A Phase 2 Study of PLX3397 in Patients With Recurrent Glioblastoma

A Phase 2 Study of Orally Administered PLX3397 in Patients With Recurrent Glioblastoma

The objective of this study is to evaluate the response of subjects with recurrent glioblastoma to continuous therapy of PLX3397.

Study Overview

• Status: Terminated
• Conditions: Recurrent Glioblastoma
• Intervention / Treatment: Drug: PLX3397

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University California, Los Angeles
    • San Francisco, California, United States, 94143
      • University California, San Francisco
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Faber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas, MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Huntsman Cancer Institute University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patients ≥18 years old with a life expectancy of at least 8 weeks
• Radiographically proven recurrent (≥ first relapse), intracranial Glioblastoma (GBM)
• For all patients, availability of at least 10 unstained slides (or archival tumor block sufficient to generate at least 10 unstained slides) from any previous GBM surgery
• Previous treatment with external beam radiation and temozolomide chemotherapy
• Before the first dose of PLX3397,adequate recovery from toxicity of prior therapy as follows:

>28 days for cytotoxic therapy >42 days for nitrosoureas >28 days for bevacizumab >7 days for non cytotoxic therapy such as interferon, tamoxifen, thalidomide, cis-retinoic acid, or erlotinib

• Women of child-bearing potential must have a negative pregnancy test within 7 days of initiation of dosing and must agree to use an acceptable method of birth control while on study drug and for 3 months after the last dose. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. Men of child-bearing potential must also agree to use an acceptable method of birth control while on study drug.
• Karnofsky performance status of ≥60
• Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.0 x 109/L, Hgb >9 g/dL, platelet count ≥50 x 109/L, Aspartate aminotransferase/Alanine aminotransferase (AST/ALT) ≤2.5x Upper Limit of Normal (ULN), creatinine ≤1.5x ULN)
• Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements

Exclusion Criteria:

• Investigational drug use within 28 days of the first dose of PLX3397
• GBM progression within 3 months of previous radiation by Response Assessment in Neuro-Oncology (RANO) criteria
• History of Grade 2 Common Toxicity Criteria for Adverse Events (CTCAE v4) or greater acute intracranial hemorrhage
• Previous failure of bevacizumab or other vascular endothelial growth factor (VEGF) therapy except in a first line setting
• History of malignant glioma with co-deletion of 1p/19q
• A concurrent active cancer that requires non-surgical therapy (e.g. chemotherapy, radiation, adjuvant therapy). Prior history of other cancer is allowed, as long as there was no active disease within the prior 3 years.
• Refractory nausea and vomiting, malabsorption, biliary shunt, or significant bowel resection that would preclude adequate absorption
• Patients with serious illnesses, uncontrolled infection, medical conditions, or other medical history including abnormal laboratory results, which in the investigator's opinion would be likely to interfere with a patient's participation in the study, or with the interpretation of the results
• Women of child-bearing potential who are pregnant or breast feeding
• corrected QT interval (QTc) ≥450 msec at Screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: PLX3397-Cohort 1; 10 patients with recurrent glioblastoma who require reoperation will be treated with PLX3397 for 7 days prior to surgery and their tumor tissue will be evaluated for pharmacokinetic levels and pharmacodynamic effects.	Drug: PLX3397; Capsules administered once or twice daily, continuous dosing; Other Names: Pexidartinib
EXPERIMENTAL: PLX3397-Cohort 2; 30 patients will be orally dosed with PLX3397 continuously on 28 day cycles.	Drug: PLX3397; Capsules administered once or twice daily, continuous dosing; Other Names: Pexidartinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of Response Rates in Participants on Treatment With PLX3397	Response to treatment was evaluated using the Response Assessment in Neuro-Oncology (RANO) criteria. All participants were evaluated for progression free survival (PFS), and overall survival (OS). The six-month PFS rate was defined as the number of subjects with PFS of at least 6-month duration, with PFS measured from the first day of treatment (Cycle 1, Day 1) to the date of the first documented disease progression or date of death, whichever occurs first, over a 6-month period and evaluated using the Kaplan Meier method. The rate of OS was defined as the number of subjects that survived until study exit.	6 months post dose
Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15	A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters, include time to maximum concentration (Tmax) and will be calculated from the Cycle 1, Day 15 values.	Pre-dose and up to 6 post dose during cycle 1, Day 15
Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15	A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters include maximum concentration (Cmax) and will be calculated from the Cycle 1, Day 15 values.	Pre-dose and up to 6 post dose during cycle 1, Day 15
Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15	A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters include an assessment of area under the curve over 0-4 hours (AUC0-4), and will be calculated from the Cycle 1, Day 15 values.	Pre-dose and up to 6 post dose during cycle 1, Day 15
Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15	A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters include an assessment of area under the curve over 0-6 hours (AUC0-6), and will be calculated from the Cycle 1, Day 15 values.	Pre-dose and up to 6 post dose during cycle 1, Day 15

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population)	Up to 1 year post dose

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.
• Collaborators: Plexxikon

Publications and helpful links

General Publications

• Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD; North American Brain Tumor Consortium. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol. 2008 Apr;10(2):162-70. doi: 10.1215/15228517-2007-062. Epub 2008 Mar 4.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 3, 2011
• Primary Completion (ACTUAL): November 5, 2013
• Study Completion (ACTUAL): November 5, 2013

Study Registration Dates

• First Submitted: May 4, 2011
• First Submitted That Met QC Criteria: May 5, 2011
• First Posted (ESTIMATE): May 6, 2011

Study Record Updates

• Last Update Posted (ACTUAL): March 3, 2020
• Last Update Submitted That Met QC Criteria: February 18, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Glioblastoma; brain cancer
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence
• Other Study ID Numbers: PLX108-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR