Ohio State's 2016 ASH Review T-cell Disorders

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

T-cell Disorders Pierluigi Porcu, MD Professor of Medicine Division of Hematology Comprehensive Cancer Center

#253 Safe and Effective Treatment of Patients with PTCL with the Novel HDAC Inhibitor, Belinostat, in Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial (23 patients)

#340 Addition of Etoposide to CHOP Is Associated with Improved Outcome in Adult ALCL Patients: A Nordic Lymphoma Group Study

#341 First Multicenter, Randomized Phase 3 Study in Pts with Relapsed/Refractory PTCL: Alisertib (MLN8237) Versus Investigator's Choice (Lumiere trial; NCT01482962)

#586 The Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) Demonstrates Marked Activity in Heavily Treated Patients with Relapsed or Refractory Hodgkin Lymphoma and ALCL: Results of an International Multi Center Phase I/II Experience

#1537 Frontline Treatment of CD30+ Peripheral T-Cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up

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ASH - 2015 Presentations on Peripheral T-cell Lymphoma

#1501 Event-Free Survival at 12 Months and Subsequent Overall Survival in Patients with PTCL

#3937 Phase II Study of the Fondazione Italiana Linfomi on Gemcitabine Plus Romidepsin (GEMRO Regimen) in Relapsed and Refractory PTCL Patients (20 patients)

#3987 High Response Rate of Romidepsin in Combination with ICE (Ifosfamide, Carboplatin and Etoposide) in Patients with Relapsed or Refractory PTCL: Updates of Phase I Trial (17 patients)

#3947 Accuracy of PET Imaging to Detect Bone Marrow Clearance in Patients with PTCL

#3952 Patterns of Treatment for Newly Diagnosed and R/R PTCL in the Community Setting

#3993 Development of Masitinib for the Treatment of PTCL

#1467 Inhibition of ITK-Mediated Chemoresistance By Ibrutinib in T-Cell Disorders

#315 Subgroups of T-PLL Discovered By High-Throughput Ex Vivo Drug Testing and Genetic Profiling

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ASH - 2015 Presentations on Peripheral T-cell Lymphoma

#1485 High-Depth, Targeted, Next Generation Sequencing Identifies Novel Genetic Alterations in Cutaneous T-Cell Lymphoma

#4403 Allogeneic Hematopoietic Cell Transplantation (HCT) for Advanced Mycosis Fungoides and Sezary Syndrome (MF/SS): Impact of Increasing the Use of Unrelated Donors (UD) - the EBMT Lymphoma Working Party Experience

#2724 Phase I Study of E7777, a Diphtheria Toxin Fragment-Interleukin-2 Fusion Protein, in Japanese Patients with Relapsed or Refractory Peripheral and Cutaneous T-Cell Lymphoma

#2677 Results from a Phase 1/2, Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-Cell Lymphoma

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ASH - 2015 Presentations on Cutaneous T-cell Lymphomas

Belinostat: Pan HDACi recently approved in the U.S. for R/R PTCL based on results from pivotal Phase 2 BELIEF study (O'Connor et al, JCO, 2015) which showed ORR 25.8%, durable benefit, and good tolerability

Study design:

Sponsor: Spectrum

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#253 Safe and Effective Treatment of Patients with PTCL with the Novel HDAC Inhibitor, Belinostat, in Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial

A total of 23 patients were enrolled in the study (10 PTCL, 9 AITL, 3 ALCL) Part A = Maximum Tolerated Dose (MTD) of the Bel-CHOP combination (11 patients) Part B = Expansion Phase (12 more patients) MTD = 1000 mg/m2 on Days 1-5 (Cohort 5) Only DLT was in Cohort 3 (G3 Nausea and Vomiting). 18/23 patients (78%) completed all 6 cycles of Bel-CHOP, 87% completing at least 4 cycles. 10 patients (43%) had at least 1 serious adverse event (SAE); 18 (78%) had at least one G3/4 AE Most frequent G3/4 AEs = neutropenia (26%), anemia (22%), leukopenia (17%). ORR = 89% (16/18 patients that completed End of Study Visit ) CR = 72% (n=13) PR = 17% (n=3) Progressive disease = 2 patients.

