.9Min -Max

NA - NA 12.5 - 13.7 12.1 - 16.6 7.71 - 14.9 7.49 - 15.1 8.36 - 15.7 9.49 - 15.2

Vz/F (L)n 1 3 5 10 9 9 4Mean (SD)

434 (NA) 861 (472) 564 (619) 326 (245) 264 (153) 216 (104) 180 (169)


NA - NA 394 - 1340 125 - 1600 72.2 - 821 96.7 - 559 87.6 - 364 68.0 - 430

CV: coefficient of variation; NA: not applicable; NC: not calculated; SD: standard deviation.

Source: Table A.12.4.2.1.1, Table A.12.4.2.2.1, Table A.12.4.2.3.1, Table A.12.4.2.4.1, Table A.12.4.2.5.1, Table A.12.4.2.6.1 and Table A.12.4.2.7.1



Table 11 Summary of Plasma Pharmacokinetic Parameters of ASP8273 on Cycle 1 Day 21 in Phase 1 (PKAS)

ParameterStatistic

25 mg 50 mg 100 mg 200 mg 300 mg 400 mg 600 mg

AUCtau (ng•h/mL)n 1 4 6 9 10 7 0Mean (SD)

1820 (NA) 1560 (671) 7650 (5080)

16900 (12200)

26700 (11000)

59300 (40700)

NA (NA)

%CV NA 43.1 66.5 72.4 41.3 68.6 NAMedian NA 1330 6940 12300 27400 42300 NAMin -Max

NA - NA 1060 -2510

2330 -14500

6650 -44700

8290 -43900

21300 -143000

NA - NA

Cmax (ng/mL)n 1 4 6 9 10 7 0Mean (SD)

224 (NA) 192 (105) 629 (300) 1350 (937) 2040 (715) 3750 (2280)

NA (NA)

%CV NA 54.5 47.7 69.4 35.1 60.7 NAMedian NA 173 719 1180 2040 2950 NAMin -Max

NA - NA 90.5 - 330 222 - 1000 502 - 2900 913 - 3030 1200 -8020

NA - NA

CL/F (L/h)n 1 4 6 9 10 7 0Mean (SD)

13.7 (NA) 36.1 (12.5) 21.2 (16.3) 16.7 (8.94) 14.7 (10.1) 9.18 (5.08) NA (NA)

%CV NA 34.7 76.8 53.4 68.9 55.3 NAMedian NA 38.6 14.4 16.3 11.0 9.46 NAMin -Max

NA - NA 19.9 - 47.2 6.89 - 42.8 4.48 - 30.1 6.84 - 36.2 2.80 - 18.8 NA - NA

tmax (h)n 1 4 6 9 10 7 0Mean (SD)

NC (NC) NC (NC) NC (NC) NC (NC) NC (NC) NC (NC) NA (NA)

%CV NC NC NC NC NC NC NAMedian NA 1.48 1.93 3.98 3.02 5.90 NAMin -Max

NA - NA 0.500 -3.90

0.983 -3.97

1.87 - 6.00 1.93 - 5.88 1.93 - 8.00 NA - NA

Rac (AUC)n 1 4 6 9 10 7 0Mean (SD)

1.80 (NA) 1.51 (0.394)

1.52 (0.472)

1.41 (0.529)

1.52 (0.641)

1.72 (0.753)

NA (NA)

%CV NA 26.1 30.9 37.4 42.3 43.9 NAMedian NA 1.40 1.37 1.42 1.46 1.61 NAMin -Max

NA - NA 1.15 - 2.07 1.10 - 2.21 0.570 -2.21

0.500 -2.69

0.812 -3.06

NA - NA

CV: coefficient of variation; NA: not applicable; NC: not calculated; SD: standard deviation.

Source: Table A.12.4.2.1.2, Table A.12.4.2.2.2, Table A.12.4.2.3.2, Table A.12.4.2.4.2, Table A.12.4.2.5.2, Table A.12.4.2.6.2 and Table A.12.4.2.7.2



Table 12 Summary of Plasma Pharmacokinetic Parameters of ASP8273 on Cycle 1 Day 1 and Cycle 1 Day 21 in Phase 2 (PKAS)

ParameterStatistic

Cycle 1 Day 1 Cycle 1 Day 21

AUClast (ng•h/mL)n 72 NCMean (SD) 28000 (26100) NC%CV 92.9 NCMedian 20800 NCMin - Max 6090 - 147000 NC

AUC24h (ng•h/mL)n 72 NCMean (SD) 28100 (26100) NC%CV 93.0 NCMedian 20800 NCMin - Max 6110 - 147000 NC

AUCtau (ng•h/mL)n NC 65Mean (SD) NC 32200 (26600)%CV NC 82.6Median NC 22500Min - Max NC 7600 - 130000

Cmax (ng/mL)n 74 66Mean (SD) 2330 (1880) 2270 (1530)%CV 80.5 67.6Median 1890 1830Min - Max 449 - 11600 673 - 7790

