A Study to Investigate the Safety and Efficacy of AT13387, Alone or in Combination With Imatinib, in Patients With GIST

A Study to Investigate the Safety and Efficacy of AT13387, Alone or in Combination With Imatinib, in Patients With GIST

Gastrointestinal Stromal Tumor

Completed

2

Start Date 03/01/2011

Age of Trial (yrs) 13.7

Gleevec-resistant

KIT/PDGFRA inhibitor + HSP90 inhibitor

Specifically GIST and only GIST

AT13387/0002

Astex Therapeutics

Valerie Ahanonu 925-560-0100 valerie.ahanonu@astx.com Gavin Choy 925-560-0100 gavin.choy@astx.com

Randomized

Oral Intravenous

The purpose of this study is to investigate if an investigational drug called AT13387 is active against GIST that is resistant to other treatments, and to understand more about the safety of AT13387.

Most subjects in the study will receive AT13387 along with another drug called imatinib (Gleevec). Imatinib is a standard (approved) drug for treating patients with GIST. Some patients may receive AT13387 on its own. As a result, we shall begin to understand the effects of AT13387 given on its own and when combined with imatinib.We shall also find out more about the side-effects of AT13387, and more about how the body breaks down (metabolizes) AT13387.

During part 1 of the study pts will receive AT13387 in combination with imatinib. Up to 5 possible dose levels of AT13387 could be evaluated in combination with imatinib 400 mg daily: 120 mg/m2, 150 mg/m2, 180 mg/m2, 220 mg/m2 and 260 mg/m2. AT13387 IV (in the vein) on day 1, 8 and 15 of each 28 day cycle, until progression or unacceptable toxicity develops, in order to establish the recommended phase II combination dose, which will be used in part 2 and/or part 3 of the study.

In part 2, an additional 6-9pts will be treated.

In part 3, provided that sufficient evidence of anti-tumour effect was observed in part 2 (disease stabilisation or reduction in tumour dimensions by RECIST), then an additional 12pts will be treated with AT13387 in combination with imatinib. Alternatively, if combination treatment is found to have excellent efficacy the randomised phase of the study may start so that 12 pts receive AT13387 monotherapy and 12 pts receive AT13387 in combination with imatinib.

Detailed Description:

The study consists of 3 parts: Part 1 is a dose escalation phase, Part 2 is a dose expansion phase and Part 3 is either a further dose expansion phase or a randomised phase in which half the patients receive AT13387 monotherapy and half continue to receive AT13387 in combination with imatinib.

All patients with receive AT13387 given by intravenous infusion on Days 1, 8, and 15 of a 28-day cycle. Most patients will also receive imatinib 400 mg by mouth every day.

Patients will have tumour imaging at baseline, and at 2, 4 and 6 months, and then at 2 month intervals until cycle 12, and then 3-monthly thereafter.

Blood samples will be taken to measure plasma drug levels of AT13387 given in combination with imatinib

Inclusion criteria include: Willing to provide a tissue block or unstained slides of archived tumour for central pathology review and genotyping, or a full pathology report and results of genotyping of a previous tumour sample, or willing to undergo a new tumour biopsy for central pathology review and genotyping during the screening period of the study (prior to dosing)

Exclusion Criteria include: # Prior anticancer therapies including tyrosine kinase inhibitors (other than imatinib) not completed within 2 weeks or 5 half-lives of the agent (including known active metabolites) prior to treatment with study drug. Patients receiving imatinib should continue to receive imatinib (400 mg daily) throughout the screening period.
# Clinically important intolerance or safety concerns with prior use of imatinib 400 mg daily.
# Prior treatment with an HSP90 inhibitor.