A Phase 1b/2 Study of PLX3397 + Radiation Therapy + Temozolomide in Patients With Newly Diagnosed Glioblastoma

NCT01790503 | Completed Phase 1 Results DMC

• 1 other identifier: PLX108-08
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 9

Brief Summary

The study objectives are to assess the potential for PLX3397 to improve the efficacy of standard of care radiation therapy (RT) + temozolomide in patients with newly diagnosed glioblastoma (GBM).

Conditions

Patients With Newly Diagnosed Glioblastoma

Keywords

glioblastoma; GBM

Outcome Measures

Primary Outcomes (2)

• Summary of the Median Progression-free Survival (mPFS) in the Combined 800 mg, 5 Days/Week Dose Group

  Progression was determined by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS) was analyzed based on the non-parametric Kaplan-Meier method.

  Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months.

• Summary of the Median Progression-free Survival (mPFS) in the Study Group Compared With Historical Control From Medical Literature

  mPFS was based on model parameters estimated by maximum likelihood with a Newton-Raphson algorithm. The Radiation Therapy Oncology Group (RTOG) 0525 study was the main historical control used for statistical analysis. Additionally, RTOG-0825 was also used to support this outcome measure.

  Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months.

Secondary Outcomes (9)

• Summary of the Median Progression-free Survival (mPFS) by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose

  Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months.

• Summary of the Overall Survival in The Study Population

  Assessed from date of first dose administered to date of death from any cause, assessed up to 4 years 4 months

• Summary of the Overall Survival in the Study Group Compared With Historical Control From Medical Literature

  Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months.

• Summary of the Overall Survival by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose

  Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months.

• Summary of Best Overall Response by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose

  Assessed from Baseline and every 8 weeks, up to 4 years 4 months

Study Arms (4)

Phase 1b dose escalation - 600mg/day PLX3397 cohort

EXPERIMENTAL

600mg/day PLX3397, Radiation Therapy, and Temozolomide

Drug: PLX3397; Radiation: Radiation Therapy; Drug: Temozolomide

Phase 1b dose escalation - 800mg/day PLX3397

EXPERIMENTAL

800mg/day PLX3397, Radiation Therapy, and Temozolomide

Drug: PLX3397; Radiation: Radiation Therapy; Drug: Temozolomide

Phase 1b dose escalation - 1000 mg/day PLX3397 cohort

EXPERIMENTAL

1000 mg/day PLX3397, Radiation Therapy, and Temozolomide

Drug: PLX3397; Radiation: Radiation Therapy; Drug: Temozolomide

Phase 2 - Recommended phase 2 dose of PLX3397

EXPERIMENTAL

Recommended phase 2 dose of PLX3397 (800mg/day), Radiation therapy, and Temozolomide

Drug: PLX3397; Radiation: Radiation Therapy; Drug: Temozolomide

Interventions

PLX3397 DRUG

Also known as: Pexidartinib

Phase 1b dose escalation - 1000 mg/day PLX3397 cohort; Phase 1b dose escalation - 600mg/day PLX3397 cohort; Phase 1b dose escalation - 800mg/day PLX3397; Phase 2 - Recommended phase 2 dose of PLX3397

Radiation Therapy RADIATION

Phase 1b dose escalation - 1000 mg/day PLX3397 cohort; Phase 1b dose escalation - 600mg/day PLX3397 cohort; Phase 1b dose escalation - 800mg/day PLX3397; Phase 2 - Recommended phase 2 dose of PLX3397

Temozolomide DRUG

Also known as: TMZ, Temodar

Phase 1b dose escalation - 1000 mg/day PLX3397 cohort; Phase 1b dose escalation - 600mg/day PLX3397 cohort; Phase 1b dose escalation - 800mg/day PLX3397; Phase 2 - Recommended phase 2 dose of PLX3397

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients ≥18 years old.
• Histologically confirmed definitive GBM or gliosarcoma by partial or complete surgical resection (i.e. not by biopsy only) within 5 weeks prior to PLX3397 administration (C1D1). Tumor must have a supratentorial component. For all patients, availability of a surgical paraffin tumor block sufficient to generate at least 20 unstained slides; or, if a paraffin tumor block is unavailable, at least 20 unstained slides.
• The patient must have recovered from the effects of surgery, post-operative infection, and other complications before study registration.
• A diagnostic contrast-enhanced MRI or CT scan of the brain must be performed preoperatively and postoperatively prior to the initiation of radiotherapy, within 28 days (preferably 14 days) prior to C1D1.
• Patients unable to undergo MR imaging because of non-compatible devices can be enrolled, provided pre- and post-operative contrast-enhanced CT scans are obtained and are of sufficient quality.
• Patients must receive RT at the participating institution.
• Women of child-bearing potential must have a negative pregnancy test within 14 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, and for 3 months after the last dose.
• Karnofsky performance status of ≥70.
• Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.5x 109/L, Hgb \>10 g/dL, platelet count ≥100 x 109/L, AST/ALT ≤2.5x 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.

You may not qualify if:

• Evidence of recurrent GBM or metastases detected outside of the cranial vault.
• Investigational drug use within 28 days of the first dose of PLX3397 or concurrently.
• Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment.
• Prior radiation or chemotherapy for glioblastoma or glioma.
• Prior chemotherapy or radiosensitizers for cancer of the head and neck (except for T1 glottic cancer) that would result in an overlap of radiation fields.
• Prior allergic reaction to temozolomide.
• History of Grade 2 (CTCAE v4) or greater acute intracranial hemorrhage.
• Active cancer (either concurrent or within the last 3 years) that requires non-surgical therapy (e.g. chemotherapy or radiation therapy), with the exception of surgically treated basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix.
• Chronic active hepatitis B or C.
• Refractory nausea and vomiting, malabsorption, biliary shunt, or significant bowel resection that would preclude adequate absorption of study drug.
• 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.
• At Screening QTcF ≥450 msec for males and ≥470 msec for females.

Sponsors & Collaborators

• Daiichi Sankyo: lead
• Plexxikon: collaborator

Study Sites (9)

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

James Cancer Hospital/Ohio State University

Columbia, Ohio, 43210, United States

Location

Huntsman Cancer Institute University of Utah

Salt Lake City, Utah, 84132, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

Related Publications (2)

• Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013 Nov 10;31(32):4085-91. doi: 10.1200/JCO.2013.49.6968. Epub 2013 Oct 7.

  PMID: 24101040 RESULT

• Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573.

  PMID: 24552317 RESULT

MeSH Terms

Conditions

Glioblastoma

Interventions

pexidartinib; Radiotherapy; Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Therapeutics; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Medical Director
• Organization: Daiichi Sankyo Inc.

CTRinfo@dsi.com

908-992-6400

Study Officials

• Global Clinical Leader

  Daiichi Sankyo

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 7, 2013
• First Posted: February 13, 2013
• Study Start: July 18, 2013
• Primary Completion: November 3, 2017
• Study Completion: March 4, 2020
• Last Updated: June 30, 2020
• Results First Posted: October 9, 2019

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• 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.
• 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.

Locations

US (9)