CL/F (L/h)n 57 65Mean (SD) 15.5 (9.03) 14.1 (7.98)%CV 58.1 56.8Median 12.6 13.3Min - Max 3.96 - 41.0 2.31 - 39.5

tmax (h)n 74 66Mean (SD) NC (NC) NC (NC)%CV NC NCMedian 3.94 3.92Min - Max 0.950 - 24.0 1.00 - 10.0

t1/2 (h)n 57 NCMean (SD) 8.56 (1.47) NC%CV 17.2 NCMedian 8.40 NCMin - Max 5.73 - 12.7 NC

Vz/F (L)n 57 NCMean (SD) 186 (102) NC%CV 54.9 NCMedian 156 NCMin - Max 52.6 - 457 NC

Table continued on next page



ParameterStatistic

Cycle 1 Day 1 Cycle 1 Day 21

Rac (AUC)n NC 63Mean (SD) NC 1.42 (0.851)%CV NC 59.8Median NC 1.23Min - Max NC 0.306 - 4.69

CV: coefficient of variation; NC: not calculated; SD: standard deviation.

Source: Table B.12.4.2.4.1 and Table B.12.4.2.4.2

Table 13 DLTs in Phase 1 (DDAS)

n (%)25 mg(N=1)

50 mg(N=4)

100 mg(N=6)

200 mg(N=10)

300 mg(N=10)

400 mg(N=10)

600 mg(N=4)

Total(N=45)

Incidence of DLT 0 0 0 0 0 5 (50.0) 4 (100) 9 (20.0)Grade 4 neutropenia 0 0 0 0 0 0 0 0Grade 3 febrile neutropenia 0 0 0 0 0 0 0 0Grade 4 thrombocytopenia or Grade 3 thrombocytopenia accompanied by bleeding which requires platelet transfusion

0 0 0 0 0 0 0 0

Any ≥ Grade 3 nonhematologic toxicity

0 0 0 0 0 5 (50.0) 4 (100) 9 (20.0)

Any toxicity requiring interruption of ASP8273 for ≥ 11 days in total.

0 0 0 0 0 0 0 0

AE: adverse event; DLT: dose limiting toxicity.

Source: Table A.12.6.5.1

Table 14 DLTs in Phase 1 (Initial Dose Level) (SAF)

MedDRA v16.1 SOC PT, n (%)

25 mg(N=1)

50 mg(N=4)

100 mg(N=6)

200 mg(N=10)

300 mg(N=10)

400 mg(N=10)

600 mg(N=4)

Total(N=45)

Overall 0 0 0 0 0 5 (50.0) 4 (100) 9 (20.0)Gastrointestinal Disorders

0 0 0 0 0 3 (30.0) 3 (75.0) 6 (13.3)

Colitis 0 0 0 0 0 0 2 (50.0) 2 (4.4) Diarrhoea 0 0 0 0 0 2 (20.0) 1 (25.0) 3 (6.7) Nausea 0 0 0 0 0 1 (10.0) 1 (25.0) 2 (4.4)General Disorders andAdministration SiteConditions

0 0 0 0 0 1 (10.0) 0 1 (2.2)

Malaise 0 0 0 0 0 1 (10.0) 0 1 (2.2)Infections and Infestations

0 0 0 0 0 0 1 (25.0) 1 (2.2)

Biliary tract infection 0 0 0 0 0 0 1 (25.0) 1 (2.2)Metabolism and Nutrition Disorders

0 0 0 0 0 1 (10.0) 0 1 (2.2)

Hyponatraemia 0 0 0 0 0 1 (10.0) 0 1 (2.2)

DLT: dose limiting toxicity.




Table 15 Overview of TEAEs in Phase 1 (Initial Dose Level) (SAF)

n (%)25 mg(N=1)

50 mg(N=4)

100 mg(N=6)

200 mg(N=10)

300 mg(N=10)

400 mg(N=10)

600 mg(N=4)

Total(N=45)

TEAEs 1 (100) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 45 (100)Drug-related † TEAEs 1 (100) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 45 (100)TEAEs Leading to Deaths 0 0 0 0 0 0 1 (25.0) 1 (2.2)Drug-related † TEAEs Leading to Deaths

0 0 0 0 0 0 0 0

Serious TEAEs 0 1 (25.0) 3 (50.0) 3 (30.0) 5 (50.0) 6 (60.0) 3 (75.0) 21 (46.7)Drug-related † Serious TEAEs 0 0 0 1 (10.0) 1 (10.0) 4 (40.0) 3 (75.0) 9 (20.0)TEAEs Leading to Permanent Discontinuation of Study Drug

0 0 1 (16.7) 0 1 (10.0) 0 2 (50.0) 4 (8.9)

Drug-related † TEAEs Leading to PermanentDiscontinuation of Study Drug

0 0 0 0 0 0 1 (25.0) 1 (2.2)

A TEAE was defined as an AE observed after starting administration of the study drug.

TEAE: treatment-emergent adverse event.

