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

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.