A PHASE 2 STUDY OF TH-302 IN COMBINATION WITH DOXORUBICIN IN ADVANCED SOFT TISSUE SARCOMA

Sant P Chawla, MDSarcoma Oncology Center

Santa Monica, CA

Sant P. Chawla1, Kristin N. Ganjoo2, Douglas Adkins3, Damon Reed4, Scott H. Okuno5, James E. Butrynski6, Daniel Rushing7, Brain Van Tine3, Esther D. Chu8, Stew Kroll8,

Lee Cranmer9

1. Oncology, Sarcoma Oncology Center, Santa Monica, CA; 2. Stanford University Medical Center, Stanford, CA; 3. Washington University, St. Louis, MO; 4. H. Lee Moffitt Cancer Center, Tampa, FL; 5. Mayo Clinic Rochester, Rochester, MN; 6. Oncology, Dana-Farber Cancer Institute, Boston, MA;

7. Indiana University Simon Cancer Center, Indianapolis, IN; 8. Threshold Pharmaceuticals, South San Francisco, CA; 9. Arizona Cancer Center, Tucson, AZ.

•TH-302 is a hypoxia activated prodrug • nitroimidazole prodrug of the cytotoxic

alkylator, bromo-isophosphoramide mustard (Br-IPM)

•Under normoxic conditions, TH-302 is designed to be essentially inactive.

• In hypoxic conditions and reductases, the nitroimidazole is reduced and Br-IPM is released to alkylate DNA

•Strong mechanistic, preclinical and clinical rationale for combining TH-302 with doxorubicin in soft tissue sarcoma

INTRODUCTION

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• Procedures/Assessments – TH-302 administered IV at MTD of 300 mg/m2 over 30-60 minutes on

Day 1 and Day 8 of 21 day cycle– Doxorubicin 75 mg/m2 administered IV on Day 1 two hours after

completion of TH-302 (for a maximum of 6 cycles , 450 mg/m2 cumulative dose)

– Response evaluated by RECIST 1.0 after every even cycle – Patients with stable or responding disease and acceptable toxicity could

receive TH-302 alone (maintenance) after 6 cycles of combination therapy until progression or discontinuation for other reason

Study TH-CR-403: Phase 2 Study Design

91 patients initiated treatment between August 2009 and June 2011Characteristic Gender (N) Female/Male 53/38 Age (years) Median 57 Range 23-78

ECOG (N/%) 01

45%55%

Prior adjuvant /neoadjuvant therapy (%) Yes 16%

Histology (%) Leiomyosarcoma 31% Unclassified/MFH 31% Liposarcoma 21% Angiosarcoma 3% Fibrosarcoma 3% Synovial sarcoma 3% Other* 8%

Disease Status (%) Locally Advanced Unresectable 18% Metastatic 82%

Study TH-CR-403: Demographics

*Other: chondrosarcoma (4), chordoma, pleomorphic rhabdomyosarcoma, endometrial stromal cell sarcoma.

Study TH-CR-403: Exposure and Status

• Study Drug Exposure– Median cycles: 6 (range: 1 to 29 cycles).– 42 patients received single agent TH-302 after 6

cycles of the combination therapy.

Study TH-CR-403: Deaths/Discontinuations

• No study drug related deaths• Thirteen discontinuations for an AE

Study TH-CR-403: Safety Non-Hematologic Toxicity

  Grade 1 Grade 2 Grade 3 Grade 4

Nausea 44% 26% 0 0

Fatigue 31% 25% 11% 0

Stomatitis 23% 18% 0 0

Anorexia 32% 8% 0 0

Diarrhea 25% 10% 2% 0

Vomiting 21% 13% 0 0

Rash* 16% 15% 0 0

Pyrexia 19% 9% 1% 0

Back Pain 7% 18% 1% 0

• Hematologic Toxicity – Febrile neutropenia was reported in 7 patients– No Grade 3/4 neutropenia or thrombocytopenia was reported during

the TH-302 maintenance.

Hematologic Toxicity per CTCAE v3 (All cycles)

 N=88 Grade 3 Grade 4 Total Grade 3/4

Neutropenia 7% 14% 20%

Thrombocytopenia 15% 10% 25%

Anemia 28% 0% 28%

Study TH-CR-403, Safety: Laboratory Results

Other Laboratory Data

• There has been no evidence of renal, liver or cardiac toxicity related to TH-302 and no other consistent laboratory abnormalities.

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Study TH-CR-403, Efficacy: RECIST ResponseMaximum Percent Change in SLD of Target Lesions

SD or better rate of 84%.*Subject 1 had a 105% increase from baseline.

Study TH-CR-403, Efficacy: RECIST Response• Best response by sarcoma subgroup classification

    Best Response

Sarcoma Classification N CR PR SD PD

Leiomyosarcoma 28 0% 46% 36% 18%

Unclassified/MFH 27 4% 37% 48% 11%

Liposarcoma 18 0% 22% 44% 33%

Other* 16 6% 19% 75% 0% 

Total 89 2% 34% 48% 16%

• Response rate of 36%.

Study TH-CR-403: TH-302 in Combination with DoxorubicinCase Report in Patient with Metastatic Leiomyosarcoma

• 65y ♀ Uterine leiomyosarcoma • TH-302 300 mg/m2

• Adjuvant gemcitabine/docetaxel• Large peritoneal metastases (including 28 cm mass) with ascites• PR by RECIST (>40% decrease SLD) and ascites resolution• Complete resection by Fritz Eilber, MD (UCLA)

Post Cycle 4Baseline CT Baseline CT Post Cycle 4

Pathologic Response

Pre-Treatment Post-Treatment

Courtesy of Scott Nelson, MD (UCLA)

• Kaplan-Meier plot for progression-free survival (PFS)– Median PFS was 6.7 months (95% CI: 6.2 to 8.1 months)– 3-month progression-free rate (PFR) was 83%. The 6-month PFR was 63%.

 

Study TH-CR-403: Progression-free Survival (PFS)

• Kaplan-Meier plot for overall survival (OS)– Median OS was 17.5 months (95% CI: 16.1 months to not reached)– 6-month survival rate was 93% and 12-month survival rate was 70%.

 

Study TH-CR-403, Efficacy: Overall Survival

• The regimen was generally well tolerated with hematologic toxicity the most dose limiting

• The response rate, PFS and OS appear to be higher than expected for single agent doxorubicin:- Overall response rate 36%- Median PFS 6.7 months (95% CI: 6.2 to 8.1 months)- Median OS 17.5 months (95% CI: 16.1 months to not reached)

• Further investigations of TH-302 plus doxorubicin are warranted. In collaboration with SARC , an international randomized controlled Phase 3 study of TH-302 plus doxorubicin versus doxorubicin is now open.

ACKNOWLEDGEMENTSWe thank the patients, families and investigative site personnel for their participation.We would like to acknowledge the contributions of John Curd, MD to this study.

Study TH-CR-403: Conclusions