† Possible or probable, as assessed by the investigator




Table 16 Most Common (≥ 10% in Any Dose Group) TEAEs in Phase 1 (Initial Dose Level) (SAF)


25 mg (N=1)

50 mg (N=4)

100 mg (N=6)

200 mg(N=10)

300 mg (N=10)

400 mg (N=10)

600 mg (N=4)

Total (N=45)

Overall 1 (100) 4 (100) 6 (100) 10 (100) 10 (100) 10 (100) 4 (100) 45 (100)Blood and Lymphatic System Disorders

0 1 (25.0) 1 (16.7) 4 (40.0) 3 (30.0) 4 (40.0) 2 (50.0) 15 (33.3)

Anaemia 0 0 0 2 (20.0) 3 (30.0) 3 (30.0) 2 (50.0) 10 (22.2) Leukopenia 0 0 1 (16.7) 0 1 (10.0) 0 1 (25.0) 3 (6.7) Neutropenia 0 1 (25.0) 1 (16.7) 1 (10.0) 1 (10.0) 1 (10.0) 1 (25.0) 6 (13.3) Thrombocytopenia 0 0 1 (16.7) 1 (10.0) 0 1 (10.0) 1 (25.0) 4 (8.9)Cardiac Disorders 0 0 0 0 0 2 (20.0) 1 (25.0) 3 (6.7) Atrial fibrillation 0 0 0 0 0 1 (10.0) 0 1 (2.2) Pericardial effusion 0 0 0 0 0 1 (10.0) 0 1 (2.2) Supraventricular tachycardia 0 0 0 0 0 0 1 (25.0) 1 (2.2)Ear and Labyrinth Disorders 0 0 0 0 0 0 1 (25.0) 1 (2.2) Vertigo 0 0 0 0 0 0 1 (25.0) 1 (2.2)Eye Disorders 1 (100) 0 2 (33.3) 5 (50.0) 1 (10.0) 2 (20.0) 1 (25.0) 12 (26.7) Blepharitis allergic 0 0 0 0 0 0 1 (25.0) 1 (2.2) Conjunctivitis 1 (100) 0 0 2 (20.0) 0 1 (10.0) 0 4 (8.9) Dry eye 0 0 2 (33.3) 2 (20.0) 1 (10.0) 0 0 5 (11.1) Eye disorder 0 0 0 0 0 1 (10.0) 0 1 (2.2) Eye pain 0 0 0 1 (10.0) 0 0 0 1 (2.2) Punctate keratitis 0 0 0 0 1 (10.0) 0 0 1 (2.2)Gastrointestinal Disorders 1 (100) 4 (100) 6 (100) 9 (90.0) 10 (100) 10 (100) 4 (100) 44 (97.8) Abdominal discomfort 0 0 0 0 0 1 (10.0) 0 1 (2.2) Abdominal pain upper 0 0 0 1 (10.0) 0 0 0 1 (2.2) Cheilitis 0 1 (25.0) 0 1 (10.0) 2 (20.0) 0 0 4 (8.9) Colitis 0 0 0 0 0 0 2 (50.0) 2 (4.4) Constipation 1 (100) 1 (25.0) 1 (16.7) 4 (40.0) 2 (20.0) 5 (50.0) 1 (25.0) 15 (33.3) Diarrhoea 0 1 (25.0) 4 (66.7) 8 (80.0) 7 (70.0) 10 (100) 4 (100) 34 (75.6) Dry mouth 0 0 0 0 0 1 (10.0) 0 1 (2.2) Dyspepsia 0 0 1 (16.7) 0 2 (20.0) 0 0 3 (6.7) Dysphagia 0 0 0 0 0 1 (10.0) 0 1 (2.2) Enterocolitis 0 0 0 1 (10.0) 0 0 1 (25.0) 2 (4.4) Gastritis 0 0 0 1 (10.0) 1 (10.0) 1 (10.0) 0 3 (6.7) Haemorrhoids 0 0 0 0 0 2 (20.0) 0 2 (4.4) Nausea 0 2 (50.0) 3 (50.0) 4 (40.0) 5 (50.0) 8 (80.0) 2 (50.0) 24 (53.3) Oesophageal stenosis 0 0 0 1 (10.0) 0 0 0 1 (2.2) Oesophagitis 0 0 1 (16.7) 0 0 0 0 1 (2.2) Stomatitis 0 3 (75.0) 1 (16.7) 1 (10.0) 0 1 (10.0) 1 (25.0) 7 (15.6) Upper gastrointestinal haemorrhage 0 0 0 0 0 0 1 (25.0) 1 (2.2) Vomiting 0 1 (25.0) 2 (33.3) 3 (30.0) 6 (60.0) 6 (60.0) 4 (100) 22 (48.9)General Disorders and Administration Site Conditions

0 2 (50.0) 1 (16.7) 4 (40.0) 2 (20.0) 9 (90.0) 4 (100) 22 (48.9)

