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

Phase I Study Evaluating Combination Therapy With the Receptor Tyrosine Kinase Inhibitor PLX3397 and Sirolimus in Patients With Unresectable Sarcoma and Phase II Study in Malignant Peripheral Nerve Sheath Tumors

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

Study Overview

• Status: Active, not recruiting
• Conditions: Sarcoma; Malignant Peripheral Nerve Sheath Tumors
• Intervention / Treatment: Drug: PLX3397; Drug: Sirolimus

Detailed Description

Malignant peripheral nerve sheath tumors (MPNSTs) represent up to 10% of adult soft tissue sarcomas. Due to its rarity, few MPNST-specific prospective trials exist, and treatments are largely based on extrapolation from results from other sarcoma subtypes. Since the molecular pathways driving pathogenesis within sarcoma subtypes are distinct, these treatment options are likely suboptimal at best. Targeted therapies that block key pathways known to drive MPNST will likely result in superior tumor responses with limited toxicities.

• Study Type: Interventional
• Enrollment (Estimated): 43
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Early Drug Development Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5848
      • University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis
  • New York
    • New York, New York, United States, 10032
      • Columbia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.
  • Creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) > 60 mL/min using the Cockcroft-Gault formula less than eight days pior to start of treatment.
• Women of child-bearing potential must have a negative serum pregnancy test at screening and must agree to use an effective form of contraception from the time of the negative pregnancy test and for a minimum of 3 months after the last dose of study drug. Effective forms of contraception include abstinence, hormonal contraceptive (injectable or implantable) in conjunction with a barrier method, or a double barrier method. Women of non-child-bearing potential must have been postmenopausal for ≥ 1 year or surgically sterile. The effects of PLX3397 and sirolimus on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of PLX3397 and sirolimus administration.
• Fertile men must agree to use an effective method of birth control during the study and for up to 3 months after the last dose of study drug.
• Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.
• Agree to pre and post-treatment tumor biopsies.
• Prior treatment-related Adverse Events must be ≤ grade 1 (CTCAE v4.0), except alopecia, at time of initiating study drug.

Exclusion Criteria:

• 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.
• Of the five major cytochrome P450 (CYP) isoforms, 3A4 (BFC) may be involved in Phase I metabolism of PLX3397, with possibly CYP1A2 playing a minor role. Until information regarding exposure toxicity and exposure-response relationships are available with PLX3397, concomitant strong CYP3A4 inhibitors and inducers are not permitted in the event they alter the systemic exposure to PLX3397 (see Attachment 1 for a list of common CYP3A4 inhibitors and inducers). These include anticonvulsants, mycin antimicrobials, and antiretrovirals. Some common examples include inhibitors such as erythromycin, fluoxetine, gemfibrozil, and inducers such as rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine. Concomitant treatment is permitted if the medication is not expected to interfere with the evaluation of safety or efficacy of the study drug. Sirolimus undergoes extensive hepatic and intestinal metabolism via CYP3A4 and CYP3A5, as well as excretion by P-glycoprotein. Strong CYP3A inhibitors such as ketoconazole or grapefruit juice are not permitted. Patients should be monitored for supratherapeutic toxic levels of sirolimus and PLX3397. As bone marrow suppression including anemia, neutropenia, and thrombocytopenia have been reported in patients receiving sirolimus monotherapy, these adverse effects may be exacerbated in combination with PLX3397 for which patients will be closely monitored.
• Any patients on warfarin therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1: PLX3397 and Sirolimus; Cohort 1 (Phase 1): Subjects with unresectable or metastatic sarcoma will take orally PLX3397 (600 - 1000mg) in combination with Sirolimus (2-6mg) daily .	Drug: PLX3397; 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.; Other Names: No other name; Drug: Sirolimus; 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.; Other Names: Rapamune
Experimental: Phase 2: PLX3397 and Sirolimus; Cohort 2 (Phase 2): 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; 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.; Other Names: No other name; Drug: Sirolimus; 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.; Other Names: Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 years.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival rate	The time from the start of treatment until death, estimated using the Kaplan Meier method, calculated in years.	Up to 3 years

Collaborators and Investigators

• Sponsor: Gulam Manji
• Collaborators: Daiichi Sankyo
• Investigators: Principal Investigator: Gulam A. Manji, MD, Columbia University

Publications and helpful links

General Publications

• 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.

Helpful Links

• Herbert Irving Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2015
• Primary Completion (Actual): July 1, 2023
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: October 21, 2015
• First Submitted That Met QC Criteria: October 21, 2015
• First Posted (Estimated): October 22, 2015

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Unresectable
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neuromuscular Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Neoplasms, Connective Tissue; Peripheral Nervous System Neoplasms; Neoplasms, Fibrous Tissue; Fibrosarcoma; Neurofibroma; Sarcoma; Nerve Sheath Neoplasms; Neurofibrosarcoma; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: AAAO6059; R01FD005745 (U.S. FDA Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No