This study includes a dose escalation portion (Part 1) in which the safety profile and
recommended phase 2 dose (RP2D) of PLX9486 as a single oral agent will be evaluated in
participants with solid tumors (including GIST), followed by signal-seeking extension cohorts
(Part 2). Enrollment in the combination treatment portions of the study (dose-finding for the
PLX9486 + pexidartinib combination [Part 2b] and the PLX9486 + sunitinib combination [Part
2e]) was planned to be accrued using standard 3+3 study designs. Parts 2a, 2c, 2d, and 2f
were not conducted due to business decisions.
Inclusion Criteria:
- Male or female ≥18 years old.
- Part 1, Part 2b, Part 2d, and Part 2e: Participants with advanced solid tumors who
have tumor progression following standard therapy, have treatment-refractory disease,
or for whom there is no effective standard of therapy.
- Part 2d: Participants with non GIST solid tumors with KIT mutations, who are TKI naïve
or have been previously treated with KIT directed TKI therapy who are appropriate for
KIT directed TKI therapy
- Part 2a, Part 2c, and Part 2f (GIST participants): Histologically confirmed locally
advanced, metastatic and/or unresectable GIST.
- Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test at
Screening (≤7 days prior to the first dose of study drug) and must agree to use an
effective form of contraception from the time of the negative pregnancy test up to 6
months after the last dose of study drug.
- Fertile men must agree to use an effective method of birth control during the study
and for up to 6 months after the last dose of study drug.
- All associated toxicity from previous or concurrent cancer therapy must be resolved
(to ≤ Grade 1 or Baseline) prior to study treatment administration.
- Willing and able to provide written informed consent prior to any study related
procedures and to comply with all study requirements.
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
- Life expectancy ≥3 months.
- Adequate hematologic, hepatic, and renal function:
- Left ventricular ejection fraction (LVEF) >50% per echocardiogram (ECHO) or
multiple-gated acquisition (MUGA) for participants on the sunitinib arms (Parts 2e and
f).
Exclusion Criteria:
- Known or demonstrated wild type KIT or platelet-derived growth factor receptors
(PDGF-R), or known or demonstrated mutations of PDGF R, sorbitol dehydrogenase (SDH),
or neurofibromin 1 (NF 1) that are causative for the observed malignancy.
- For Part 1 (phase 1, single agent): Participants with a known or presumed pathogenic
KIT exon 13 or 14 resistance mutation.
- Parts 2a and 2d: Participants with known or presumed pathogenic KIT exon 13 or 14
resistance mutations. (However, such participants are permitted on the combination
arms of Parts 2b, 2c, 2e, or 2f.)
- Presence of symptomatic or uncontrolled brain or central nervous system metastases.
Participants with stable, treated brain metastases are eligible for this trial.
However, participants must not have required steroid treatment for their brain
metastases within 30 days of Screening.
- Known or suspected allergy to the investigational agent or any agent given in
association with this trial.
- Clinically significant cardiac disease
- Inability to take oral medication or significant nausea and vomiting, malabsorption,
external biliary shunt, or significant bowel resection that would preclude adequate
absorption.
- Ongoing infection of ≥ Grade 2 severity.
- Non-healing wound, ulcer, or bone fracture.
- Known human immunodeficiency virus (HIV)-positive individuals on combination
antiretroviral therapy, participants with known active hepatitis B or C, or chronic
hepatitis B or C requiring treatment with antiviral therapy
- Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis,
inflammation, fibrosis, or cirrhosis of liver caused by viral, alcohol, or genetic
reasons. Gilbert's disease is allowed if total bilirubin is ≤1.5 * upper limit of
normal (ULN).
- Interstitial lung disease with ongoing signs and symptoms at the time of informed
consent.
- Females who are pregnant or nursing.
- Any psychological, familial, sociological, or geographical condition that could hamper
compliance with the study protocol.
- Strong CYP3A4 inhibitors or inducers within 14 days or 5 drug half-lives of the agent,
whichever is longer, of study drug initiation or the need to continue these drugs
during this study.
- Major surgery or significant traumatic injury within 14 days of Cycle 1 Day 1.
- History (within 2 years prior to first study drug administration) of another
malignancy unless the malignancy was treated with curative intent and likelihood of
relapse is small (<5% in 2 years in the judgment of the investigator).
- Anti-cancer therapy within the period immediately before Cycle 1 Day 1
