666O - TH-302 + gemcitabine (G+T) vs gemcitabine (G) in patients with previously untreated advanced pancreatic cancer (PAC)

Date 29 September 2012
Event ESMO Congress 2012
Session Gastrointestinal tumors, non-colorectal
Topics Anti-Cancer Agents & Biologic Therapy
Pancreatic Cancer
Presenter Mitesh Borad
Authors M. Borad1, S. Reddy2, N. Bahary3, H. Uronis4, D.S. Sigal5, A.L. Cohn6, W. Schelman7, J. Stephenson, Jr8, C. Eng9, D.P. Ryan10
  • 1Hematology/oncology, Mayo Clinic Cancer Center - Arizona, Scottsdale/US
  • 2Oncology, Louisiana State University Health Sciences Center, Shreveport/US
  • 3Oncology, University of Pittsburgh Medical Center, Pittsburgh/US
  • 4Oncology, Duke University, Durham/US
  • 5Oncology, Scripps Clinical Medical Group, La Jolla/US
  • 6Oncology, Rocky Mountain Cancer Centers, Denver/US
  • 7Oncology, University of Wisconsin, Madison/US
  • 8Oncology, Institute for Translational Oncology Research, Greenville/US
  • 9Clinical Development, Threshold Pharmaceuticals, 94080 - South San Francisco/US
  • 10Oncology, Massachusetts General Hospital, Boston/US

 

Abstract

Background

TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC.

Materials and methods

An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G + T arm. The primary efficacy endpoint was a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Summary PFS outcome has previously been reported; more detailed PFS as well as the initial overall survival (OS) data are presented.

Results

214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer prognostic factors (older age, poorer performance status, reduced albumin) were associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G + T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G + T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 and 59% G + T340.

Conclusions

The combination of G plus TH-302 improved the efficacy of G. A TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation.

Disclosure

All authors have declared no conflicts of interest.