Chest pain 0 0 0 0 0 1 (10.0) 0 1 (2.2) Fatigue 0 1 (25.0) 0 2 (20.0) 1 (10.0) 2 (20.0) 2 (50.0) 8 (17.8) Gait disturbance 0 0 0 0 0 1 (10.0) 0 1 (2.2) Malaise 0 1 (25.0) 1 (16.7) 1 (10.0) 0 5 (50.0) 1 (25.0) 9 (20.0) Oedema peripheral 0 1 (25.0) 0 0 1 (10.0) 1 (10.0) 1 (25.0) 4 (8.9) Pain 0 0 0 0 0 0 1 (25.0) 1 (2.2) Pyrexia 0 0 0 2 (20.0) 0 3 (30.0) 3 (75.0) 8 (17.8)Hepatobiliary Disorders 0 0 0 0 0 1 (10.0) 2 (50.0) 3 (6.7) Hepatic function abnormal 0 0 0 0 0 0 2 (50.0) 2 (4.4) Jaundice 0 0 0 0 0 1 (10.0) 0 1 (2.2)Immune System Disorders 0 0 0 1 (10.0) 0 0 0 1 (2.2) Hypersensitivity 0 0 0 1 (10.0) 0 0 0 1 (2.2)Table continued on next page




25 mg (N=1)

50 mg (N=4)

100 mg (N=6)

200 mg(N=10)

300 mg (N=10)

400 mg (N=10)

600 mg (N=4)

Total (N=45)

Infections and Infestations 0 3 (75.0) 3 (50.0) 6 (60.0) 5 (50.0) 6 (60.0) 2 (50.0) 25 (55.6) Biliary tract infection 0 0 0 0 0 1 (10.0) 1 (25.0) 2 (4.4) Bronchitis 0 0 0 0 1 (10.0) 1 (10.0) 0 2 (4.4) Cystitis 0 0 0 1 (10.0) 2 (20.0) 1 (10.0) 0 4 (8.9) Enteritis infectious 0 0 0 0 1 (10.0) 0 0 1 (2.2) Herpes zoster 0 0 2 (33.3) 0 0 1 (10.0) 0 3 (6.7) Infection 0 0 0 0 0 1 (10.0) 1 (25.0) 2 (4.4) Influenza 0 0 0 1 (10.0) 0 0 0 1 (2.2) Lung infection 0 1 (25.0) 1 (16.7) 1 (10.0) 0 0 1 (25.0) 4 (8.9) Nail infection 0 1 (25.0) 0 0 0 0 1 (25.0) 2 (4.4) Nasopharyngitis 0 0 0 3 (30.0) 0 0 0 3 (6.7) Oral herpes 0 0 0 1 (10.0) 0 0 0 1 (2.2) Otitis media 0 0 0 0 2 (20.0) 0 0 2 (4.4) Paronychia 0 1 (25.0) 0 0 1 (10.0) 1 (10.0) 0 3 (6.7) Pneumonia 0 0 0 1 (10.0) 0 0 0 1 (2.2) Pneumonia bacterial 0 0 0 1 (10.0) 0 0 0 1 (2.2) Rhinitis 0 0 0 0 1 (10.0) 0 0 1 (2.2) Sepsis 0 0 0 0 0 0 1 (25.0) 1 (2.2) Skin infection 0 0 0 0 1 (10.0) 0 1 (25.0) 2 (4.4) Upper respiratory tract infection 0 0 1 (16.7) 0 0 0 0 1 (2.2) Urinary tract infection 0 1 (25.0) 0 1 (10.0) 2 (20.0) 3 (30.0) 2 (50.0) 9 (20.0)Injury, Poisoning and Procedural Complications

0 1 (25.0) 1 (16.7) 2 (20.0) 0 1 (10.0) 1 (25.0) 6 (13.3)

Arthropod bite 0 0 0 1 (10.0) 0 0 0 1 (2.2) Contusion 0 0 0 1 (10.0) 0 0 0 1 (2.2) Excoriation 0 0 0 0 0 0 1 (25.0) 1 (2.2) Fall 0 0 0 0 0 0 1 (25.0) 1 (2.2) Fracture 0 1 (25.0) 0 0 0 0 0 1 (2.2) Ligament sprain 0 0 0 1 (10.0) 0 0 0 1 (2.2) Overdose 0 0 0 0 0 1 (10.0) 0 1 (2.2) Rib fracture 0 0 1 (16.7) 0 0 0 0 1 (2.2)Investigations 0 3 (75.0) 4 (66.7) 7 (70.0) 9 (90.0) 10 (100) 4 (100) 37 (82.2) Alanine aminotransferase increased 0 1 (25.0) 1 (16.7) 5 (50.0) 5 (50.0) 7 (70.0) 2 (50.0) 21 (46.7) Aspartate aminotransferase increased

0 1 (25.0) 0 4 (40.0) 4 (40.0) 5 (50.0) 2 (50.0) 16 (35.6)

Blood alkaline phosphatase increased

0 1 (25.0) 0 1 (10.0) 0 2 (20.0) 0 4 (8.9)

Blood bilirubin increased 0 0 1 (16.7) 1 (10.0) 2 (20.0) 1 (10.0) 0 5 (11.1) Blood creatine increased 0 1 (25.0) 0 0 0 0 0 1 (2.2) Blood creatine phosphokinase increased

0 0 0 0 0 1 (10.0) 0 1 (2.2)

