Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Skin and Connective Tissue Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Recurrence

Sarcoma

Shock

Nerve Sheath Neoplasms

Neurofibrosarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Peripheral Nervous System Diseases

Neuromuscular Diseases

Fibrosarcoma

Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Neurofibromatoses

Neurofibroma

Soft Tissue Sarcoma

Malignant Peripheral Nerve Sheath Tumor

Neurofibromatosis

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Vasoconstrictor Agents

Respiratory System Agents

Sirolimus

Temsirolimus

MTOR Inhibitors

Xylometazoline

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

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

ganetespib

4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

AeRang Kim, MD, PhD

Brigitte Widemann, MD

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.

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.

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

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

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.

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.

To describe the plasma pharmacokinetic profile of ganetespib and sirolimus when administered in combination therapy.

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.

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.

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.

To describe the plasma pharmacokinetic profile of ganetespib in terms of half life.

A conventional 3+3 dose escalation design was used for phase 1. All patients in phase 2 were treated with the recommended dose.

Synta Pharmaceuticals Corp.

United States Department of Defense

Sarcoma Alliance for Research through Collaboration

For each 28-day cycle, subjects took doses of both ganetespib + sirolimus:

ganetespib: 150 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour

Sirolimus: 4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

Phase 1 Dose 1

For each 28-day cycle, subjects took doses of both ganetespib + sirolimus:

ganetespib: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour

Sirolimus: 4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

Phase 1 Dose 2

Phase 2

28-day cycles of ganetespib + sirolimus

ganetespib: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour

Sirolimus: 2mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

Ganetespib / Sirolimus

Phase I

10 patients were enrolled in Phase 1 and 10 patients were enrolled in Phase 2 of the study. Overall number of patients enrolled was 20.

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Sarcoma subtype

Tumor location at diagnosis

Phase 1

History of metastatic disease

Prior chemotherapy regimen

Prior radiation

Prior surgery

SARC

Dose Level 1

Dose Level 2

10 patients were enrolled in Phase 1 of the study to determine MTD/RD. Three patients were enrolled in the first dose level. Six patients were enrolled at dose level 2. 1 patient was inevaluable.

Number of Dose Limiting Toxicities of Ganetespib When Administered in Combination With Sirolimus.

Clinical Benefit of Ganetespib in Combination With Sirolimus

Dose Level 1- Sirolimus trough

Dose Level 2- Sirolimus trough

10 patients were enrolled in Phase 1 of the study. Three patients were enrolled in the first dose level. Six patients were enrolled at dose level 2. 1 patient was inevaluable.

Change in Plasma Pharmacokinetic Profile of Ganetespib and Sirolimus When Administered in Combination-Observed Maximum Plasma Concentration (Cmax)

Hsp70 at Baseline

Hsp70 at Cycle 1 Day 15

pAKT at Baseline

pAKT at Cycle 1 Day 15

p-S6 at Baseline

p-S6 at Cycle 1 Day 15

p-eiF2alpha at Baseline

p-eiF2alpha at Cycle 1 Day 15

11 subjects provided consent and had adequate specimens for analysis.

Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells

Baseline- Overall pain intensity

Baseline- Tumor pain intensity

Baseline- Pain interference

Prior to Cycle 3- Overall pain intensity

Prior to Cycle 3- Tumor pain intensity

Prior to Cycle 3- Pain interference

Thirteen subjects in phase 1 and phase 2 cohorts combined had MPNST and completed the pain evaluations. 4/13 subjects completed both baseline and pre-cycle 3 evaluations for pain.

Patient-reported Pain Severity and the Impact of Pain on Daily Activities

The 3D-MRI were not measurable with current modalities. Due to their nature and incomplete imaging, volumetric analysis was not feasible.

Utility of Three-dimensional MRI (3D-MRI) Analysis in Comparison to 1-dimensional and 2-dimensional Measurements

Ganetespib half life for dose level 1

Ganetespib half life for dose level 2

10 patients were enrolled in Phase 1 of the study. 1 patient was inevaluable.

Plasma Pharmacokinetic Profile of Ganetespib When Administered in Combination With Sirolimus

Phase 1 Dose Level 1

Phase 1 Dose Level 2

1 patient was inevaluable in Phase 1 of study. The recommended dose of ganetespib was determined to be 200 mg/m2 intravenously on days 1, 8, 15 with sirolimus 4mg orally once daily with a cycle 1 day 1 loading dose of 12mg. All patients in phase 2 were treated with the recommended dose.

Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib

Overall Study

Decitabine

Decitabine and cedazuridine drug combination

Antimetabolites

Patients who meet the eligibility criteria will be treated with oral ASTX727 (INQOVI) on days 1-5 of each 21-day cycle with Pegfilgrastim support on day 7. A delay in the start of subsequent cycles due to holidays, weather, or other circumstances will be permitted up to 7 days and not considered a protocol deviation. Drug dosing will be interrupted for any Grade 4 adverse events or clinically significant laboratory abnormalities. For Grade 3 or 4 AE, if the AE returns to Grade 1 or baseline, the patient may be re-escalated.

ASTX727 will be self-administered orally by the patient on a once daily basis, days 1 through 5 of each 21-day cycle. Cycle 1 day 1 (C1D1) is defined as the first day that ASTX727 is administered.

ASTX727

Ping Chi, MD, PhD

Ciara Kelly, MBBCH BAO

The purpose of this study is to see whether the study drug ASTX727 is an effective treatment for people who have MPNST with a PCR2 mutation.

ASTX727 is a combination of two drugs (cedazuridine and decitabine) that have been designed to target cancer cells with a PCR2 mutation and to disrupt the cells' ability to survive and grow. The study researchers think that the study drug allows decitabine to work better than decitabine given alone.

This is a phase II trial to evaluate the efficacy of ASTX727 in patients with PRC2-loss MPNST.

A Study of ASTX727 in People With Malignant Peripheral Nerve Sheath Tumors (MPNST)

A Phase II Study of ASTX727 in Patients With PRC2 Loss Malignant Peripheral Nerve Sheath Tumor (MPNST)

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

(complete response \[CR\] + partial response \[PR\] + stable disease \[SD\]) by RECIST1.1

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
SARC023: Ganetespib and Sirolimus in Patients With MPNST (Malignant Peripheral Nerve Sheath Tumors)	NCT02008877	Malignant Perip... Sarcoma	ganetespib Sirolimus	16 Years -	Sarcoma Alliance for Research through Collaboration
A Study of ASTX727 in People With Malignant Peripheral Nerve Sheath Tumors (MPNST)	NCT04872543	Malignant Perip...	ASTX727	18 Years -	Memorial Sloan Kettering Cancer Center
A Study of ASTX727 in People With Malignant Peripheral Nerve Sheath Tumors (MPNST)	NCT04872543	Malignant Perip...	ASTX727	18 Years -	Memorial Sloan Kettering Cancer Center

Spots Global Cancer Trial Database for malignant peripheral nerve sheath tumors (mpnst)