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

• 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.

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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

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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

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Study TH-CR-403 Demographics

• 91 patients initiated treatment between August
  2009 and June 2011

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

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Study TH-CR-403 Deaths/Discontinuations

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

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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
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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.

 N88 Grade 3 Grade 4 Total Grade 3/4
Neutropenia 7 14 20
Thrombocytopenia 15 10 25
Anemia 28 0 28
Hematologic Toxicity per CTCAE v3 (All cycles)
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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 Response

• Maximum Percent Change in SLD of Target Lesions

SD or better rate of 84.
Subject 1 had a 105 increase from baseline.
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Study TH-CR-403, Efficacy RECIST Response

• Best response by sarcoma subgroup classification

    Best Response Best Response Best Response 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.

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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 (gt40 decrease SLD) and ascites
  resolution
• Complete resection by Fritz Eilber, MD (UCLA)

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Pathologic Response

• Pre-Treatment

• Post-Treatment

Courtesy of Scott Nelson, MD (UCLA)
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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. 

 
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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. 

 
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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.