Blood creatinine increased 0 1 (25.0) 1 (16.7) 2 (20.0) 3 (30.0) 5 (50.0) 3 (75.0) 15 (33.3) Blood lactate dehydrogenase increased

0 0 0 0 0 1 (10.0) 0 1 (2.2)

Blood sodium increased 0 0 1 (16.7) 0 0 0 0 1 (2.2) Electrocardiogram QT prolonged 0 0 1 (16.7) 0 2 (20.0) 1 (10.0) 0 4 (8.9) Gamma-glutamyltransferase increased

0 1 (25.0) 0 0 0 0 1 (25.0) 2 (4.4)

Haemoglobin decreased 0 1 (25.0) 0 0 0 0 0 1 (2.2) Lymphocyte count decreased 0 0 1 (16.7) 0 0 0 0 1 (2.2) Neutrophil count decreased 0 1 (25.0) 0 0 0 3 (30.0) 0 4 (8.9) Platelet count decreased 0 2 (50.0) 1 (16.7) 2 (20.0) 3 (30.0) 3 (30.0) 3 (75.0) 14 (31.1) Urine analysis abnormal 0 0 0 0 1 (10.0) 0 0 1 (2.2) Weight decreased 0 0 1 (16.7) 1 (10.0) 1 (10.0) 3 (30.0) 2 (50.0) 8 (17.8) Weight increased 0 0 0 0 0 1 (10.0) 0 1 (2.2) White blood cell count decreased 0 2 (50.0) 2 (33.3) 0 1 (10.0) 2 (20.0) 0 7 (15.6)Table continued on next page




25 mg (N=1)

50 mg (N=4)

100 mg (N=6)

200 mg(N=10)

300 mg (N=10)

400 mg (N=10)

600 mg (N=4)

Total (N=45)

Metabolism and Nutrition Disorders

0 1 (25.0) 4 (66.7) 7 (70.0) 8 (80.0) 8 (80.0) 3 (75.0) 31 (68.9)

Decreased appetite 0 1 (25.0) 2 (33.3) 4 (40.0) 4 (40.0) 4 (40.0) 2 (50.0) 17 (37.8) Dehydration 0 0 0 1 (10.0) 1 (10.0) 1 (10.0) 0 3 (6.7) Hyperkalaemia 0 0 0 1 (10.0) 1 (10.0) 0 0 2 (4.4) Hyperphosphataemia 0 0 0 2 (20.0) 1 (10.0) 2 (20.0) 1 (25.0) 6 (13.3) Hypoalbuminaemia 0 0 1 (16.7) 0 3 (30.0) 5 (50.0) 2 (50.0) 11 (24.4) Hypokalaemia 0 0 1 (16.7) 1 (10.0) 1 (10.0) 1 (10.0) 0 4 (8.9) Hyponatraemia 0 0 1 (16.7) 4 (40.0) 2 (20.0) 5 (50.0) 2 (50.0) 14 (31.1) Hypophosphataemia 0 0 1 (16.7) 0 1 (10.0) 1 (10.0) 0 3 (6.7) Hypovolaemia 0 0 0 0 0 1 (10.0) 0 1 (2.2)Musculoskeletal and Connective Tissue Disorders

0 3 (75.0) 1 (16.7) 2 (20.0) 1 (10.0) 3 (30.0) 1 (25.0) 11 (24.4)

Arthralgia 0 0 0 1 (10.0) 0 0 0 1 (2.2) Back pain 0 0 1 (16.7) 1 (10.0) 0 2 (20.0) 0 4 (8.9) Muscle spasms 0 0 0 1 (10.0) 0 1 (10.0) 0 2 (4.4) Musculoskeletal chest pain 0 0 0 0 0 0 1 (25.0) 1 (2.2) Musculoskeletal stiffness 0 1 (25.0) 0 0 0 0 0 1 (2.2) Neck pain 0 0 1 (16.7) 0 0 0 0 1 (2.2) Osteoarthritis 0 1 (25.0) 0 0 0 0 0 1 (2.2) Pain in extremity 0 2 (50.0) 0 0 0 0 0 2 (4.4) Periarthritis 0 0 0 0 0 1 (10.0) 0 1 (2.2) Spinal column stenosis 0 0 0 0 1 (10.0) 0 0 1 (2.2)Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps)

0 2 (50.0) 2 (33.3) 1 (10.0) 4 (40.0) 2 (20.0) 0 11 (24.4)

