A Trial of Ganetespib Plus Sirolimus: Phase 1 Includes Multiple Sarcoma Subtypes and Phase 2 MPNST
Phase 1: To assess the safety, tolerability, and maximum tolerated dose (MTD)/ recommended dose of ganetespib when administered in combination with sirolimus in patients with refractory or relapsed sarcomas including unresectable or metastatic sporadic or neurofibromatosis type 1 (NF1) associated MPNST.
Phase 2: To determine the clinical benefit of ganetespib in combination with sirolimus for patients with unresectable or metastatic sporadic or NF1 associated MPNST.
Malignant Peripheral Nerve Sheath Tumors (MPNST)
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 1/Phase 2 Trial of Ganetespib in Combination With the mTOR Inhibitor Sirolimus for Patients With Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors (MPNST)|
- Grade the toxicity of ganetespib when administered in combination with sirolimus. [ Time Frame: Toxicities will be evaluated each 28 day cycle for a maximum of 1 year (13 cycles). ] [ Designated as safety issue: Yes ]
- Clinical benefit of combined study drugs. [ Time Frame: 4 months ] [ Designated as safety issue: No ]Assessed using the World Health Organization (WHO) criteria. Tumor assessments will be obtained every 2 cycles. Clinical benefit is defined as stable disease, Partial Response (PR), Complete Response (CR).
|Study Start Date:||December 2013|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||June 2017 (Final data collection date for primary outcome measure)|
Experimental: ganetespib/ sirolimus
28-day cycles of ganetespib + sirolimus
150 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour
Other Name: STA-9090Drug: Sirolimus
4mg (4 X 1mg tablets) taken orally once daily on a continuous dosing schedule
Other Name: Rapamycin
Previously, no targeted agents have been able to cause tumor regression in a genetically engineered MPNST mouse model or human MPNST. Recently published data from Dr. Cichowski's laboratory demonstrated using Hsp90 inhibitors to enhance endoplasmic reticulum stress coupled with the mammalian target of rapamycin (mTOR) inhibitor sirolimus led to dramatic tumor shrinkage in a transgenic MPNST mouse model, which correlated with profound damage to the endoplasmic reticulum and cell death. Ganetespib is a novel, injectable, small molecule inhibitor of Hsp90 and is currently being investigated in adults with a broad range of tumor types with a favorable safety profile and promising early results. Ganetespib has been studied in preclinical in vivo models with a variety of targeted agents with no marked apparent pharmacological interactions. Sirolimus is a commercially available orally administered mTOR inhibitor and is the active metabolite of temsirolimus, which is FDA approved agent for advanced metastatic renal cell carcinoma. Sirolimus has been studied and tolerated in combination with multiple cytotoxic and targeted agents in a variety of tumor types. Based on strong preclinical rationale, the investigators hypothesize that ganetespib in combination with sirolimus will cause tumor regression in patients with refractory MPNSTs.
The investigators propose a multi-institutional open label phase I/II trial of ganetespib in combination with sirolimus in patients with refractory sarcoma including MPNST. Hsp90 inhibitors and mTOR inhibitors have also both demonstrated benefit in a variety of preclinical bone and soft tissue sarcoma models. The investigators hypothesize that these agents that work on separate and potentially synergistic pathways will also be beneficial for other refractory bone and soft tissue sarcomas. Thus, the phase I component will be open to patients with refractory sarcomas, which will also expedite enrollment. Upon determination of the recommended dosing, a phase II study will be conducted. The phase II study population will be limited to patients with a diagnosis of MPNST.
|Contact: Denise Reinke, MS, NPfirstname.lastname@example.org|
|Principal Investigator:||AeRang Kim, MD, PhD||Children's National|
|Principal Investigator:||Brigitte Widemann, MD||National Cancer Institute (NCI)|