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#253 Safe and Effective Treatment of Patients with PTCL with the Novel HDAC Inhibitor, Belinostat, in Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial

Population-based study, Swedish and Danish Lymphoma Registries

Goal: analyzing outcome and risk factors for survival in patients with systemic ALCL (ALK+ and ALK-)

Adult (>18 years) patients with ALCL diagnosed between 2000 and 2010

Primary cutaneous ALCL cases excluded.

No central review of pathology

N = 371 patients (ALK+ ALCL N=122; ALK- N=216; ALK unknown N=33)

Largest cohort of adult ALCL patients published

The median follow-up 7.2 years

ALK+ patients younger than ALK- patients (median age 40 versus 66 years, p<0.001

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118/328 assessable patients relapsed or progressed (ALK+ n=20, ALK- n= 83, ALK u n=15) 5-yr OS and PFS, respectively were 78% and 64% in ALK+ ALCL, 37% and 32% in ALK- ALCL and 27%

and 25% in ALK u ALCL. Data on primary treatment available in 341/371 patients (92%). The majority of patients (n=278, 82%) was

treated with CHOP (N=233) or CHOEP (N=108). Up-front ASCT performed in 38 patients with ALK- ALCL (most CHOEP) and 6 patients with ALK+ ALCL. Independent variable in multivariable analysis were:

1. Treatment with CHOEP = better OS (HR 0.48 95% CI 0.32-0.74, p=0.001) 2. Increasing NCCN-IPI score (HR [for each increment] 1.6 95% CI 1.5-1.8, p<0.001) = inferior OS.

Risk factors for worse OS by multivariable analysis for patients treated with CHOEP: Age (HR 2.9 95% CI 1.5-5.3, p=0.001) ALK-negativity (HR 2.6 95% CI 1.2-6.0, p=0.020) Elevated LDH (HR 2.1 95% CI 1.0-4.3, p=0.047)

Assigning 0,1 and 2 points for age <40, 40-60 and 60-75, 1 for ALK-, and 1 for LDH, a new score identified 4 groups with different OS. Patients with a score of 3 or 4 had a similar OS.

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CONCLUSIONS Study confirms the favorable outcome of ALK+ ALCL patients and the association with low-risk features

Addition of etoposide to CHOP was independently associated with a superior OS

Addition of etoposide to CHOP, if tolerated, is an important component in the treatment of ALCL

When adjusting for this treatment modification, the impact of ALK-expression on OS was mitigated.

Risk analysis in the CHOEP treatment group: age, ALK-, LDH independent risk factors for OS

Novel prognostic score proposed

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Alisertib investigational, oral, selective inhibitor of Aurora A kinase, key mitotic regulator overexpressed/amplified in various cancers, including lymphomas.

Phase 2 data with single-agent alisertib in R/R NHL (Friedberg et al JCO 2014) and R/R PTCL (Barr et al JCO 2015) suggested promising antitumor activity.

This international phase 3 trial evaluated single-agent alisertib vs investigator's choice in pts with R/R PTCL, and was the first initiated randomized trial in this setting.

Eligibility: Adult pts with R/R PTCL ≥1 prior systemic therapy Measurable disease by 2007 IWG criteria Tumor biopsy for central hematopathology review ECOG PS 0–2 No prior exposure to comparator drug (pralatrexate, romidepsin, or gemcitabine)

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Study Design: Stratification: Nodal vs Extranodal, IPI 0/1/2 vs 3/4/5, North America + EU vs Rest of World

Randomized (1:1) to Alisertib 50 mg PO bid on d 1–7 in 21d cycles vs. investigator's choice

Pralatrexate, Romidepsin, or Gemcitabine (all at standard dosing schedule)

Treated until disease progression, unacceptable toxicity, or 2 yrs (extendable if benefit shown).

Crossover to other drug not permitted.

Primary endpoints: ORR (CR+PR) and PFS by IWG criteria per central (IRC) assessment.

Secondary endpoints: OS, DOR, and safety.

