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

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

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

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  1. A PHASE 2 STUDY OF TH-302 IN COMBINATION WITH DOXORUBICIN IN ADVANCED SOFT TISSUE SARCOMA Sant P Chawla, MDSarcoma Oncology CenterSanta Monica, CASant 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.

  2. 0% O2 0.5% O2 5% O2 10% O2 INTRODUCTION 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

  3. Study TH-CR-403: Phase 2 Study Design • 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

  4. Study TH-CR-403: Demographics 91 patients initiated treatment between August 2009 and June 2011 *Other: chondrosarcoma (4), chordoma, pleomorphic rhabdomyosarcoma, endometrial stromal cell sarcoma.

  5. 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.

  6. Study TH-CR-403: Deaths/Discontinuations • No study drug related deaths • Thirteen discontinuations for an AE

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

  8. Study TH-CR-403, Safety: Laboratory Results • 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)

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

  10. Study TH-CR-403, Efficacy: RECIST Response Maximum Percent Change in SLD of Target Lesions SD or better rate of 84%. *Subject 1 had a 105% increase from baseline.

  11. Study TH-CR-403, Efficacy: RECIST Response • Best response by sarcoma subgroup classification • Response rate of 36%.

  12. Study TH-CR-403: TH-302 in Combination with DoxorubicinCase Report in Patient with Metastatic Leiomyosarcoma Post Cycle 4 Baseline CT Post Cycle 4 Baseline CT • 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)

  13. Pathologic Response Pre-Treatment Post-Treatment Courtesy of Scott Nelson, MD (UCLA)

  14. Study TH-CR-403: Progression-free Survival (PFS) • 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%.

  15. Study TH-CR-403, Efficacy: Overall Survival • 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%. 

  16. Study TH-CR-403: Conclusions • 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. Acknowledgements We 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.

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