Phase I Trial of TURALIO(R) (Pexidartinib, PLX3397) in Children and Young Adults With Refractory Leukemias and Refractory Solid Tumors Including Neurofibromatosis Type 1 (NF1) Associated Plexiform Neurofibromas (PN) and Tenosynovial Giant Cell Tumor ...

• INCLUSION CRITERIA:

• Diagnosis:

• Patients must have recurrent or refractory solid tumors or acute leukemia (limited to AML or ALL) or have been intolerant of prior therapies, confirmedby the Laboratory of Pathology, NCI, e.g., solid tumors includingrhabdomyosarcoma, Ewing sarcoma, soft tissue sarcomas. These may includeprimary neoplasms of the central nervous system, such as high-grade (WHO gradeIII-IV) glioma. Patients with diffuse intrinsic pontine glioma (DIPG) or opticpathway glioma are exempt from histologic verification. For DIPG typical MRIfindings must be present which include hypo- or isointense on T1-weightedimaging, hyperintense on FLAIR or T2-weighted imaging, epicenter in the pons inthe face of a typical clinical presentation. Optic pathway gliomas are locatedin the optic pathway and are typically hypo- or iso-intense on T1 andhyperintense on T2-weighted images.

• In addition, patients with NF1 and with malignant peripheral nerve sheath tumor (MPNST).

• Patients must have relapsed after or be refractory to effective standardtherapies. There are no limits on number of prior therapeutic regimens.

• Disease status: Patients with refractory solid tumors including patients with NF1and MPNST must have evaluable disease, patients with leukemia must have measurableor evaluable disease at the time of enrollment, which may include any evidence ofdisease including minimal residual disease detected by flow cytometry.

• Age >= 3 and <= 35 years of age (must have BSA >= 0.55 m^2):

• Ability of subject or Legally Authorized Representative [LAR] (the parent/guardianif subject is a minor) to understand and the willingness to sign a written informedconsent document.

• Patients must be able to swallow capsules.

• Performance Status: Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50% for patients <= 16 years of age. Subjects who are wheelchair bound because ofparalysis will be considered "ambulatory" when they are up in their wheelchair.Subjects have to be able to travel to the NIH for evaluations.

• Prior therapy:

Patients must have fully recovered (to Grade 1) from the acute toxic effects of all prior anti-cancer therapy.

• Myelosuppressive chemotherapy: At least 21 days after the last dose ofmyelosuppressive chemotherapy (42 days if prior nitrosourea).

• Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologicagent. For agents that have known adverse events occurring beyond 7 days afteradministration, this period must be extended beyond the time during which adverseevents are known to occur. The duration of this interval must be discussed with thestudy chair.

• Immunotherapy: At least 42 days after the completion of any type of immunotherapy,e.g. tumor vaccines.

• Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose ofa monoclonal antibody.

• XRT: At least 7 days after local palliative XRT (small port); At least 150 days musthave elapsed if prior TBI or if >= 50% radiation of pelvis; >= 14 days from wholebrain radiation, craniospinal radiation, or targeted radiation to CNS tumors. Atleast 42 days must have elapsed if other substantial BM radiation.

• HSCT: >= 56 days from stem cell transplant with no evidence of active graft vs. hostdisease; must be off immunosuppressive therapy for at least 4 weeks and have noactive graft-versus-host disease (GVHD) at the time of entry onto this trial.

• Surgery: >= 14 days from surgery

• Others: >= 7 days from last dose of short active hematopoietic growth factors, i.e.filgrastim, >= 14 days for long-acting, i.e. pegfilgrastim.

• Steroids: Patients with CNS tumors who are managed with steroids are eligible ifthey have no worsening neurologic deficits and are on a stable or decreasing dose ofcorticosteroids for greater than or equal to 7 days prior to registration. Patientswith leukemia receiving corticosteroids or hydroxyurea are eligible provided thatthe corticosteroids are not being used to manage GVHD and there has been no increasein corticosteroid of hydroxyurea dose for 7 days prior to starting TURALIO(R).

• Patient must have adequate hematologic, hepatic, and renal function, definedby:

• Absolute neutrophil count >= 1.5 x 10^9/L

• Hemoglobin > 10 g/dL

• Platelet count >= 100 x 10^9/L

• AST and ALT <= upper limit of normal (ULN)

• TBil and DBil <= ULN with an exception of patients with confirmed Gilbert'ssyndrome. For patients with confirmed Gilberts syndrome, the TBil should be <= 1.5 xULN

• Serum creatinine <= 1.5 x ULN

• Exceptions:

• Cytopenias due to underlying disease (i.e. potentially reversible withanti-neoplastic therapy); A subject will not be excluded because of cytopeniadue to disease, based on the results of bone marrow studies.

• Known active or chronic human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infection, or positive hepatitis B (Hep B) surface antigen. Priorhepatitis infection that has been treated with highly effective therapy with noevidence of residual infection and with normal liver function (ALT, AST, totaland direct bilirubin <= ULN) is allowed.

• Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis,inflammation, fibrosis, cirrhosis of liver caused by viral, alcohol, or geneticreasons. Gilbert's disease is allowed if TBil is <= 1.5 x ULN.

• Cardiac ejection fraction >= 50%, and QTcF < 450 ms (male) or <470 ms (female) on ECG at Baseline. (Fridericia's Formula: QTcF = (QT)/RR0.33)

• Contraception: Women of child-bearing potential must agree to use aneffective method of birth control during treatment and for 1 month afterreceiving their last dose of study drug. Fertile men must also agree touse an acceptable method of birth control while on study drug and for atleast one week after last dose.

EXCLUSION CRITERIA:

• Individuals who are pregnant or breast feeding or who become pregnant while enrolledon this trial will be excluded from participation, due to the unknown effects ofTURALIO(R) on a growing fetus or newborn child.

• Ongoing treatment with any other cancer therapy or investigational agent, with theexception of IT chemotherapy for leukemia, when indicated.

• Individuals who require therapy with warfarin.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

• Active untreated infection.

• Known active hepatitis A, B, C or HIV infection, chronic Hepatitis B or C, or HIVinfection or inactive Hepatitis B carrier.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to TURALIO(R) or other agents used in study.

• Patients with PT and/or INR higher than or equal to 1.5 times upper limit of normal,unless patients have lupus anticoagulant in which case they are eligible if clearedby hematology.

• Drugs that strongly inhibit or potentiate CYP3A4, which includes CYP3A4 inducer, UGTinhibitors and acid reducing agents and avoid concomitant use of PPIs:

• Patients who have received these drugs within 14 days or within 5 half-lives ofthe drug (whichever is longer) prior to study initiation will be excluded.