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 Anticancer agents
Pancreatic Cancer
Therapy
Biological Therapy
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.