Clinical Trials /

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

NCT02428712

Description:

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

Related Conditions:
  • Histiocytosis
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of PLX8394 as a Single Agent in Patients With Advanced Unresectable Solid Tumors
  • Official Title: A Phase 1/2a Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of PLX8394 in Patients With Advanced Unresectable Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: PLX120-03
  • NCT ID: NCT02428712

Conditions

  • Advanced Unresectable Solid Tumors
  • BRAF-mutated Tumors

Interventions

DrugSynonymsArms
PLX8394PLX8394

Purpose

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

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
PLX8394ExperimentalPart 1: Open-label, sequential, PLX8394 single-agent dose escalation in approximately 42 patients (adults- Group A and pediatrics- Group B) with advanced, unresectable solid tumors. Part 2: Extension cohort at the R2PD of single-agent PLX8394 in approximately 65 patients (adults- Group A and pediatrics- Group B) with advanced cancers with an activating BRAF mutuation.
  • PLX8394

Eligibility Criteria

        Inclusion Criteria- 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

               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- 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:

        A. Diagnosis of pediatric brain tumor (e.g., pilocytic astrocytoma, pleomorphic
        xanthoastrocytoma, ganglioglioma, astrocytoma, papillary craniopharyngioma, glioblastoma)
        with an activating BRAF mutation.

        B. 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.

        D. 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.

        B. 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.

          -  ECOG performance status of 0-2.

          -  Adequate hematologic, hepatic, and renal function.

          -  .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.

          -  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 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.

          -  .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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered PLX8394 in patients with advanced solid tumors [Part 1]
Time Frame:1 year
Safety Issue:
Description:

Secondary Outcome Measures

Measure:To assess objective tumor response in patients with advanced BRAF-mutated cancers treated with PLX8394. [Part 2]
Time Frame:1 year
Safety Issue:
Description:
Measure:To assess response rate by Response Evaluation Criteria in Solid Tumors [Part 2]
Time Frame:1 year
Safety Issue:
Description:
Measure:To assess the PK, PD, and safety of PLX8394 [Part 2]
Time Frame:1 year
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Plexxikon

Last Updated

December 15, 2017