Patient case: 70-year-old male with gastrointestinal stromal tumor; genetic feature: KIT (V654A)

Clinical trial: PLX9486 as a Single Agent and in Combination With PLX3397 or PLX9486 With Sunitinib in Patients With Advanced Solid Tumors

Summary: The goal of this clinical research study is to learn how PLX9486 may affect cancer cells with certain mutations in the KIT gene, specifically in patients with types of advanced solid tumors including Gastrointestinal Stromal Tumor (GIST).
  PLX9486 is designed to block KIT gene mutations. These mutations can cause cancer and cancer cell growth. By blocking these mutations, the drug may kill the cancer cells with the mutation and/or stop the tumor from growing. By combining PLX9486 with PLX3397 and PLX9486 with Sunitinib, the investigators hope to block most gene mutations in KIT.


Eligibility: Inclusion Criteria:
  -  Male or female ≥18 years old.
  -  Part 1, Part 2b, Part 2d, and Part 2e: Patients 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: Patients 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 patients): 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.
  -  ECOG Performance Status 0-2
  -  Life expectancy ≥3 months.
  -  Adequate hematologic, hepatic, and renal function:
  -  Left ventricular ejection fraction (LVEF) >50% per ECHO or MUGA for patients on the sunitinib arms (Parts 2e and f).
  Exclusion Criteria:
  -  Known or demonstrated wild type KIT or PDGF-R, or known or demonstrated mutations of PDGF R, SDH, or NF 1 that are causative for the observed malignancy.
  -  For Part 1 (phase 1, single agent): Patients with a known or presumed pathogenic KIT exon 13 or 14 resistance mutation.
  -  Parts 2a and 2d: Patients with known or presumed pathogenic KIT exon 13 or 14 resistance mutations. (However, such patients are permitted on the combination arms of Parts 2b, 2c, 2e, or 2f.)
  -  Presence of symptomatic or uncontrolled brain or central nervous system metastases. Patients with stable, treated brain metastases are eligible for this trial. However, patients 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 HIV-positive individuals on combination antiretroviral therapy, patients 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 × 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

Relevance to patient case: definitely relevant