Safety Study of IPI-504 in Patients With Gastrointestinal Stromal Tumors (GIST) or Soft Tissue Sarcomas (STS)

Study Overview
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Brief Summary
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The primary objectives of the study are: Determine the safety and maximum tolerated dose (MTD) of IPI-504 in GIST and STS patients who have failed prior therapies Recommend a dose for subsequent studies of IPI-504

Detailed Description
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IPI-504 is a novel, water-soluble analog of 17-AAG and a potent inhibitor of Hsp90. Hsp90's role in the cell is to control the proper folding, function, and viability of various client proteins. Many of these client proteins (such as AKT, Her-2, Bcr-Abl, PDGFR-α, and c-Kit) are oncoproteins or important cell signaling proteins. In patients with GIST, mutations in the tyrosine kinase receptor Kit play a critical role in the pathogenesis of this disease. Inhibition of Kit signaling with the tyrosine kinase inhibitor Imatinib (IM) is a very effective treatment for GIST patients. However, new mutations arise in Kit conferring resistance to IM treatment which results in disease progression. Kit is a client protein of Hsp90 and is sensitive to IPI-504. In Soft Tissue Sarcomas, there may be genetic abnormalities that lead to the expression of certain proteins that drive the growth of cancer. These cancer-driving proteins may be stimulated by HSP90. This provides a scientific rationale for Phase 1 clinical testing of IPI-504 in patients with advanced GIST and STS who have failed prior therapies.

Official Title
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A Phase 1, Safety Assessment and Pharmacokinetic Study of IPI-504 in Patients With Either Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GIST) or Advanced or Metastatic Soft Tissue Sarcomas (STS)

Conditions
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Gastrointestinal Stromal Tumors, Soft Tissue Sarcomas

Intervention / Treatment
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* Drug: IPI-504


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed diagnosis of GIST or STS Failed prior therapies ECOG performance status of 0-2 Ability to adhere to the study visit schedule and all protocol requirements Exclusion Criteria: Previous treatment with 17-AAG, DMAG, or other known Hsp90 inhibitor Participation in any investigational drug study or treatment with any other kinase inhibitor therapy within 2 weeks preceding start of treatment Concurrent radiation therapy is not permitted Concurrent treatment with any agent that alters CYP3A activity Concurrent treatment with any agent that may prolong the QTc interval Myocardial infarction or active ischemic heart disease within 6 months History of arrhythmia Baseline QTc >450 Grade 3 or greater peripheral neuropathy Renal insufficiency, serum creatinine >1.5 x ULN Platelets < 100,000 mm3 AST and / or ALT > 2.5 x ULN ANC <1,500 cells/mm3 Alkaline phosphatase > 2.5 x ULN Amylase and lipase > 1.5 x ULN Hemoglobin < 9.0 g/dL

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Schedule A: Doses occur on Days 1, 4, 8, and 11 followed by 10 days with no study drug administration. | Drug: IPI-504<br>* IV administration of IPI-504 for 21-day cycles. Two different schedules of treatment will be tested. On Schedule A, doses occur on Days 1, 4, 8, and 11 followed by 10 days with no study drug administration. On Schedule B, doses occur on Days 1, 4, 8, 11, 15, and 18, or twice weekly for 3 weeks continuously. For both Schedule A and B doses will be administered ≥ 72 hours apart.<br>|
| Experimental: 2<br>Schedule B: Doses occur on Days 1, 4, 8, 11, 15, and 18 (twice weekly for 3 weeks continuously). | Drug: IPI-504<br>* IV administration of IPI-504 for 21-day cycles. Two different schedules of treatment will be tested. On Schedule A, doses occur on Days 1, 4, 8, and 11 followed by 10 days with no study drug administration. On Schedule B, doses occur on Days 1, 4, 8, 11, 15, and 18, or twice weekly for 3 weeks continuously. For both Schedule A and B doses will be administered ≥ 72 hours apart.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety and maximum tolerated dose (MTD) of IPI-504 in GIST and STS patients who have failed prior therapies |  | 18 months | 
| To recommend a dose for subsequent studies of IPI-504 |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To examine the pharmacokinetic (PK) parameters of IPI-504 in GIST and STS patients |  | 18 months | 
| To assess in a preliminary way the potential anti-tumor activity of IPI-504 in GIST and STS. |  | 18 months | 
| To explore potential pharmacodynamic (PD) markers of biologic activity of IPI-504 in GIST and STS. |  | 18 months |