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

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

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.