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

Inclusion Criteria- Group A:

• Age ≥ 18 years.
• Phase 1-Dose Escalation: Patients with histologically confirmed advanced solid tumors who are refractory to, relapsed after, or intolerant to standard therapy or for whom no standard therapy exists.

• Phase 2a-RP2D Confirmation (Formulation 2) and Phase 2a-Dose Extension: Patients with a history of histologically confirmed solid tumors with a BRAF mutation.

  • Phase 2a-Dose Extension—Cohort 1

    1. Patients with solid tumors driven by a BRAF-V600 mutation
    2. Patients with no prior exposure to BRAF-directed therapy and for whom no standard therapy exists.

  • Phase 2a-Dose Extension—Cohort 2

    1. Patients with solid tumors driven by BRAF non-V600 mutation.
    2. Patients with no prior exposure to BRAF-directed therapy and for whom no standard therapy exists.
• Measurable disease by RECIST 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Adequate hematologic, hepatic, and renal function.
• Women of child-bearing potential must have a negative pregnancy test 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. 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 at least 2 weeks before study drug initiation.

Exclusion Criteria- Group A:

• Phase 1 and Phase 2a RP2D confirmation-Dose Escalation: 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 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. 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.
• Clinically significant cardiac disease.
• Known infection with HIV, HBV, or HCV or a known carrier of HBV or HCV.

Inclusion Criteria — Group B:

• Age (all criteria are required):

  • ≥3 and <18 years;
  • Ability to swallow and retain study drug;
  • A minimum BSA that allows for adequate dosing with PLX8394.

  • Patients with a history of activating BRAF mutation, such patients include those with the following:

    1. Diagnosis of pediatric brain tumor (e.g., pilocytic astrocytoma, pleomorphic xanthoastrocytoma, ganglioglioma, astrocytoma, papillary craniopharyngioma, glioblastoma) with an activating BRAF mutation.
    2. LCH (Langerhans cell histiocytosis) i.) Patients with either high-risk disease are eligible. ii) Patients with overlap histiocytic disorders (e.g., LCH/juvenile xanthogranuloma, LCH/Erdheim-Chester disease, or LCH/Rosai-Dorfman disease) are eligible.
    3. Diagnosis of LCH-associated neurodegenerative disease (LCH-ND).
    4. Other advanced malignancy with an activating BRAF mutation.
• ECOG performance status of 0-1.
• Adequate hematologic, hepatic, and renal function.
• Females of child-bearing potential must have a negative pregnancy test and must agree to use an effective form of contraception from the time of the negative pregnancy test and for 3 months after the last dose of study drug. Females of non-child-bearing potential may be included if they are either surgically sterile, have been postmenopausal for ≥1 year, or are premenopausal.
• Fertile male patients must agree to use an effective method of birth control during the study and for 3 months after the last dose of study drug.
• Completion of previous anti-cancer therapy at least 2 weeks before study drug initiation.
• All patients or their legal guardians (if the patient is <18 years old) must sign an IRB-approved document of informed consent to demonstrate their understanding of the investigational nature and the risks of this study before any protocol-related procedures are performed. When appropriate, pediatric subjects will be included in all discussions.

Exclusion Criteria — Group B:

• Major surgical procedure, open biopsy (excluding skin cancer resection), or significant traumatic injury within 14 days of initiating the study drug or anticipation of the need for major surgery during the study.
• Dose Escalation and Dose Extension — Investigational drug use within 28 days (or 5 half-lives, whichever is shorter) of the first dose of PLX8394.
• 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.
• Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption.
• Clinically significant cardiac disease.
• Known infection with HIV, HBV, HAV, or HCV or a known carrier of HBV, HAV or HCV.