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

Information source: Astex Pharmaceuticals
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Gastrointestinal Stromal Tumor (GIST)

Intervention: AT13387 and Imatinib (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: Astex Pharmaceuticals

Official(s) and/or principal investigator(s):
George D Demetri, MD, Principal Investigator, Affiliation: Dana-Farber Cancer Institute

Summary

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.

Clinical Details

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

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Rate of reduction/stabilisation of tumour size at 4 months according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria

Secondary outcome:

Rate of reduction/stabilisation of tumour size at 6 months (6-month 'disease control rate' [DCR]), determined according to RECIST version 1.1 criteria.

Progression-free survival at 6 months, and estimated proportion of patients surviving at 6 months.

Objective responses, using RECIST version 1.1 criteria

Changes in pharmacodynamic biomarkers assessed in tumour biopsies and plasma samples, and changes in tumour metabolism by Fludeoxyglucose - Positron emission tomography scans (FDG-PET).

Relationships between KIT and PDGRFA tumour mutational status, changes in tumour dimensions, and exploratory pharmacodynamic biomarkers.

Pharmacokinetic profile of AT13387 given in combination with imatinib.

Treatment emergent adverse events, classified by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

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 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

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Ability to understand the risks of the study and to provide signed and dated informed

consent and authorization to use protected health information (in accordance with national and local subject privacy regulations).

- Age 18 years or older.

- Unresectable and/or metastatic malignant GIST with objective progression of disease

following treatment with a maximum of 3 tyrosine kinase inhibitors (TKIs) including

imatinib. To clarify, it is the number of TKIs - up to a maximum of three agents,

including imatinib - that is the criterion for entry, not the number of prior courses

of TKI treatment.

- Measurable disease.

- ECOG performance status 0 or 1.

- Negative blood or urine pregnancy test (within 7 days prior to commencing treatment),

or documented evidence of surgical sterility, or natural or treatment-induced post-menopausal status with last menses >1 year ago.

- 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:

- Pregnancy or lactation (women of childbearing potential must have a negative serum or

urine pregnancy test within 7 days prior to commencing treatment ). Male and female patients of childbearing potential must use appropriate birth control (abstinence, barrier methods, oral contraceptives and/or intrauterine devices) during the entire duration of the study, or the patient must be surgically sterile (with documentation in the patient's medical records).

- Impaired liver function, as evidenced by prior liver segmentectomy or

hemi-hepatectomy; or alanine or aspartate aminotransferase (ALAT/ASAT) >2. 5x ULN; or alkaline phosphatase >2. 0x ULN; or bilirubin >2. 0x ULN.

- Abnormal clotting, as evidenced by PT or PTT >1. 5x ULN, or therapeutic/prophylactic

anticoagulation.

- Renal impairment, defined as either serum creatinine higher than the institution

ULN,or estimated creatinine clearance lower than LLN (i. e. patients should have both normal serum creatinine, and normal estimated creatinine clearance)

- Impaired marrow function, defined as haemoglobin <9. 0 g/dL, neutrophils <1. 5 x10^9/L,

or platelets <100 x10^9/L. Patients may receive a blood transfusion for anaemia to allow entry to the study but should not be transfusion-dependent.

- Left ventricular ejection fraction <50% on echocardiography or MUGA scan.

- Known metastases of the central nervous system.

- 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.

- Major surgery within 14 days prior to treatment with study drug, or failure to

recover from the effects of such surgery.

- Wide field radiotherapy within 4 weeks prior to treatment with study drug, limited

field radiation within 2 weeks, or failure to recover from such therapies.

- History of an ischaemic cardiac event or unstable cardiac disease within 3 months of

study entry.

- QTc >450 ms using Fredericia's correction.

- Previous malignancy, except for basal cell and squamous cell skin carcinomas or

carcinoma of the uterine cervix, unless treated with curative intent more than 2 years prior to study entry.

- Evidence of severe or uncontrolled systemic medical conditions which make it

undesirable for the patient to take part in the study, or which could jeopardize protocol compliance. Patients with multiple comorbidities and/or requiring multiple concomitant medications (especially conditions/medications which may impair renal function or predispose to renal impairment) should be discussed with the Astex Medical Monitor at the discretion of the Investigator before enrollment.

- Prior history of infection with HIV, or known active hepatitis B or C viral infection

(active screening for viral infections is not required for study entry).

- Significant visual impairment such that in the opinion of the investigator, further

minor deterioration would have unacceptable consequences (eg. loss of ability to drive or live at home.

- The Safety Monitoring Committee may add other specific exclusion criteria to enhance

the safety of the patients based on emerging safety data.

Locations and Contacts

Arizona Cancer Center at UMC North, Tucson, Arizona 85719, United States

Robert H. Lurie Cancer Center of Northwestern University, Chicago, Illinois 60611, United States

Johns Hopkins University, Baltimore, Maryland 21231, United States

Dana-Farber Cancer Institute, Boston, Massachusetts 02459, United States

Duke University Medical Center, Durham, North Carolina 27710, United States

Oregon Health and Sciences University, Portland, Oregon 97239, United States

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111-2412, United States

University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402, United States

Additional Information

Starting date: March 2011
Last updated: March 9, 2015

Page last updated: August 23, 2015

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