A Study to Investigate the Safety and Efficacy of AT13387, Alone or in Combination With Imatinib, in Patients With GIST
The purpose of this study is to investigate if an investigational drug called AT13387 is active against Gastrointestinal Stromal Tumor (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.
Gastrointestinal Stromal Tumor (GIST)
Drug: AT13387 and Imatinib
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||An Open-Label, Randomised, Multi-Centre, Phase II Study to Investigate the Safety and Efficacy of AT13387, Either as Monotherapy or in Combination With Imatinib, in Patients With Unresectable and/or Metastatic Malignant GIST Whose Tumour Has Progressed Following Treatment With a Maximum of Three Tyrosine Kinase Inhibitors|
- Rate of reduction/stabilisation of tumour size at 4 months according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria [ Time Frame: 4 months ] [ Designated as safety issue: No ]
- Rate of reduction/stabilisation of tumour size at 6 months (6-month 'disease control rate' [DCR]), determined according to RECIST version 1.1 criteria. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Progression-free survival at 6 months, and estimated proportion of patients surviving at 6 months. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Objective responses, using RECIST version 1.1 criteria [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Changes in pharmacodynamic biomarkers assessed in tumour biopsies and plasma samples, and changes in tumour metabolism by Fludeoxyglucose - Positron emission tomography scans (FDG-PET). [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Relationships between KIT and PDGRFA tumour mutational status, changes in tumour dimensions, and exploratory pharmacodynamic biomarkers. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Pharmacokinetic profile of AT13387 given in combination with imatinib. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Treatment emergent adverse events, classified by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
|Study Start Date:||March 2011|
|Estimated Study Completion Date:||August 2013|
|Estimated Primary Completion Date:||May 2013 (Final data collection date for primary outcome measure)|
Drug: AT13387 and Imatinib
In part 1 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 on its own (monotherapy) and 12 pts receive AT13387 in combination with imatinib.
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 will 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
|United States, Arizona|
|Arizona Cancer Center at UMC North|
|Tucson, Arizona, United States, 85719|
|United States, Illinois|
|Robert H. Lurie Cancer Center of Northwestern University|
|Chicago, Illinois, United States, 60611|
|United States, Maryland|
|Johns Hopkins University|
|Baltimore, Maryland, United States, 21231|
|United States, Massachusetts|
|Dana-Farber Cancer Institute|
|Boston, Massachusetts, United States, 02459|
|United States, North Carolina|
|Duke University Medical Center|
|Durham, North Carolina, United States, 27710|
|United States, Oregon|
|Oregon Health and Sciences University|
|Portland, Oregon, United States, 97239|
|United States, Pennsylvania|
|Fox Chase Cancer Center|
|Philadelphia, Pennsylvania, United States, 19111-2412|
|United States, Texas|
|University of Texas MD Anderson Cancer Center|
|Houston, Texas, United States, 77230-1402|
|Principal Investigator:||George D Demetri, MD||Dana-Farber Cancer Institute|