human neural stem cells

A Phase 1/2a Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of FORE8394 in Patients with Advanced, Unresectable Solid Tumors

Summary

The purpose of this Phase I/IIa clinical trial is to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of FORE8394 in participants with advanced solid tumors, advanced, unresectable solid tumors with activating BRAF mutations, or primary central nervous system (CNS) tumors harboring BRAF mutations. Alterations in the BRAF genomic sequence-- including V600 and non-V600 mutations, in-frame deletions, and BRAF gene fusions -- activate BRAF and promote tumor growth growth.

FORE8394 is a is a next-generation orally available small-molecule selective inhibitor of mutated BRAF. Unlike first-generation BRAF inhibitors, nonclinical data indicates that FORE8394 has broad activity against all of the aforementioned types of activating BRAF mutations.

Inclusion Criteria
  1. Age ≥10 years and at least 30 kg.
  2. Participants with a history of histologically confirmed solid tumors driven by an activating BRAF mutation, determined using a commercially available Clinical Laboratory Improvement Amendments (CLIA)-certified next-generation sequencing (NGS) panel such as FoundationOne®, GUARDANT360®, or a local NGS panel from another CLIA-certified laboratory.
  3. Phase 1–Dose Escalation (Enrollment Complete): Participants with histologically confirmed advanced solid tumors who are refractory to, relapsed after, or intolerant to standard therapy or for whom no standard therapy exists.
  4. Phase 2A - Dose Extension (HME Formulation): Criteria for Dose Extension [HME] Cohort 1 or Cohort 2 are specified below:

