SARC023: Ganetespib and Sirolimus in Patients With MPNST (Malignant Peripheral Nerve Sheath Tumors)

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.

• ganetespib (Drug), also known as STA-9090: Phase 1 Dose 1: 150 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Phase 1 Dose 2: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Phase 2: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour
• Sirolimus (Drug), also known as Rapamycin: 4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

Primary outcomes

• Number of Dose Limiting Toxicities of Ganetespib When Administered in Combination With Sirolimus. [Toxicities will be evaluated over the first treatment cycle (each cycle=28 days)]: 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.
• Clinical Benefit of Ganetespib in Combination With Sirolimus [Response evaluations will be performed after every 2 treatment cycles (each cycle=28 days)]: 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). For patients who experience progression by WHO but in the opinion of the treating investigator are deriving benefit from therapy and have not otherwise met off treatment or off study criteria, may continue on treatment as long as patient has not met progression by RECIST 1.1.

Secondary outcomes

• Change in Plasma Pharmacokinetic Profile of Ganetespib and Sirolimus When Administered in Combination-Observed Maximum Plasma Concentration (Cmax) [Pre-therapy levels drawn at baseline and pharmacokinetic analysis occurs on Cycle 1 Day 15]: To describe the plasma pharmacokinetic profile of ganetespib and sirolimus when administered in combination therapy.
• Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells [Baseline and Cycle 1 Day 15]: 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.
• Patient-reported Pain Severity and the Impact of Pain on Daily Activities [Baseline and prior to Cycle 3]: 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.
• Utility of Three-dimensional MRI (3D-MRI) Analysis in Comparison to 1-dimensional and 2-dimensional Measurements [4 months]: 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.
• Plasma Pharmacokinetic Profile of Ganetespib When Administered in Combination With Sirolimus [Cycle 1 Day 15]: To describe the plasma pharmacokinetic profile of ganetespib in terms of half life.
• Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib [Phase 1 of study]: A conventional 3+3 dose escalation design was used for phase 1. All patients in phase 2 were treated with the recommended dose.

Sex: All, ages: 16 Years to any

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

Participant flow

Outcome results

• Number of Dose Limiting Toxicities of Ganetespib When Administered in Combination With Sirolimus. (Primary), Number, DLTs: Ganetespib / Sirolimus 0
• Clinical Benefit of Ganetespib in Combination With Sirolimus (Primary), Count of participants, Participants: Ganetespib / Sirolimus 1
• Change in Plasma Pharmacokinetic Profile of Ganetespib and Sirolimus When Administered in Combination-Observed Maximum Plasma Concentration (Cmax) (Secondary), Mean, ng/mL: Ganetespib / Sirolimus 12.1 +/- 3.6
• Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells (Secondary), Mean, ratio: Ganetespib / Sirolimus 0.81 +/- 0.39
• Patient-reported Pain Severity and the Impact of Pain on Daily Activities (Secondary), Mean, units on a scale: Ganetespib / Sirolimus 7.5 (0 to 10)
• Utility of Three-dimensional MRI (3D-MRI) Analysis in Comparison to 1-dimensional and 2-dimensional Measurements (Secondary)
• Plasma Pharmacokinetic Profile of Ganetespib When Administered in Combination With Sirolimus (Secondary), Mean, hours: Ganetespib / Sirolimus 6.4 +/- 2.1
• Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib (Secondary), Count of participants, Participants: Phase 1 Dose Level 1 3; Phase 1 Dose Level 2 6; Phase 2 10

Adverse events

Time frame: 3 years

Serious adverse events by term

Other adverse events by term

31 more terms not shown.

• Results publication: Kim A, Lu Y, Okuno SH, Reinke D, Maertens O, Perentesis J, Basu M, Wolters PL, De Raedt T, Chawla S, Chugh R, Van Tine BA, O'Sullivan G, Chen A, Cichowski K, Widemann BC. Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I/II Study of Sirolimus in Combination with Ganetespib (SARC023). Sarcoma. 2020 Jan 30;2020:5784876. doi: 10.1155/2020/5784876. eCollection 2020. PMID 32089640

• Study Protocol and Statistical Analysis Plan (PDF, 2016-01-13)

• AeRang Kim, MD, PhD, Principal investigator, Children's National Research Institute
• Brigitte Widemann, MD, Principal investigator, National Cancer Institute (NCI)