Transcript Title of Module/Lecture

A PHASE 2 STUDY OF TH-302
IN COMBINATION WITH DOXORUBICIN
IN ADVANCED SOFT TISSUE SARCOMA
Sant P Chawla, MD
Sarcoma 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.
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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0.5% O
5% OO22
5%
10%OO22
10%
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
Study TH-CR-403: Demographics
91 patients initiated treatment between August 2009 and June 2011
Characteristic
Gender (N)
Female/Male
53/38
Median
Range
57
23-78
ECOG (N/%)
0
1
45%
55%
Prior adjuvant /neoadjuvant
therapy (%)
Yes
16%
Leiomyosarcoma
Unclassified/MFH
Liposarcoma
Angiosarcoma
Fibrosarcoma
Synovial sarcoma
Other*
31%
31%
21%
3%
3%
3%
8%
Age (years)
Histology (%)
Disease Status (%)
Locally Advanced Unresectable
18%
Metastatic
82%
*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
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.
N=88
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)
Other Laboratory Data
• There has been no evidence of renal, liver or
cardiac toxicity related to TH-302 and no other
consistent laboratory abnormalities.
Study TH-CR-403, Efficacy: RECIST Response
Maximum Percent Change in SLD of Target Lesions
60
50
40
30
20
10
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21222324 2526 27282930 31323334 3536 37383940 41424344 4546 474849 50 5152 53 54 55 56 57 58 5960 61626364 6566 676869 70 7172 73 74 75 76 77 78 7980 81828384 8586 878889
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
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 Doxorubicin
Case Report in Patient with Metastatic Leiomyosarcoma
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)
Post Cycle 4
Pathologic Response
Pre-Treatment
Courtesy of Scott Nelson, MD (UCLA)
Post-Treatment
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%.
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%.
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.