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Summary

at San Francisco, California and other locations
study started
estimated completion:

Description

Summary

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

Official Title

A Phase 1/2a Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of PLX8394 in Patients With Advanced Unresectable Solid Tumors

Details

Dose Escalation (Part 1): To evaluate safety, pharmacokinetics, pharmacodynamics of PLX8394 in adults and pediatrics with advanced BRAF- mutated tumors, and to identify the recommended Phase 2 Dose.

Dose Extension (Part 2): To access objective tumor response to PLX8394 treatment in adults and in pediatric patients with advanced BRAF- mutated tumors, to access RECIST, and to access pharmacokinetics, pharmacodynamics, and safety.

Keywords

Advanced Unresectable Solid Tumors BRAF-mutated Tumors Neoplasms

Eligibility

You can join if…

  • Group A:

    • 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
    • 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
    • Non-melanoma solid tumors:
    • No prior exposure to RAS/RAF/MEK/ERK pathway inhibitors
    • 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.

You CAN'T join if...

  • Group A:

    • 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.

Inclusion Criteria — Group B:

  • Minimum developmental age: the ability to swallow and retain study drug and a minimum body surface area (BSA) that allows a PLX8394 dose level of at least 75 mg BID.
  • Patients with a history of activating BRAF mutation, including the following:
  • Diagnosis of pediatric brain tumor (e.g., pilocytic astrocytoma, pleomorphic xanthoastrocytoma, ganglioglioma, astrocytoma, papillary craniopharyngioma, glioblastoma)with an activating BRAF mutation.
  • Histologically proven LCH with an activating BRAF mutation. C. Diagnosis of LCH-associated neurodegenerative disease (LCH-ND) with an activating BRAF mutation in tumor biopsy or in circulating cells and radiologic progression within the past 3 months or radiologic evidence of neurodegeneration with an ataxia rating score >20.
  • Other advanced malignancy with an activating BRAF mutation.

• The following previous therapy experience: A. Pediatric brain tumors with measurable disease — failure of front-line therapy.

  1. High-risk LCH with measurable disease — failure of front-line therapy. C. Low-risk LCH with measurable disease — failure of second-line therapy. D. LCH-ND — no previous therapy required. E. Other measurable solid tumors (e.g., melanoma, Wilm's tumor, papillary thyroid carcinoma) refractory to, relapsed after, or intolerant to standard therapy or for whom no standard therapy exists.
  2. ECOG performance status of 0-2.
  3. Adequate hematologic, hepatic, and renal function.
  4. .Females of child-bearing potential must have a negative serum pregnancy at 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.Females of non-child-bearing potential may be included if they are either surgically sterile, have been postmenopausal for ≥1 year, or are premenopausal.
  5. 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.
  6. Completion of previous chemotherapy, immunotherapy, or targeted therapy (including MAPK pathway inhibitors) at least 1 month (or 5 half-lives, whichever is longer)before study drug initiation, with resolution of all associated toxicity prior to PLX8394 administration.
  7. .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 (unless the wound has healed), or anticipation of the need for major surgery during the study.
  • Dose Escalation — Investigational drug use within 28 days (or 5 half-lives, whichever is longer) of the first dose of PLX8394.
  • 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.
  • Patients with >Grade 1 (high or low) serum potassium, magnesium, or calcium levels.
  • Baseline QTcF interval >450 msec (males) or >470 msec (females).
  • Patients with clinically significant cardiac arrhythmias, including brady-arrhythmias,and/or patients who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Patients with controlled atrial fibrillation are not excluded.
  • Patients with congenital long QT syndrome or patients taking concomitant mediations known to prolong the QT interval.
  • History of clinically significant cardiac disease or congestive heart failure >NYHA class 2. Patients must not have unstable angina or new-onset angina within the last 3 months or myocardial infarction within the past 6 months.
  • Females who are breast-feeding or pregnant.
  • Known chronic HIV, HCV, or HBV infection.
  • The presence of a medical or psychiatric condition that, in the opinion of the investigator, makes the patient inappropriate for study inclusion.

Locations

  • University of California, San Francisco not yet accepting patients
    San Francisco, California, 94143, United States
  • Stanford Hospitals and Clinics accepting new patients
    Stanford, California, 94305, United States

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Plexxikon
ID
NCT02428712
Phase
Phase 1/2
Lead Scientist
Alain Algazi
Study Type
Interventional
Last Updated
September 19, 2017
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