142TiP - Randomized, double-blind, placebo-controlled trial of evofosfamide (TH-302) in combination with pemetrexed in advanced non-squamous non-small cell l...

Date 17 April 2015
Event ELCC 2015
Session Poster lunch
Topics Anti-Cancer Agents & Biologic Therapy
Non-Small-Cell Lung Cancer, Metastatic
Translational Research
Presenter Jonathan Goldman
Citation Annals of Oncology (2015) 26 (suppl_1): 29-44. 10.1093/annonc/mdv050
Authors J. Goldman1, C. Belani2, S. Novello3, J. von Pawel4, T. Csoszi5, S. Orlov6, S. Kroll7, T. Pearce8
  • 1Hematology And Oncology, UCLA, 90404 - Los Angeles/US
  • 2Medical Oncology, Penn State Cancer Institute, Hershey/US
  • 3Oncology, University of Turin, Turin/IT
  • 4Oncology, Asklepios-Fachklinikum, 82131 - Gauting/DE
  • 5Onkologiai, Hetenyi Geza Korhaz, Onkologiai Kozpont, 5004 - Szolnok/HU
  • 6Oncology, Pavlov State Medical University, St. Petersburg/RU
  • 7Clinical Operations & Biostatistics, Threshold Pharmaceuticals, Inc., South San Francisco/US
  • 8Clinical Development, Threshold Pharmaceuticals, Inc., 94080 - South San Francisco/US

Abstract

Background

Tumor hypoxia is associated with chemo- and radioresistance and is a prevalent characteristic in tumors of patients with non-small cell lung cancer (NSCLC). Evofosfamide (TH-302) is a hypoxia activated prodrug designed to release the bis-alkylating DNA crosslinker bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. In a Phase 1/2 study (NCT00743379) that included a single arm evofosfamide in combination with pemetrexed in 18 patients with relapsed/refractory non-squamous NSCLC, median PFS was 7.0 months and median OS was 14.9 months. Response in 15 evaluable patients: 6 partial responses (4 confirmed), 6 stable disease and 3 progressive disease. The most common adverse events were fatigue, anemia, stomatitis and nausea.

Trial design

An international, multicenter, randomized, double-blind, placebo-controlled trial was initiated to evaluate evofosfamide in combination with pemetrexed versus placebo and pemetrexed as a potential second-line treatment for patients with non-squamous NSCLC (NCT02093962). Approximately 440 patients will be enrolled with histologically confirmed stage IIIB or IV NSCLC with non-squamous histology, measureable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients have recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance. EGFR-activating and ALK rearrangements status must be known, and if present, patients must have received a targeted kinase inhibitor. Evofosfamide (400 mg/m2) or matched placebo is administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m2) is administered by IV infusion 2 to 4 hours after evofosfamide administration on Day 1. Overall survival (OS) is the primary endpoint; secondary endpoints include safety, progression-free survival and RECIST response rate. The study design has 85% power to detect a 40% improvement in OS. The first patient was enrolled in June 2014; recruitment is ongoing.

Clinical trial identification NCT02093962, March 18, 2014

Disclosure

S. Novello: AB or lectures: Eli Lilly, Boheringer Ingelheim, Astra Zeneca, Novartis, MSD, Pfizer.

S. Kroll and T. Pearce: employee of Threshold Pharmaceuticals and hold stock and/or stock options.

All other authors have declared no conflicts of interest.