Cancer pain 0 1 (25.0) 0 0 1 (10.0) 2 (20.0) 0 4 (8.9) Metastases to central nervous system 0 0 0 0 1 (10.0) 0 0 1 (2.2) Metastases to meninges 0 0 1 (16.7) 0 2 (20.0) 0 0 3 (6.7) Tumour pain 0 1 (25.0) 1 (16.7) 1 (10.0) 1 (10.0) 0 0 4 (8.9)Nervous System Disorders 0 3 (75.0) 6 (100) 7 (70.0) 4 (40.0) 9 (90.0) 3 (75.0) 32 (71.1) Amnesia 0 0 0 0 1 (10.0) 0 0 1 (2.2) Brain oedema 0 0 1 (16.7) 0 0 0 1 (25.0) 2 (4.4) Convulsion 0 0 0 0 1 (10.0) 0 0 1 (2.2) Depressed level of consciousness 0 0 0 0 1 (10.0) 0 0 1 (2.2) Dizziness 0 1 (25.0) 0 0 1 (10.0) 1 (10.0) 0 3 (6.7) Dysaesthesia 0 0 1 (16.7) 0 0 0 0 1 (2.2) Dysarthria 0 0 0 0 0 1 (10.0) 0 1 (2.2) Dysgeusia 0 1 (25.0) 0 3 (30.0) 1 (10.0) 1 (10.0) 3 (75.0) 9 (20.0) Headache 0 1 (25.0) 2 (33.3) 1 (10.0) 1 (10.0) 3 (30.0) 0 8 (17.8) Neuropathy peripheral 0 0 0 1 (10.0) 0 0 0 1 (2.2) Peripheral sensory neuropathy 0 1 (25.0) 3 (50.0) 3 (30.0) 2 (20.0) 5 (50.0) 3 (75.0) 17 (37.8) Sciatica 0 0 0 0 0 0 1 (25.0) 1 (2.2) Syncope 0 0 0 0 0 1 (10.0) 0 1 (2.2)Psychiatric Disorders 0 1 (25.0) 2 (33.3) 1 (10.0) 2 (20.0) 2 (20.0) 3 (75.0) 11 (24.4) Anxiety 0 0 1 (16.7) 1 (10.0) 0 1 (10.0) 1 (25.0) 4 (8.9) Delirium 0 0 0 0 1 (10.0) 0 2 (50.0) 3 (6.7) Insomnia 0 1 (25.0) 1 (16.7) 0 1 (10.0) 1 (10.0) 1 (25.0) 5 (11.1) Restlessness 0 0 1 (16.7) 0 0 0 0 1 (2.2)Renal and Urinary Disorders 0 0 0 1 (10.0) 1 (10.0) 7 (70.0) 3 (75.0) 12 (26.7) Dysuria 0 0 0 0 0 1 (10.0) 0 1 (2.2) Haematuria 0 0 0 0 1 (10.0) 5 (50.0) 1 (25.0) 7 (15.6) Ketonuria 0 0 0 1 (10.0) 0 0 0 1 (2.2) Pollakiuria 0 0 0 0 0 1 (10.0) 0 1 (2.2) Renal failure acute 0 0 0 0 0 0 1 (25.0) 1 (2.2) Urinary retention 0 0 0 0 0 0 1 (25.0) 1 (2.2)Table continued on next page




25 mg (N=1)

50 mg (N=4)

100 mg (N=6)

200 mg(N=10)

300 mg (N=10)

400 mg (N=10)

600 mg (N=4)

Total (N=45)

Reproductive System and Breast Disorders

0 0 0 0 0 1 (10.0) 0 1 (2.2)

Uterine prolapse 0 0 0 0 0 1 (10.0) 0 1 (2.2)Respiratory, Thoracic and Mediastinal Disorders

0 1 (25.0) 3 (50.0) 2 (20.0) 1 (10.0) 3 (30.0) 2 (50.0) 12 (26.7)

Cough 0 1 (25.0) 1 (16.7) 2 (20.0) 1 (10.0) 1 (10.0) 1 (25.0) 7 (15.6) Dyspnoea 0 0 1 (16.7) 0 0 2 (20.0) 2 (50.0) 5 (11.1) Haemoptysis 0 0 1 (16.7) 1 (10.0) 0 0 0 2 (4.4) Interstitial lung disease 0 0 0 0 0 0 1 (25.0) 1 (2.2) Pleural effusion 0 0 0 0 1 (10.0) 1 (10.0) 0 2 (4.4) Productive cough 0 0 0 1 (10.0) 0 0 0 1 (2.2) Sputum increased 0 0 0 0 0 0 1 (25.0) 1 (2.2)Skin and Subcutaneous Tissue Disorders

0 2 (50.0) 4 (66.7) 3 (30.0) 5 (50.0) 6 (60.0) 3 (75.0) 23 (51.1)

Alopecia 0 1 (25.0) 0 0 0 0 1 (25.0) 2 (4.4) Dermatitis acneiform 0 1 (25.0) 0 1 (10.0) 0 0 0 2 (4.4) Dry skin 0 0 2 (33.3) 1 (10.0) 2 (20.0) 3 (30.0) 1 (25.0) 9 (20.0) Erythema 0 0 1 (16.7) 0 0 1 (10.0) 0 2 (4.4) Haemorrhage subcutaneous 0 0 0 0 0 1 (10.0) 0 1 (2.2) Nail disorder 0 1 (25.0) 0 0 0 0 0 1 (2.2) Onychomadesis 0 0 0 0 0 0 1 (25.0) 1 (2.2) Pruritus 0 0 2 (33.3) 1 (10.0) 0 2 (20.0) 0 5 (11.1) Purpura 0 0 0 0 1 (10.0) 0 0 1 (2.2) Rash 0 1 (25.0) 0 1 (10.0) 2 (20.0) 1 (10.0) 1 (25.0) 6 (13.3) Skin exfoliation 0 0 0 0 0 1 (10.0) 0 1 (2.2)Vascular Disorders 0 0 0 0 1 (10.0) 2 (20.0) 1 (25.0) 4 (8.9) Deep vein thrombosis 0 0 0 0 0 0 1 (25.0) 1 (2.2) Haemorrhage 0 0 0 0 0 1 (10.0) 0 1 (2.2) Hypertension 0 0 0 0 1 (10.0) 0 0 1 (2.2) Hypotension 0 0 0 0 0 2 (20.0) 0 2 (4.4)


AE: adverse event; TEAE: treatment-emergent adverse event.




