Study Evaluating IPI-504 in Patients With Gastrointestinal Stromal Tumors (GIST) Following Failure of at Least Imatinib and Sunitinib

Study Overview
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Brief Summary
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IPI-504-06 is a Phase 3, randomized, double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of IPI-504 as compared to placebo in patients with metastatic and/or unresectable GIST following failure of at least imatinib and sunitinib. Approximately 195 patients will be randomized using a 2:1 ratio to receive either IPI-504 (N=130) or placebo (N=65). Upon unblinding, patients receiving either IPI-504 or placebo may receive IPI-504 in the open-label portion of the study if defined inclusion criteria are met. Early and frequent imaging timepoints (Weeks 2, 5, 8, 14 and every 6 weeks thereafter) are incorporated into this study to capture progression events and limit patient exposure to ineffective agents.

Official Title
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A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study Evaluating the Efficacy and Safety of IPI-504 in Patients With Metastatic and/or Unresectable GIST Following Failure of at Least Imatinib and Sunitinib

Conditions
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Gastrointestinal Stromal Tumors

Intervention / Treatment
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* Drug: retaspimycin hydrochloride (IPI-504)
* Drug: placebo
* Other: Best supportive care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age at the time of study randomization. Histologically confirmed metastatic and/or unresectable GIST. Measurable disease on CT or MRI as defined by RECIST. Documented radiographic progression or intolerance to imatinib and sunitinib. Clinical failure of the most recent prior therapy for GIST. Note: There is no limit to the number of prior therapies a patient may have received. Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1. Hemoglobin ≥ 8.0 g/dL (80 g/L). Absolute Neutrophil Count ≥ 1500/µL (1.5 x 109/L). Platelets ≥ 100,000 /µL (100 x 109/L). ALT and AST ≤ 2.5 x upper limit of normal (ULN), or ≤ 5.0 x ULN if considered secondary to liver metastases. Alkaline phosphatase ≤ 2.5 x ULN, or ≤ 5.0 x ULN if considered secondary to liver metastases. Serum bilirubin ≤ 1.5 x ULN. PT and PTT ≤ 1.5 x ULN unless the patient is receiving warfarin. If the patient is receiving warfarin, the INR must be within therapeutic range. Serum creatinine ≤ 1.5 x ULN. Exclusion Criteria: Previous administration of other known heat shock protein 90 (Hsp90) inhibitors. Surgery, radiotherapy, or lesion ablative procedure to the only area of measurable disease. Initiation or discontinuation of concurrent medication that is a potent CYP3A inhibitor less than 2 weeks prior to administration of IPI-504 or placebo. History of any of the following within the last 6 months: cardiac disease such as acute coronary syndrome or unstable angina, symptomatic congestive heart failure, uncontrolled hypertension, cirrhotic liver disease, cerebrovascular accident, or any other significant co-morbid condition or disease which, in the judgment of the investigator, would place the patient at undue risk or interfere with the study. Grade 3 or 4 hemorrhagic event within the last 6 months. Known human immunodeficiency virus positivity. Sinus bradycardia (resting heart rate < 50 bpm) secondary to intrinsic conduction system disease. QTcF ≥ 470 milliseconds, or previous history of clinically significant QTc prolongation while taking other medications. History of prior malignancies within the past 3 years other than non-melanomatous skin cancers that have been controlled, prostate cancer that has been treated and has not recurred, non-muscle-invasive bladder cancer, and carcinoma in situ of the cervix. Active or recent history (within 3 months) of keratitis or keratoconjunctivitis confirmed by ophthalmology or optometry exam. Presence of Left Bundle Branch Block, Right Bundle Branch Block plus left anterior hemiblock, bifascicular block, or 3rd degree heart block. This does not include patients with a history of these events with adequate control by pacemaker. Known CNS metastases. Women who are pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IPI-504<br>retaspimycin hydrochloride (IPI-504) plus best supportive care | Drug: retaspimycin hydrochloride (IPI-504)<br>* IPI-504 is a novel small molecule inhibitor of heat shock protein 90 (Hsp90). Patients will receive 400 mg/m2 of IPI-504 as a 30-minute IV infusion twice weekly for 2 weeks followed by 1 week off.<br>Other: Best supportive care<br>* Best supportive care will be according to institutional standard, but will not include administration of systemic cancer-specific therapies including chemotherapies, biologic therapies, investigational therapies, TKIs (e.g., imatinib, sunitinib, nilotinib, dasatinib), or local therapies such as surgery, radiotherapy, or lesion ablative therapies.<br>|
| Placebo Comparator: Placebo<br>Placebo plus best supportive care | Drug: placebo<br>* Patients will receive a 30-minute IV infusion twice weekly for 2 weeks followed by 1 week off.<br>Other: Best supportive care<br>* Best supportive care will be according to institutional standard, but will not include administration of systemic cancer-specific therapies including chemotherapies, biologic therapies, investigational therapies, TKIs (e.g., imatinib, sunitinib, nilotinib, dasatinib), or local therapies such as surgery, radiotherapy, or lesion ablative therapies.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the progression free survival (PFS) in both study arms |  | Multiple timepoints | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the disease control rate (DCR) in both arms |  | Multiple timepoints | 
| Compare the time to progression (TTP) in both arms |  | Multiple timepoints | 
| Compare the overall survival (OS) in both arms |  | Continuous | 
| Evaluate the safety and tolerability of IPI-504 in this patient population |  | Signing of the informed consent to 30 days after discontinuation of drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GIST, Metastatic and/or Unresectable Gastrointestinal Stromal