Description:
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 I enrollment has been closed.
Phase 2: To determine the clinical benefit of ganetespib in combination with sirolimus for
patients with unresectable or metastatic sporadic or NF1 associated MPNST.
Title
- Brief Title: SARC023: Ganetespib and Sirolimus in Patients With MPNST (Malignant Peripheral Nerve Sheath Tumors)
- Official Title: A Phase I/II Trial of Ganetespib in Combination With the mTOR Inhibitor Sirolimus for Patients With Recurrent or Refractory Sarcomas Including Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors
Clinical Trial IDs
- ORG STUDY ID:
SARC023
- SECONDARY ID:
CDMRP-NF120087
- NCT ID:
NCT02008877
Conditions
- Malignant Peripheral Nerve Sheath Tumors (MPNST)
- Sarcoma
Interventions
Drug | Synonyms | Arms |
---|
ganetespib | STA-9090 | ganetespib / sirolimus |
Sirolimus | Rapamycin | ganetespib / sirolimus |
Purpose
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 I enrollment has been closed.
Phase 2: To determine the clinical benefit of ganetespib in combination with sirolimus for
patients with unresectable or metastatic sporadic or NF1 associated MPNST.
Detailed Description
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.
Trial Arms
Name | Type | Description | Interventions |
---|
ganetespib / sirolimus | Experimental | 28-day cycles of ganetespib + sirolimus | |
Eligibility Criteria
Inclusion Criteria:
- Patients ≥ 16 years old
- Patients with unresectable or metastatic histologically confirmed sporadic or NF1
associated high grade MPNST
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- Patients must have at least 1 measurable tumor
- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy (toxicity < grade 2)
- Must be able to swallow whole pills
- Adequate organ function
- Normal fasting cholesterol and triglycerides
- May be on cholesterol medications
Exclusion Criteria:
- Patients receiving current treatment with corticosteroids or another
immunosuppressive. Topical or inhaled corticosteroids are allowed.
- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases
- Symptomatic congestive heart failure
- Severely impaired lung function
- Significant vascular disease
- Uncontrolled diabetes
- Active (acute or chronic) or uncontrolled severe infections hepatitis
- Impairment of gastrointestinal function
- Patients with an active, bleeding diathesis or significant coagulopathy
- Use of cytochrome P450 isoenzyme 3A4 (CYP3A4)/ CYP2C19 substrates
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 16 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Number of Dose Limiting Toxicities of Ganetespib When Administered in Combination With Sirolimus. |
Time Frame: | Toxicities will be evaluated over the first treatment cycle (each cycle=28 days) |
Safety Issue: | |
Description: | To assess the safety, tolerability, and maximum tolerated/ recommended dose of ganetespib when administered in combination with sirolimus in patients with refractory sarcomas or unresectable or metastatic sporadic or neurofibromatosis type 1 (NF1) associated MPNST. Toxicities observed during the first cycle will be used to define the MTD/Recommended dose. Toxicity will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. DLT will be defined as any of the following events that are possibly, probably, or definitely attributable to ganetespib or sirolimus. The DLT observation period for the purposes of dose escalation will be the first cycle of therapy. |
Secondary Outcome Measures
Measure: | Change in Plasma Pharmacokinetic Profile of Ganetespib and Sirolimus When Administered in Combination-Observed Maximum Plasma Concentration (Cmax) |
Time Frame: | Pre-therapy levels drawn at baseline and pharmacokinetic analysis occurs on Cycle 1 Day 15 |
Safety Issue: | |
Description: | To describe the plasma pharmacokinetic profile of ganetespib and sirolimus when administered in combination therapy. |
Measure: | Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells |
Time Frame: | Baseline and Cycle 1 Day 15 |
Safety Issue: | |
Description: | To explore changes in pharmacodynamic parameters in peripheral blood mononuclear cells performed on day 1 prior to ganetespib and sirolimus administration, and on day 15, 6 hours post drug administration. Hsp inhibition (Hsp70), mTOR inhibition (phospho-S6 and Akt Phosphorylation), UPR activation (EIF2alpha phosphorylation) will be explored. Western blot analyses were performed for phospho (p)-Akt, p-eIF2α, p-S6, and Hsp70. The absorbance of each phosphoprotein lane was recorded and protein levels were determined after normalizing for levels of corresponding total protein. |
Measure: | Patient-reported Pain Severity and the Impact of Pain on Daily Activities |
Time Frame: | Baseline and prior to Cycle 3 |
Safety Issue: | |
Description: | To assess patient-reported pain severity and the impact of pain on daily activities before and during treatment with ganetespib and sirolimus. The Numerical Rating Scale-11 (NRS-11) will be used to assess pain severity. The NRS-11 is a self-report segmented 11-point numeric scale that assesses pain severity. It consists of a horizontal line with 0 representing "no pain" at the right end of the line and 10 representing "worst pain you can imagine" at the left end.The Brief Pain Inventory is a 7-item self-report questionnaire that measures the extent to which pain interferes with daily functioning. Patients are asked to indicate how much pain interfered with various activities in the past week, with scores ranging from 0 (does not interfere) to 10 (completely interferes). A total score is obtained by taking the mean of the scores for all 7 items; thus, the total pain interference score can range from 0 to 10. |
Measure: | Utility of Three-dimensional MRI (3D-MRI) Analysis in Comparison to 1-dimensional and 2-dimensional Measurements |
Time Frame: | 4 months |
Safety Issue: | |
Description: | To evaluate the utility of three-dimensional MRI (3D-MRI) analysis in comparison to 1-dimensional and 2-dimensional measurements as a method to more sensitively monitor response. |
Measure: | Plasma Pharmacokinetic Profile of Ganetespib When Administered in Combination With Sirolimus |
Time Frame: | Cycle 1 Day 15 |
Safety Issue: | |
Description: | To describe the plasma pharmacokinetic profile of ganetespib in terms of half life. |
Measure: | Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib |
Time Frame: | Phase 1 of study |
Safety Issue: | |
Description: | A conventional 3+3 dose escalation design was used for phase 1. All patients in phase 2 were treated with the recommended dose. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Completed |
Lead Sponsor: | Sarcoma Alliance for Research through Collaboration |
Trial Keywords
- Malignant Peripheral Nerve Sheath Tumors
- MPNST
- Sarcoma
- Ganetespib
- Sirolimus
- mTOR inhibitor
- Heat shock protein
- Hsp90
Last Updated
May 15, 2019