PLX3397 Plus Sirolimus in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors

NCT02584647 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: AAAO6059R01FD005745
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 5

Brief Summary

The purpose of this study is to determine if treatment with PLX3397 and Sirolimus will be tolerated and result in shrinking of the cancer or stopping the cancer from growing. In the phase I portion, the maximum tolerate dose of the study drug will be determined. In the Phase II portion, progression free survival will be assessed at the dose level found in Phase I. Participants will continue to take the study drug until they experience an unacceptable side effect or their disease progresses. Funding Source - FDA OOPD

Conditions

Sarcoma; Malignant Peripheral Nerve Sheath Tumors

Keywords

Unresectable

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) - Phase 1

  The highest dose of a drug or treatment that does not cause unacceptable side effects, which will be used in Phase 2.

  Up to 3 years

• Progression Free Survival (PFS) Rate - Phase 2

  The time from the start of treatment until disease progression or death from any cause, calculated in weeks.

  Up to 3 years

Secondary Outcomes (1)

• Overall Survival Rate

  Up to 3 years

Study Arms (2)

Phase 1: PLX3397 and Sirolimus

EXPERIMENTAL

Subjects with unresectable or metastatic sarcoma will take orally PLX3397 (600 - 1000mg) in combination with Sirolimus (2-6mg) daily.

Drug: PLX3397; Drug: sirolimus

Phase 2: PLX3397 and Sirolimus

EXPERIMENTAL

Subjects with unresectable or metastatic Malignant Peripheral Nerve Sheath Tumors (MPNSTs) will take PLX3397 and Sirolimus at the recommended Phase 2 dose (RP2D).

Drug: PLX3397; Drug: sirolimus

Interventions

PLX3397 DRUG

PLX3397 is a small molecule that potently and selectively inhibits macrophage colony-stimulating factor receptor (FMS), Kit, and FMS-like tyrosine kinase 3 (Flt3)-internal tandem duplication (ITD) kinases, which regulate key components of the tumor microenvironment and oncogenic variants of these kinases that drive certain tumors.

Also known as: pexidartinib

Phase 1: PLX3397 and Sirolimus; Phase 2: PLX3397 and Sirolimus

sirolimus DRUG

Sirolimus is a macrocyclic lactone that binds to tacrolimus (FK506) binding protein 12 and inhibits mammalian target of rapamycin (mTOR) resulting in cell-cycle arrest and apoptosis. Sirolimus is currently approved as an immunosuppressive agent for organ transplantation and more recently, as a component of cardiac arterial stents because of its potent antiproliferative effects on fibroblasts responsible for restenosis after such a procedure (26) Sirolimus is commonly administered orally on a daily basis, in doses ranging from 2 to 40 mg/day.

Also known as: Rapamune

Phase 1: PLX3397 and Sirolimus; Phase 2: PLX3397 and Sirolimus

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Disease site/type with pathologic confirmation of diagnosis at participating cancer site.
• Phase 1: Advanced, unresectable sarcoma (any subtype)
• Phase 2: Advanced, unresectable malignant peripheral nerve sheath tumors (MPNSTs)
• Extent of disease: Unresectable
• Allowable prior therapy
• Phase 1: Progressed on standard of care therapy with up to three prior treatments
• Phase 2: MPNST with 0-3 prior systemic treatments (no prior radiotherapy is necessary).
• Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1, or 2
• Age greater or equal to 18 years. Because no dosing or adverse event data are currently available on the use of PLX3397 in combination with sirolimus in patients \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Presence of measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Allowable laboratory values with date range
• Absolute neutrophil count (ANC) ≥1.5 x 10\^9/L, hemoglobin (Hgb) \>9 g/dL, and platelet count ≥100 X 10\^9/L
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ upper limit of normal (ULN) or \< 2.5 x ULN in the presence of liver metastases, bilirubin ≤ 1.5 x ULN, albumin ≥ 3.0g/dL.
• Bilirubin ≤ ULN; patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the principal investigator.
• Albumin ≥ 3.0g/dL.

