Patient case: 39-year-old female with melanoma; genetic feature: KIT (N822Y)

Clinical trial: PLX9486 as a Single Agent and in Combination With PLX3397 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, the investigators hope to block most gene mutations in KIT.


Eligibility: Inclusion Criteria:
  -  Male or female ≥ 18 years old
  -  Part 1 and Part 2b: 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 2a and Part 2c: Histologically confirmed locally advanced, metastatic and/or unresectable GIST.
  -  Women of child-bearing potential must have a negative pregnancy test within 7 days prior to initiation of dosing and must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 3 months after the last dose of study drug, Fertile men must also agree to use an acceptable method of birth control while on study drug and up to 3 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.
  -  Patients with stable, treated brain metastases are eligible for this trial.
  -  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:
  Exclusion Criteria:
  -  Use of any approved tyrosine kinase inhibitors or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is shorter, prior to receiving study drugs. Treatment-related adverse events must have resolved or reduced to Grade 1 prior to enrollment.
  -  Presence of symptomatic or uncontrolled brain or central nervous system metastases
  -  Known or suspected allergy to the investigational agent or any agent given in association with this trial
  -  Clinically significant cardiac arrhythmias including bradyarrhythmias and/or patients who require anti-arrhythmic therapy (excluding beta blockers or digoxin).
  -  Congenital long QT syndrome or patients taking concomitant medications known to prolong the QT interval
  -  History of clinically significant cardiac disease or congestive heart failure > New York Heart Association (NYHA) class 2. Patients must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months.
  -  Hypertension as defined by systolic blood pressure > 140 mmHg or diastolic blood pressure > 95 mmHg despite optimal medical management
  -  Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than 1 month before the start of study medication)
  -  Inability to take oral medication
  -  Refractory nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption
  -  QTcF ≥ 450 msec (for males) or ≥ 470 msec (for females) at Screening
  -  Ongoing infection ≥ Grade 2
  -  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
  -  Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
  -  Pregnant or lactating females
  -  Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol
  -  Strong CYP3A4 inhibitors or inducers within 14 days or 5 drug half-lives, whichever is longer, before start of study drug.
  -  Patients with > Grade 1 (high or low) serum potassium, magnesium, or calcium levels
  -  Other than the primary malignancy, active cancer (either concurrent or within the last 3 years) that requires non-surgical therapy (e.g., chemotherapy or radiation therapy), with the exception of surgically treated basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix
  -  Major surgery or significant traumatic injury within 14 days prior to Cycle 1 Day 1
  -  Chemotherapy within 14 days prior to Cycle 1 Day 1
  -  Biological therapy within 14 days prior to Cycle 1 Day 1
  -  Radiation therapy within 14 days prior to Cycle 1 Day 1
  -  Uncontrolled illness or concurrent condition that, in the opinion of the Investigator, would interfere with the study endpoints or the patient's ability to participate

Relevance to patient case: not relevant