sarc021
DESCRIPTION
SARC021. A Randomized Phase 3, Multicenter, Open-Label Study Comparing TH-302 in Combination with Doxorubicin vs. Doxorubicin Alone in Subjects with Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma PI: William Tap, MD Memorial Sloan-Kettering Cancer Center. - PowerPoint PPT PresentationTRANSCRIPT
SARC021
A Randomized Phase 3, Multicenter, Open-Label Study Comparing TH-302 in Combination with Doxorubicin vs.
Doxorubicin Alone in Subjects with Locally Advanced Unresectable or Metastatic Soft
Tissue Sarcoma
PI: William Tap, MD Memorial Sloan-Kettering Cancer Center
TH-302 Combination Therapy in Soft Tissue Sarcoma Phase 3 Study Design
Collaborative Trial by Threshold Pharmaceuticals and Sarcoma Alliance for Research through Collaboration (SARC)
Trial managed (including data management) by PAREXEL
An Independent Data Monitoring Committee (IDMC) will monitor the safety and efficacy. (Ron Blum)
An Independent Review Facility will be used to collect radiographs and may be used to independently evaluate tumor response and PFS
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Hypoxia Activated Prodrugs (HAPs)
Hypoxia-activated prodrugs (HAPs) selectively target hypoxic tumor cells
Hypoxia is a feature of solid tumors
Associated with a worse prognosis
Associated with an aggressive phenotype, invasiveness, metastasis, and relapse
Often underlies treatment failure
HAPs should complement conventional cancer therapies
Chemotherapy Targets Oxygenated Tumor Compartment
Vessels: RedDoxorubicin: BlueHypoxia: Green
Minchinton, A. and Tannock, I. Nat. Rev. Cancer. 6: 583-92, 2006 Mouse mammary tumor
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PHN
O NH
O
N
NO2N
Br
Br
PHN
O NH
O
N
NN
Br
Br
O
O
e.g. NADPH-cytochrome P450 reductase O2 O2
superoxide
TH-302
Radical anion
- Non-toxic prodrug reduced to radical anion (by 1e- reductase)
- Back-oxidation to the original compound in presence of O2
and production of superoxide
•-
PHN
O NH
O
N
NO2N
Br
Br
PHN
O NH
O
N
NN
Br
Br
O
O
e.g. NADPH-cytochrome P450 reductase O2
TH-302
•-•-
PHN
O NH
O
N
NHN
Br
Br
HO
PHN
O NH
HO
Br
Br
Radical anion
Hydroxyl amine
Br-IPM
Further reduction
Fragmentation
Chemistry Strategy for Targeting HypoxiaHypoxia-Activated Prodrugs (HAPs)
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Chemistry Strategy for Targeting HypoxiaHypoxia-Activated Prodrugs (HAPs)
10% O2
5% O2
0.5% O2
10% O2
5% O2
0.5% O2
0% O2
0.5% O2
5% O2
10% O2
Blood vessel
Normoxic zone Hypoxic zone
TH-302Chemotherapy
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
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50
60
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Waterfall Plot: Change in Target Lesion Diameters
TH-302 + Doxorubicin in Soft Tissue Sarcoma The 403 Phase 1/2 Trial: 84% of Patients Experienced SD or Better (10/27/11)
Phase 2 Response by Sarcoma Subtype
Response rate (CR + PR): 36%
TH-302 MAINTENANCE FOLLOWING TH-302 PLUS DOXORUBICIN INDUCTION: THE RESULTS OF A
PHASE 2 STUDY OF TH-302 IN COMBINATION WITH DOXORUBICIN IN SOFT TISSUE SARCOMA
Ganjoo KN1, Cranmer LD2, Van Tine B3, Reed DR4, Okuno SH5, Butrynski JE6, Adkins D3, Hendifar A7, Chu ED8, Kroll SM8, Chawla SP7
1. Stanford University Medical Center, Stanford, CA, USA; 2. Arizona Cancer Center, Tucson, AZ, USA; 3. Washington University, St. Louis, MO, USA; 4. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 5. Mayo Clinic, Rochester, MN, USA; 6. Dana-Farber Cancer Institute, Boston, MA, USA; 7.