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier or within 14 days from cycle 1 day 1 of PLX3397 and sirolimus.
• Patients who are receiving any other investigational agents concurrently.
• Concomitant treatment with other anti-neoplastic agents (hormonal therapy acceptable).
• Patients with symptomatic brain metastases. Subjects with untreated brain metastasis ≤ 1 cm can be considered eligible if deemed asymptomatic by the investigator upon consultation with the medical monitor and do not require immediate radiation or steroids. Subjects with brain metastasis that is treated and stable for 1 month may be considered eligible if they are asymptomatic and on stable dose of steroids or if they do not require steroids following successful local therapy.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to PLX3397 or sirolimus.
• For Phase 2 - Prior exposure to a receptor tyrosine kinase or mammalian target of Rapamycin inhibitor.
• Pregnant women are excluded from this study because PLX3397 and sirolimus are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with PLX3397 and sirolimus, breastfeeding should be discontinued if the mother is treated with PLX3397 and sirolimus.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active liver disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Active secondary malignancy unless the malignancy is not expected to interfere with the evaluation of safety and is approved by the Sponsor. Examples of the latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, and isolated elevation of prostate-specific antigen. Subjects with a completely treated prior malignancy and no evidence of disease for ≥ 2 years are eligible.
• Major surgical procedure or significant traumatic injury within 14 days of initiating study drug or anticipation of the need for major surgery during the study.
• Previous radiotherapy to 25% or more of the bone marrow and/or radiation therapy within 28 days prior to study entry.
• Inability to swallow capsules, or refractory nausea and vomiting, malabsorption, an external biliary shunt, or significant bowel resection that would preclude adequate absorption.
• Congestive heart failure (CHF) New York (NY) Heart Association class III or IV; unstable coronary artery disease (myocardial infarction (MI) more than 6 months prior to study entry is permitted); or serious cardiac arrhythmia.
• Baseline QTc corrected by Fridericia's formula (QTcF) ≥ 450 ms (males) or ≥ 470 ms (females)
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with PLX3397. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Similarly, patients with chronic or acute hepatitis C virus (HCV) or hepatitis B virus (HBV) infection are also ineligible.

Sponsors & Collaborators

• Gulam Manji: lead
• Daiichi Sankyo: collaborator

Study Sites (5)

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Early Drug Development Center

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109-5848, United States

Location

Washington University in St. Louis

St Louis, Missouri, 63110, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Related Publications (1)

• Manji GA, Van Tine BA, Lee SM, Raufi AG, Pellicciotta I, Hirbe AC, Pradhan J, Chen A, Rabadan R, Schwartz GK. A Phase I Study of the Combination of Pexidartinib and Sirolimus to Target Tumor-Associated Macrophages in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors. Clin Cancer Res. 2021 Oct 15;27(20):5519-5527. doi: 10.1158/1078-0432.CCR-21-1779. Epub 2021 Jul 28.

  PMID: 34321280 DERIVED

Related Links

• Herbert Irving Comprehensive Cancer Center

MeSH Terms

Conditions

Sarcoma; Neurofibrosarcoma

Interventions

pexidartinib; Sirolimus

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Fibrosarcoma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

In the present study, the combination of pexidartinib and sirolimus failed to meet the primary endpoint in a study that was stopped due to poor enrollment due to COVID-19.

Results Point of Contact

• Title: Gulam A. Manji
• Organization: Columbia University

gam2140@cumc.columbia.edu

212 305 0592

Study Officials

• Gulam A. Manji, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine (Oncology)

Study Record Dates

• First Submitted: October 21, 2015
• First Posted: October 22, 2015
• Study Start: November 4, 2015
• Primary Completion: July 1, 2023
• Study Completion: October 1, 2024
• Last Updated: March 21, 2025
• Results First Posted: March 21, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)