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

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ClinicalTrials.gov Identifier: NCT02428712
Recruitment Status : Active, not recruiting
First Posted : April 29, 2015
Last Update Posted : November 15, 2018
Sponsor:
Information provided by (Responsible Party):
Plexxikon

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

Condition or disease Intervention/treatment Phase
Advanced Unresectable Solid Tumors BRAF-mutated Tumors Drug: PLX8394 Phase 1 Phase 2

Detailed Description:

Dose Escalation (Part 1): To evaluate safety, pharmacokinetics, pharmacodynamics of PLX8394 in adult and pediatric patients 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 adult and in pediatric patients with advanced BRAF- mutated tumors, to access RECIST, and to access pharmacokinetics, pharmacodynamics, and safety.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 78 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2a Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of PLX8394 in Patients With Advanced Unresectable Solid Tumors
Study Start Date : April 2015
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : April 2020

Arm Intervention/treatment
Experimental: PLX8394

Group A: Phase 1-Dose Escalation: Adult patients.

Phase 2a-RP2D Confirmation (Formulation 2): Adult and pediatric patients.

Phase 2a-Dose Extension: Adult patients with advanced unresectable solid tumors will be enrolled among two cohorts.

  • Cohort 1: Activating BRAF V600 mutations
  • Cohort 2: Activating BRAF non-V600 mutations

Group B: Phase 1-Dose Escalation: Pediatric patients.

Phase 2a-Dose Extension: Pediatric patients with advanced unresectable BRAF-mutated tumors, including LCH.

Drug: PLX8394
(Formulation 1 or Formulation 2)




Primary Outcome Measures :
  1. Area under the curve (AUC) of PLX8394 (Formulation 1 and Formulation 2) [ Time Frame: First dose of PLX8394 up to 30 days after end of treatment ]
  2. Maximum concentration (Cmax) of PLX8394 (Formulation 1 and Formulation 2) [ Time Frame: First dose of PLX8394 up to 30 days after end of treatment ]
  3. Time to peak concentration (Tmax) of PLX8394 (Formulation 1 and Formulation 2) [ Time Frame: First dose of PLX8394 up to 30 days after end of treatment ]
  4. Half life (T1/2) of PLX8394 (Formulation 1 and Formulation 2) [ Time Frame: First dose of PLX8394 up to 30 days after end of treatment ]
  5. Number of participants with Treatment Emergent Adverse Events (TEAEs) as assessed by CTCAE v4.0 (Formulation 1 and Formulation 2). [ Time Frame: First dose of PLX8394 up to 30 days after end of treatment ]
  6. To identify the recommended Phase 2 dose (RP2D) of PLX8394 (Formulation 1) in Group A (adult patients) for further evaluation in Dose Extension. [ Time Frame: 2 years ]
  7. To identify the RP2D of PLX8394 (Formulation 1) in Group B (pediatric patients) for further evaluation in Dose Extension. [ Time Frame: 1 year ]
  8. Compare AUC of PLX8394 (Formulation 1) with PLX8394 (Formulation 2) [ Time Frame: First dose of PLX8394 up to 30 days after end of treatment ]
  9. Compare Cmax of PLX8394 (Formulation 1) with PLX8394 (Formulation 2) [ Time Frame: First dose of PLX8394 up to 30 days after end of treatment ]
  10. Compare Tmax of PLX8394 (Formulation 1) with PLX8394 (Formulation 2) [ Time Frame: First dose of PLX8394 up to 30 days after end of treatment ]
  11. Compare T1/2 of PLX8394 (Formulation 1) with PLX8394 (Formulation 2) [ Time Frame: First dose of PLX8394 up to 30 days after end of treatment ]
  12. To determine the overall response rate of PLX8394 treatment at the applicable RP2D in a) Group A, Cohort 1, b) Group A, Cohort 2, and c) Group B. [ Time Frame: 5 years ]

Secondary Outcome Measures :
  1. To evaluate the duration of response (defined as time of initial response to progressive disease or death) at the applicable RP2D in Dose Extension. [ Time Frame: 5 years ]
  2. To evaluate the progression free survival (defined as time of first dose to progressive disease or death) at the applicable RP2D in Dose Extension. [ Time Frame: 5 years ]
  3. Clinical benefit rate (defined as stable disease, partial response and complete response) after 24 weeks on study [ Time Frame: 5 years ]


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 0-2.
  • 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 0-2.
  • 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, or HCV or a known carrier of HBV or HCV.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02428712


Locations
United States, Arizona
HonorHealth
Scottsdale, Arizona, United States, 85258
United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
Stanford Hospitals and Clinics
Stanford, California, United States, 94305
United States, Florida
University of Miami
Miami, Florida, United States, 33136
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Pennsylvania
Thomas Jefferson University Medical Oncology Clinica
Philadelphia, Pennsylvania, United States, 19107
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Texas Children's Hospital (Baylor College of Medicine)
Houston, Texas, United States, 77030
United States, Utah
Huntsman Cancer Institute
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
Plexxikon

Responsible Party: Plexxikon
ClinicalTrials.gov Identifier: NCT02428712     History of Changes
Other Study ID Numbers: PLX120-03
First Posted: April 29, 2015    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: October 2018

Additional relevant MeSH terms:
Neoplasms