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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.

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sarc021
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
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
hypoxia activated prodrugs haps

3

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
Chemotherapy Targets Oxygenated Tumor Compartment

Vessels: Red

Doxorubicin: Blue

Hypoxia: Green

Minchinton, A. and Tannock, I. Nat. Rev. Cancer. 6: 583-92, 2006 Mouse mammary tumor

slide5

5

Chemistry Strategy for Targeting HypoxiaHypoxia-Activated Prodrugs (HAPs)

TH-302

TH-302

e.g. NADPH-cytochrome

P450 reductase

O

e.g. NADPH-cytochrome

P450 reductase

O

O

2

superoxide

2

2

•-

•-

•-

Radical

anion

Further reduction

Radical

anion

Fragmentation

- Non-toxic prodrug reduced to

radical anion (by 1e- reductase)

- Back-oxidation to the original

compound in presence of O2

and production of superoxide

Hydroxyl

amine

Br-IPM

chemistry strategy for targeting hypoxia h ypoxia a ctivated p rodrug s haps

6

Chemistry Strategy for Targeting HypoxiaHypoxia-Activated Prodrugs (HAPs)

0% O2

0.5% O2

Chemotherapy

TH-302

5% O2

10% O2

Blood vessel

Normoxic zone

Hypoxic zone

slide7

TH-302 + Doxorubicin in Soft Tissue Sarcoma The 403 Phase 1/2 Trial: 84% of Patients Experienced SD or Better (10/27/11)

Waterfall Plot: Change in Target Lesion Diameters

phase 2 response by sarcoma subtype
Phase 2 Response by Sarcoma Subtype

Response rate (CR + PR): 36%

slide9

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
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

* 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
TH-302 Maintenance in Soft Tissue Sarcoma- Progression-free Survival

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)

Figure 1B: Progression-free Survival after Initiating Maintenance (N=48)

slide12

SARC021

Schema

Eligible Patients (N=450)

≥ 15 Years of Age

Locally Advanced Unresectableor Metastatic Soft Tissue Sarcoma

Stratification/Randomization

TH-302 + Doxorubicin

21 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

Doxorubicin

21 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
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
Thank You
  • William Tap, MD

Memorial Sloan-Kettering Cancer Ctr/SARC

P: 646-888-4163

tapw@mskcc.org

  • Denise Reinke, MS, NP

SARC

P: 734-930-7600

dreinke@sarctrials.org

  • Clarence Eng

Threshold

P: 650-474-8222

ceng@thresholdpharm.com

  • Katherine RandolphPAREXEL InternationalP:858-487-8259

Katherine.Randolph@parexel.com

Who to contact if interested or with questions: