Patient case: 64-year-old male with melanoma; genetic feature: BRAF (V600E)

Clinical trial: A Study of PLX8394 as a Single Agent in Patients With Advanced Unresectable Solid Tumors

Summary: The objective of this study is to determine the safety, pharmacokinetics, maximum tolerated dose/recommended Phase 2 dose, and efficacy of PLX8394.


Eligibility: Inclusion Criteria:
  -  Age ≥ 18 years.
  -  Dose-escalation Cohorts: Patients with advanced solid tumors who are refractory to, relapsed after or intolerant to standard therapy, or for whom no standard therapy exists.
  -  Extension Cohorts: Patients with a history of solid tumors with an activating BRAF mutation
  1. Melanoma: Patients with unresectable Stage IIIC or Stage IV disease; Refractory to, relapsed after, or intolerant to treatment with (a) a BRAF or BRAF/MEK inhibitor and/or (b) FDA-approved immunotherapy
  2. Non-melanoma solid tumors:
  1. No prior exposure to RAS/RAF/MEK/ERK pathway inhibitors
  2. Patients who are refractory to, relapsed after or intolerant to standard therapy, or for whom no standard therapy exists: (i) Advanced thyroid carcinoma -- Anaplastic thyroid carcinoma: Positive (IHC) for V600E (or known history of BRAF mutation) is allowed to enroll; Locoregional disease no longer amenable to curative surgery or radiation, or advanced disease with measurable primary or metastatic disease; Papillary thyroid carcinoma -- Must be beyond 3 weeks from last radioactive iodine treatment and AEs associated with previous therapy must be resolved to Grade 1 or baseline; Thyroid stimulating hormone (TSH) less than the upper limit of normal (ULN) per institutional laboratory ranges. (ii) Other advanced tumors (eg. colorectal cancer, non-small cell lung cancer, cholangiocarcinoma.
  -  Measurable disease by RECIST 1.1.
  -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  -  Adequate hematologic, hepatic, and renal function.
  -  Women of child-bearing potential must have a negative serum pregnancy at Screening and must agree to use an effective form of contraception from the time of the negative pregnancy test up to 3 months after the last dose of study drug. Effective forms of contraception include abstinence, hormonal contraceptive in conjunction with a barrier method, or a double barrier method. Women of non-child-bearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year.
  -  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.
  -  Completion of previous anti-cancer therapy (e.g. chemotherapy, immunotherapy, tyrosine kinase inhibitor, or radiation therapy) at least 2 weeks before study drug initiation, with resolution of all associated toxicity (to ≤ Grade 1 or Baseline) prior to PLX8394 administration.
  -  Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.
  Exclusion Criteria:
  -  Symptomatic brain metastases. Patients 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. Patients with brain metastasis that is treated and stable for 1 month may be considered eligible if they are asymptomatic and on stable dose (>2 weeks) of steroids or if they do not require steroids following successful local therapy.
  -  Dose-escalation Cohorts: Investigational drug use within 28 days (or 5 half-lives, whichever is longer) of the first dose of PLX8394
  -  Extension Cohorts: Investigational drug use within 28 days (or 5 half-lives, whichever is shorter) of the first dose of PLX8394.
  -  Major surgical procedure, open biopsy (excluding skin cancer resection), or significant traumatic injury within 14 days of initiating study drug (unless the wound has healed), or anticipation of the need for major surgery during the study.
  -  Uncontrolled intercurrent illness.
  -  Active secondary malignancy unless the malignancy is not expected to interfere with the evaluation of safety and is approved by the Medical Monitor. 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. Patients with a completely treated prior malignancy and no evidence of disease for ≥ 2 years are eligible.
  -  Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption.
  -  Baseline mean QT interval corrected using Fridericia's equation (QTcF) ≥ 450 msec (males) or ≥ 470 msec (females).
  -  Clinically significant cardiac arrhythmias including bradyarrhythmias and/or patients who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Patients with controlled atrial fibrillation are not excluded.
  -  Congenital long QT syndrome or patients taking concomitant medications known to prolong the QT interval (e.g., tricyclics, azithromycin, methadome).
  -  History of clinically significant cardiac disease or congestive heart failure >New York Heart Association (NYHA) class 2. Patient must not have unstable angina (angina symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months.
  -  Women who are breast-feeding or pregnant.
  -  Known chronic human immunodeficiency virus (HIV), Hepatitis C virus (HCV), or Hepatitis B virus (HBV) infection.
  -  Imprisonment or under legal guardianship.
  -  The presence of a medical or psychiatric condition that, in the opinion of the investigator, makes the patient inappropriate for study inclusion.
  -  Inability to swallow and retain study drug.

Relevance to patient case: possibly relevant