Table 17 Serious TEAEs in Phase 1 (Initial Dose Level) (SAF)


25 mg(N=1)

50 mg(N=4)

100 mg(N=6)

200 mg(N=10)

300 mg(N=10)

400 mg(N=10)

600 mg(N=4)

Total(N=45)

Overall 0 1 (25.0) 3 (50.0) 3 (30.0) 5 (50.0) 6 (60.0) 3 (75.0) 21 (46.7)Gastrointestinal Disorders 0 0 0 1 (10.0) 1 (10.0) 1 (10.0) 2 (50.0) 5 (11.1) Colitis 0 0 0 0 0 0 1 (25.0) 1 (2.2) Diarrhoea 0 0 0 0 1 (10.0) 0 1 (25.0) 2 (4.4) Enterocolitis 0 0 0 1 (10.0) 0 0 0 1 (2.2) Nausea 0 0 0 0 0 1 (10.0) 0 1 (2.2)General Disorders andAdministration SiteConditions

0 0 0 0 0 1 (10.0) 1 (25.0) 2 (4.4)

Malaise 0 0 0 0 0 1 (10.0) 0 1 (2.2) Pain 0 0 0 0 0 0 1 (25.0) 1 (2.2)Hepatobiliary Disorders 0 0 0 0 0 1 (10.0) 0 1 (2.2) Jaundice 0 0 0 0 0 1 (10.0) 0 1 (2.2)Infections and Infestations 0 1 (25.0) 1 (16.7) 2 (20.0) 0 0 2 (50.0) 6 (13.3) Biliary tract infection 0 0 0 0 0 0 1 (25.0) 1 (2.2) Infection 0 0 0 0 0 0 1 (25.0) 1 (2.2) Lung infection 0 1 (25.0) 1 (16.7) 0 0 0 1 (25.0) 3 (6.7) Pneumonia 0 0 0 1 (10.0) 0 0 0 1 (2.2) Pneumonia bacterial 0 0 0 1 (10.0) 0 0 0 1 (2.2) Sepsis 0 0 0 0 0 0 1 (25.0) 1 (2.2) Urinary tract infection 0 0 0 0 0 0 1 (25.0) 1 (2.2)Injury, Poisoning andProcedural Complications

0 0 0 0 0 1 (10.0) 0 1 (2.2)

Overdose 0 0 0 0 0 1 (10.0) 0 1 (2.2)Metabolism and NutritionDisorders

0 0 0 1 (10.0) 1 (10.0) 3 (30.0) 0 5 (11.1)

Decreased appetite 0 0 0 1 (10.0) 0 0 0 1 (2.2) Dehydration 0 0 0 0 1 (10.0) 1 (10.0) 0 2 (4.4) Hyponatraemia 0 0 0 0 0 2 (20.0) 0 2 (4.4)Musculoskeletal andConnective Tissue Disorders

0 1 (25.0) 0 0 0 0 0 1 (2.2)

Pain in extremity 0 1 (25.0) 0 0 0 0 0 1 (2.2)Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps)

0 0 2 (33.3) 0 4 (40.0) 2 (20.0) 0 8 (17.8)

Cancer pain 0 0 0 0 0 2 (20.0) 0 2 (4.4) Metastases to central nervous system

0 0 0 0 1 (10.0) 0 0 1 (2.2)

Metastases to meninges 0 0 1 (16.7) 0 2 (20.0) 0 0 3 (6.7) Tumour pain 0 0 1 (16.7) 0 1 (10.0) 0 0 2 (4.4)Nervous System Disorders 0 0 0 0 0 0 1 (25.0) 1 (2.2) Sciatica 0 0 0 0 0 0 1 (25.0) 1 (2.2)Psychiatric Disorders 0 0 0 0 0 1 (10.0) 1 (25.0) 2 (4.4) Anxiety 0 0 0 0 0 1 (10.0) 1 (25.0) 2 (4.4)Renal and Urinary Disorders 0 0 0 0 0 0 1 (25.0) 1 (2.2) Renal failure acute 0 0 0 0 0 0 1 (25.0) 1 (2.2)Respiratory, Thoracic andMediastinal Disorders

0 0 0 0 1 (10.0) 1 (10.0) 0 2 (4.4)

Dyspnoea 0 0 0 0 0 1 (10.0) 0 1 (2.2) Pleural effusion 0 0 0 0 1 (10.0) 0 0 1 (2.2)



Source: Table A.12.6.1.6.1.1



Table 18 Overview of TEAEs and Deaths in Phase 2 (Initial Dose Level) (SAF)

n (%)300 mg(N=76)

TEAEs 76 (100)Drug-related † TEAEs 72 (94.7)TEAEs Leading to Deaths 2 (2.6)Drug-related † TEAEs Leading to Deaths 0Serious TEAEs 38 (50.0)Drug-related † Serious TEAEs 18 (23.7)TEAEs Leading to Permanent Discontinuation of Study Drug 6 (7.9)Drug-related † TEAEs Leading to Permanent Discontinuation of Study Drug 3 (3.9)Death ‡ 37 (48.7)



† Possible or probable, as assessed by the investigator

‡ All reported deaths after the first study drug administration (including additional follow-up period).




