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Pexidartinib and Sirolimus in Treating Patients with Sarcoma or Malignant Peripheral Nerve Sheath Tumors That Cannot Be Removed by Surgery

Trial Status: Active

This phase 1 / 2 trial studies the side effects and best dose of pexidartinib and sirolimus when given together and to see how well they work in treating patients with sarcoma or malignant peripheral nerve sheath tumors (MPNSTs) that has spread from the primary site (place where it started) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Pexidartinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sirolimus is used to decrease the body's immune response and may increase blood cell counts.Giving pexidartinib and sirolimus together may work better in treating patients with sarcoma or malignant peripheral nerve sheath tumors.

Inclusion Criteria

  • Disease site/type with pathologic confirmation of diagnosis at participating cancer site; Note: if recurrence occurred greater than two years after resection, a biopsy to confirm recurrence should be performed and used for confirmation of diagnosis at the participating site * Phase 1: Advanced, unresectable sarcoma (any subtype, except for patients with pigmented villonodular synovitis for which metastatic disease is required) * 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, if one is available * Phase 2: MPNST with 0-3 prior cytotoxic systemic therapies (no prior radiotherapy is necessary)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
  • Presence of measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
  • Absolute neutrophil count (ANC) >= 1.5 X 10^9/L within 14 days of starting cycle 1 day 1 treatment
  • Hemoglobin (Hgb) > 10 g/dL within 14 days of starting cycle 1 day 1 treatment
  • Platelet count >= 100 X 10^9/L within 14 days of starting cycle 1 day 1 treatment
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< upper limit of normal (ULN) in the absence of malignancy within the liver within 14 days of starting cycle 1 day 1 treatment
  • Total bilirubin and direct 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 if total bilirubin is =< 1.5 X ULN
  • Albumin >= 3.0 g/dL within 14 days of starting cycle 1 day 1 treatment
  • Creatinine =< 1.5 X ULN or calculated creatinine clearance (CrCl) > 60 mL/min using the Cockcroft-Gault formula less than eight days prior to start of treatment within 14 days of starting cycle 1 day 1 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 pexidartinib (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 pexidartinib (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
  • For phase 2 specifically, agree to pre- and on-treatment tumor biopsies
  • Prior treatment-related adverse events (AEs) must be =< grade 1 (Common Terminology Criteria for Adverse Events [CTCAE] v4.0), except alopecia, at time of initiating study drug

Exclusion Criteria

  • Prior treatments: * Patients who have had systemic cytotoxic therapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or targeted therapy with small molecule inhibitors within 2 weeks prior to entering the study * Patients who have not recovered from adverse events (=< grade 1; except alopecia) due to agents administered more than 4 weeks earlier * Patients need to be free of adverse effects (=< grade 1; except alopecia) from prior treatments for at least 14 days from cycle 1 day 1 of pexidartinib (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 pexidartinib (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 pexidartinib (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 pexidartinib (PLX3397) and sirolimus; breastfeeding should be discontinued if the mother is treated with pexidartinib (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 corrected Fridericia QT (QTcF) >= 450 ms (males) or >= 470 ms (females)
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with PLX3997; 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; prior hepatitis infection that has been treated with highly effective therapy with no evidence of residual infection and with normal liver function (ALT, AST, total and direct bilirubin =< ULN) is allowed
  • Of the five major cytochrome P450 (CYP) isoforms, 3A4 (BFC) may be involved in phase I metabolism of pexidartinib (PLX3397), with possibly cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) playing a minor role; until information regarding exposure toxicity and exposure-response relationships are available with pexidartinib (PLX3397), concomitant strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors and inducers are not permitted in the event they alter the systemic exposure to pexidartinib (PLX3397); 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; during the study, if the use of any concomitant treatment becomes necessary (e.g., for treatment of an adverse event), the treatment must be recorded on the electronic case report form (eCRF), including the reason for treatment, generic name of the drug, dosage, route, and start and stop dates of administration; sirolimus undergoes extensive hepatic and intestinal metabolism via CYP3A4 and cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5), as well as excretion by permeability (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 pexidartinib (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 pexidartinib (PLX3397) for which patients will be closely monitored
  • Any patients on warfarin therapy
  • Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis, inflammation, fibrosis, cirrhosis of liver caused by viral, alcohol, or genetic reasons; Gilbert’s disease is allowed if total bilirubin (TBil) is =< 1.5 x ULN


Iowa City
University of Iowa / Holden Comprehensive Cancer Center
Status: ACTIVE
Contact: Varun Monga
Phone: 319-384-9497


Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Khanh Tu Do


Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE
Contact: Rashmi Chugh
Phone: 734-232-0753


Saint Louis
Siteman Cancer Center at Washington University
Status: ACTIVE
Contact: Brian Andrew Van Tine
Phone: 314-747-3096

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: ACTIVE
Contact: Gulam Abbas Manji
Phone: 212-305-0592


I. To determine the recommended phase 2 dose (RP2D) for pexidartinib (PLX3397) when administered orally in combination with sirolimus in patients with unresectable or metastatic sarcoma. (Phase 1)

II. To evaluate the safety profile of pexidartinib (PLX3397) with sirolimus in patients with unresectable or metastatic sarcoma. (Phase 1)

III. To determine the preliminary efficacy of pexidartinib (PLX3397) in combination with sirolimus in patients with unresectable or metastatic MPNST by determining the median progression free survival. (Phase 2)

IV. To evaluate the safety profile of pexidartinib (PLX3397) with sirolimus at the RP2D in patients with unresectable or metastatic MPNST. (Phase 2)


I. To investigate the objective response rate (ORR) and overall survival (OS) of patients with unresectable malignant peripheral nerve sheath tumors (MPNSTs).


I. Analysis of transducer of regulated CREB (TORC)1/TORC2 signaling pathways and receptor tyrosine kinase activity including colony stimulating factor receptor (c-FMS), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (c-KIT), v-akt murine thymoma viral oncogene homolog 1 (AKT), ribosomal protein S6 kinase (S6), and assessment of macrophage activation.

OUTLINE: This is a phase 1, dose-escalation study followed by a phase 2 study.

Patients receive pexidartinib orally (PO) twice daily (BID) and sirolimus PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months thereafter.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center

Principal Investigator
Gulam Abbas Manji

  • Primary ID AAAO6059
  • Secondary IDs NCI-2015-01768
  • ID NCT02584647