    Phase 2a – Dose Extension: Cohort 1

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

    Phase 2a - Dose Extension: Cohort 2

    1. Participants with solid tumors driven by an activating BRAF non-V600 mutation, which can include a point mutation, gene amplification, fusion, insertion, or deletion.
    2. Participants with no prior exposure to BRAF-directed therapy and for whom no standard therapy exists.
  5. Phase 2a - RP2D Redefinition Extension: Following RP2D redefinition, extension participants must meet criteria for Cohort 3 or Cohort 4 as specified below:
    1. Cohort 3: Participants with advanced unresectable gliomas driven by an activating BRAF V600 or activating non-V600 mutation who have no prior exposure to a BRAF, MEK, or ERK inhibitor and for whom no standard therapy exists.
    2. Cohort 4: Participants with advanced solid tumors driven by activating BRAF non V600 mutations, which can include a point mutation, gene amplification, fusion, insertion, deletion, or alternative splicing, who have no prior exposure to a BRAF, MEK, or ERK inhibitor. Participants with prior exposure to BRAF-directed therapy will be allowed, pending confirmation of mutations in either a re-biopsy or ctDNA, if the mutational profile identifies a potential for response based on FORE8394 mechanism of action and after investigator discussion.
  6. Measurable disease defined as follows:
    1. RECIST v1.1 (non-CNS tumors) - For the purposes of this protocol, superficial lesions, such as cutaneous lesions, that are detectable only by physical examination are not considered measurable. However, they may be considered non-target lesions.
    2. RANO (CNS tumors) - high grade glioma (HGG) (Wen 2010) for high grade glioma (Grades 3 and 4) and RANO-low grade glioma (LGG) (Van den Bent 2011) for low grade glioma.
  7. Eastern Cooperative Oncology Group (ECOG) performance status of 0–1.
  8. Adequate hematologic, hepatic, and renal function. Participants must meet the following criteria within 10 days of initiating study drug:
    1. Absolute neutrophil count (ANC) ≥1.5 × 109/L
    2. Hemoglobin (Hgb) >9 g/dL
    3. Platelet count ≥100 × 109/L
    4. Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤2 × upper limit of normal (ULN)
    5. Total bilirubin ≤1.5 × ULN, or ≤2 × ULN if hepatic metastases/involvement
    6. Creatinine ≤1.5 × ULN or calculated creatinine clearance (CrCl) >50 mL/min (Cockcroft-Gault formula)
  9. Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to Cycle 1 Day 1 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. Effective forms of contraception include abstinence, hormonal contraceptive in conjunction with a barrier method, or a double barrier method. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year.
  10. Fertile men must agree to use an effective method of birth control during the study and for 3 months after the last dose of study drug.
  11. Completion of previous anti-cancer therapy with resolution of all associated clinically significant toxicity (to ≤Grade 1 or Baseline) prior to FORE8394 administration.
    1. Chemotherapy, tyrosine kinase inhibitor, or radiation therapy at least 2 weeks before FORE8394 initiation,
    2. Immunotherapy at least 3 months before FORE8394 initiation.
  12. Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Exclusion Criteria
  1. Participants with known co-occurring RAS-related mutations or RTK activation are not allowed.
  2. Symptomatic brain metastases. Participants 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. Participants 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. Participants with leptomeningeal disease are not eligible.
  3. Participants with PTC who:
    1. Are less than 3 weeks from their last radioactive iodine treatment;
    2. Have experienced clinically significant AEs associated with previous therapy that have not resolved to either Grade 1 or baseline; and/or
    3. Have a TSH level greater than the ULN per institutional laboratory range.
  4. Participants with colorectal cancer or pancreatic ductal adenocarcinoma. (Participants with fusions and with no other oncogenic driver alterations [e.g., KRAS, EGFR, ALK fusions] may be enrolled with the approval of the medical monitor.)
  5. Investigational drug use within 21 days (or 5 half-lives, whichever is shorter) of the first dose of FORE8394. For investigational immunotherapies: use within 3 months of the first dose of FORE8394.
  6. 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.
  7. Uncontrolled intercurrent illness
  8. 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 (PSA). Participants with a completely treated prior malignancy and no evidence of disease for ≥2 years are eligible.
  9. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption.
  10. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation in this study:
    1. Agents that are known strong inducers or inhibitors of CYP3A4. Restrictions include foods or herbal medications, including grapefruit juice, grapefruit/grapefruit-related citrus fruits [e.g., Seville oranges, pomelos]), and St. John’s Wort.
    2. Agents that are contraindicated with cobicistat. For participants with no other option except agents with potential drug interactions with cobicistat, but which are not contraindicated, the dose of that agent must be altered or the regimen must follow the cobicistat prescribing information and be approved by the Medical Monitor.
  11. Baseline QT interval corrected using Fridericia’s equation (QTcF) ≥450 msec (males) or ≥470 msec (females).
  12. Clinically significant cardiac arrhythmias including bradyarrhythmias and/or participants who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Participants with controlled atrial fibrillation are not excluded.
  13. Congenital long QT syndrome or participants taking concomitant medications known to prolong the QT interval (e.g., tricyclics, azithromycin, methadone).
  14. History of clinically significant cardiac disease or congestive heart failure >New York Heart Association (NYHA) class 2. Participant 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.
  15. Women who are breast-feeding or pregnant.
  16. Current active liver disease from any cause, including positive screening test for hepatitis A (hepatitis A virus immunoglobulin M [IgM]), hepatitis B (hepatitis B virus surface antigen [HBsAg]), or hepatitis C (hepatitis C virus [HCV] antibody, confirmed by HCV ribonucleic acid). EXCEPTIONS: Participants who are seropositive for HCV antibody but negative for HCV RNA by polymerase chain reaction (PCR) are eligible. Participants with occult or prior hepatitis B virus (HBV) infection, defined as seropositivity for total hepatitis B core antibody (HBcAb) and seronegativity for hepatitis B surface antigen (HBsAg), are eligible if HBV DNA is undetectable; these participants must be willing to undergo additional testing per local standard of care.
  17. Imprisoned or under legal guardianship.
  18. A medical or psychiatric condition that, in the opinion of the investigator, makes the participant inappropriate for study inclusion.
  19. Inability to swallow and retain study drug(s).

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Investigator(s)

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