Table 19 Most Common (≥ 10% of Patients) TEAEs in Phase 2 (Initial Dose Level) (SAF)


300 mg(N=76)

Overall 76 (100)Blood and Lymphatic System Disorders 19 (25.0) Anaemia 15 (19.7)Gastrointestinal Disorders 68 (89.5) Constipation 22 (28.9) Diarrhoea 51 (67.1) Dry mouth 8 (10.5) Nausea 33 (43.4) Vomiting 28 (36.8)General Disorders and Administration Site Conditions 42 (55.3) Fatigue 13 (17.1) Malaise 13 (17.1) Pyrexia 8 (10.5)Infections and Infestations 39 (51.3) Urinary tract infection 11 (14.5)Investigations 50 (65.8) Alanine aminotransferase increased 30 (39.5) Aspartate aminotransferase increased 21 (27.6) Blood creatinine increased 8 (10.5) Platelet count decreased 14 (18.4) Weight decreased 12 (15.8)Metabolism and Nutrition Disorders 46 (60.5) Decreased appetite 27 (35.5) Hypoalbuminaemia 10 (13.2) Hyponatraemia 25 (32.9)Nervous System Disorders 54 (71.1) Dizziness 10 (13.2) Dysgeusia 9 (11.8) Headache 9 (11.8) Hypoaesthesia 9 (11.8) Peripheral sensory neuropathy 22 (28.9)Psychiatric Disorders 14 (18.4) Insomnia 12 (15.8)Respiratory, Thoracic and Mediastinal Disorders 32 (42.1) Cough 13 (17.1)Skin and Subcutaneous Tissue Disorders 29 (38.2) Pruritus 8 (10.5) Rash 9 (11.8)Vascular Disorders 16 (21.1) Hypotension 9 (11.8)






Table 20 Serious TEAEs in Phase 2 (Initial Dose Level) (SAF)


300 mg(N=76)

Overall 38 (50.0)Blood and Lymphatic System Disorders 1 (1.3) Anaemia 1 (1.3)Cardiac Disorders 2 (2.6) Myocardial ischaemia 1 (1.3) Pericardial effusion 1 (1.3)Ear and Labyrinth Disorders 1 (1.3) Vertigo 1 (1.3)Gastrointestinal Disorders 3 (3.9) Nausea 3 (3.9)General Disorders and Administration Site Conditions 4 (5.3) Fatigue 1 (1.3) General physical health deterioration 1 (1.3) Pyrexia 2 (2.6)Hepatobiliary Disorders 4 (5.3) Bile duct stone 1 (1.3) Cholecystitis acute 1 (1.3) Hepatic function abnormal 2 (2.6)Infections and Infestations 10 (13.2) Bronchitis 1 (1.3) Device related infection 1 (1.3) Infectious pleural effusion 1 (1.3) Pneumonia 3 (3.9) Pyelonephritis 1 (1.3) Sepsis 2 (2.6) Streptococcal bacteraemia 1 (1.3) Urinary tract infection 2 (2.6)Injury, Poisoning and Procedural Complications 3 (3.9) Femoral neck fracture 2 (2.6) Fracture 1 (1.3)Investigations 4 (5.3) Alanine aminotransferase increased 3 (3.9) Aspartate aminotransferase increased 2 (2.6) Blood alkaline phosphatase increased 1 (1.3) Electrocardiogram T wave inversion 1 (1.3)Metabolism and Nutrition Disorders 7 (9.2) Decreased appetite 2 (2.6) Dehydration 2 (2.6) Hyponatraemia 5 (6.6)Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps) 3 (3.9) Cancer pain 1 (1.3) Metastases to meninges 2 (2.6)Nervous System Disorders 7 (9.2) Brain oedema 1 (1.3) Cerebral haemorrhage 1 (1.3) Convulsion 4 (5.3) Headache 2 (2.6)Renal and Urinary Disorders 3 (3.9) Cystitis haemorrhagic 1 (1.3) Renal disorder 1 (1.3) Renal failure acute 1 (1.3)Table continued on next page




300 mg(N=76)

Respiratory, Thoracic and Mediastinal Disorders 6 (7.9) Cough 1 (1.3) Dyspnoea 2 (2.6) Haemothorax 1 (1.3) Organising pneumonia 1 (1.3) Pleural effusion 3 (3.9)



Source: Table B.12.6.1.6.1.1

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