Sarcoma Oncology Center, Santa Monica, CA, USA; 8. Threshold Pharmaceuticals, South San Francisco, CA, USA.
Update on Overall Survival of 91 pts and Maintenance of 48 pts
TH-302 Maintenance in Soft Tissue Sarcoma- Response Rates
Response Rates:•Overall response rate for 48 subjects receiving maintenance was 44% prior to receiving maintenance and 54% including both induction and maintenance.
•During the maintenance portion of the study 6 subjects had an upgrade in response category:• 5 SDs converting to PR• 1 PR converting to CR
Table 5: Best Response (Unconfirmed) to Overall Treatment
All(N=91*)
Maintenance after Induction (N=48)
Maintenance (N=48)
Best Response Complete Response 2 (2%) 1 (2%) 2 (4%) Partial Response 30 (34%) 20 (42%) 24 (50%) Stable Disease 43 (48%) 27 (56%) 22 (46%) Progressive Disease 14(16%) 0 (0%) 0 (0%)Overall Response Rate (RR) (Partial Response + Complete Response) 32 (36%) 21 (44%) 26(54%)
* Two patients discontinued with reason subject decision (1) and PI decision (1) prior to initial tumor response assessment.
TH-302 Maintenance in Soft Tissue Sarcoma- Progression-free Survival
Figure 1B: Progression-free Survival after Initiating Maintenance (N=48)
Progression-free Survival: •The median PFS on study was 6.7 months (95% CI: 6.2 to 7.8 months). Figure 1A. •The median PFS after TH-302 maintenance was 3.7 months (95% CI: 2.5 to 5.5 months). Figure1B.
Figure 1A: Progression-free Survival on Study (N=91)
Months from Cycle 1 Day 1
Pro
porti
on P
rogr
essi
on-fr
ee
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Kaplan-Meier Estimate95% Confidence Limits
Months from Cycle 7 Day 1
Pro
porti
on P
rogr
essi
on-fr
ee
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Kaplan-Meier Estimate95% Confidence Limits
SARC021Schema Eligible Patients (N=450)
≥ 15 Years of AgeLocally Advanced Unresectable or Metastatic Soft Tissue
Sarcoma
Stratification/Randomization
TH-302 + Doxorubicin21 Day Cycle
Day 1 = TH-302 (300 mg/m2) and Doxorubicin (75 mg/m2)
Day 8 = Th-302 (300 mg/m2) andDay 8 or Day 9 = G-CSF
Doxorubicin21 Day Cycle
Day 1 = Doxorubicin (75 mg/m2)
Response evaluations end of cycles 2, 4 and 6 until progression or discontinuation
Note: Patient continues monotherapy TH-302 maintenance after cycle 6 without doxorubicin and G-CSF until discontinuation
Response evaluations end of cycles 2, 4 and 6 until progression or discontinuation
Note: Patient is discontinued after cycle 6
Survival Follow-up
TH-302 Combination Therapy in Soft Tissue Sarcoma Phase 3 Study Status
Approximately 25% of 450 subjects enrolled Approximately 50% of planned sites now active Sites open in Belgium, Canada, Germany, Israel, Italy,
Hungary, Poland, Spain and United States Sites soon to open in Austria, Denmark, France and Russia Initial PFS futility analysis (113 events) projected to occur in
2nd quarter of 2013 Enrollment on schedule to be completed by end of 2013 Initial OS interim for early efficacy stoppage (175 deaths)
projected for end of 2013 Primary analysis (323 deaths) projected for end of
2014/beginning of 2015
Thank You
William Tap, MD Memorial Sloan-Kettering Cancer Ctr/SARCP: [email protected]
Denise Reinke, MS, NPSARCP: [email protected]
Clarence EngThresholdP: [email protected]
Katherine RandolphPAREXEL InternationalP:[email protected]
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Who to contact if interested or with questions: