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

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
• Age greater or equal to 18 years. Because no dosing or adverse event data are currently available on the use of turalio (registered trademark) 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) 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)/alkaline phosphatase (ALP)/gamma-glutamyl transpeptidase (GGT) =< 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, diaphragm or cerival cap with a cream or gel that kills sperm, bilartreal tubal occlusion, vasectomy, or an intrauterine device (IUD). Women of non-child-bearing potential must have been postmenopausal for >= 1 year or surgically sterile. The effects of turalio 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 and 3 months after completion of turalio and sirolimus administration. 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 turalio 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. If subject is unable to undergo paired research biopsies safely, subject may enroll onto the study without a research biopsy(ies) pending number of evaluable paired biopsies available at the discretion of the principal investigator
• 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 turalio (registered trademark). 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 turalio (registered trademark) 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 turalio (registered trademark) or 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 turalio (registered trademark) or sirolimus; breastfeeding should be discontinued if the mother is treated with turalio (registered trademark) or 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 turalio (registered trademark), 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 turalio (registered trademark), 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 turalio (registered trademark); 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 turalio (registered trademark); 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 turalio (registered trademark) 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