Adaptive sample size reassessment approach, with two interim analyses (IA1, futility; IA2) and one final analysis

Sample size: 80% power for ORR (assumed 55% alisertib vs 30% comparator); ~85% power for PFS

Assumed 55% ORR for alisertib vs 30% ORR for comparator

Planned final analysis N=354 randomized pts + N=261 PFS events

PFS analysis at IA2 could determined futility assessment (reported at ASH)

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Results: 238 pts randomized across 27 countries (120 alisertib, 118 comparator)

Baseline characteristics were balanced between arms (alisertib vs comparator) Median age 63 vs 64 yrs

Male 68% vs 64%

Ann Arbor stage III/IV 74% vs 72%

Bone marrow involvement 29% vs 35%.

Efficacy: ORR: 33% alisertib vs 43% comparator (OR 0.65 [95% CI: 0.34–1.23]), 16% vs 25% CR

Median duration of follow-up 9.5 vs 9.2 mos

Median PFS 3.7 vs 3.4 mos (HR 0.939 [95% CI: 0.681–1.293])

Median OS was 9.9 vs 12.2 mos (HR 0.901 [95% CI: 0.607–1.337]

Median treatment duration with alisertib vs comparator was 12 vs 10 weeks

Overall safety and rates of specific Aes similar between the two arms

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https://ash.confex.com/data/abstract/ash/2015/7/4/Paper_80447_abstract_163397_0.jpg

Conclusions:

Alisertib showed activity in R/R PTCL, but….

No significant efficacy benefit vs comparator

Based on IA2, there was a low probability of claiming superiority of alisertib for PFS at the final analysis

Per IDMC recommendation enrollment stopped at 271 pts and pts deriving benefit continue on treatment.

The study was unblinded and final data are pending.

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Phase 1 trial of brentuximab vedotin (BV) in sequence with CHOP or in combination with CHP (no vincristine) in treatment-naive pts with PTCL, including systemic ALCL (Fanale 2014)

Updated durability data and peripheral neuropathy resolution from the combination-therapy arm of this trial

Analysis set consisted of pts who received BV+CHP x 6 cycles, q3wk.

Pts who achieved at least PR could receive up to 10 additional cycles of single-agent BV (1.8 mg/kg q3wk)

ALK+ ALCL pts must have IPI score ≥2

No centralized response assessment

Efficacy endpoints included PFS and OS

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Cohort size N= 26 ALCL (n=19; 3ALK+, 16 ALK-), PTCL-NOS (n=2), AITL (n=2), ATLL (n=2), and EATL (n=1) OR rate = 100%; CR rate = 88% Treatment-emergent adverse events >G3: febrile neutropenia, neutropenia, anemia and pulm. embolism Peripheral neuropathy (any grade): 73% 20 pts on study, median observation time = 38.7 months (range, 4.6 to 44.3) 3 yr OS: 80% (95% CI: 59, 91 months) Median PFS not reached. Twenty one pts received a median of 10 doses (range, 1-10) of BV post BV-CHP Nine/19 (47%) ALCL and 5/7 (71%) non-ALCL pts have not experienced disease progression or death

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Eighteen of 19 (95%) patients experienced either complete resolution (n=7, 37%) or improvement by at least 1 grade level (n=11, 58%) in neuropathy

There were a total of 44 PN events of which 23 (52%) resolved and 14 (32%) improved Five pts (19%) who experienced disease progression post-treatment received subsequent BV Three patients received stem cell transplants (1 autologous, 2 allogenic) No patients received a consolidative ASCT in first remission

Conclusions: Durable remissions observed with BV-CHP in newly diagnosed pts with PTCL After >3 years of follow-up, clinical outcomes compare favorably with historical data in PTCL pts. An ongoing randomized trial with 450 pts is comparing BV+CHP with CHOP for the frontline treatment of

CD30+ PTCL (ClinicalTrials.gov NCT01777152) Final results from this trial are expected in 2017 to 2018.

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Progression-Free Survival: BV-CHP

https://ash.confex.com/data/abstract/ash/2015/8/2/Paper_83328_abstract_157724_0.jpg

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Ohio State's 2016 ASH Review T-cell Disorders