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

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by Plexxikon
Sponsor:
Information provided by (Responsible Party):
Plexxikon
ClinicalTrials.gov Identifier:
NCT01790503
First received: February 7, 2013
Last updated: December 10, 2013
Last verified: December 2013
  Purpose

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).


Condition Intervention Phase
Patients With Newly Diagnosed Glioblastoma
Drug: PLX3397
Radiation: Radiation Therapy
Drug: Temozolomide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label Phase 1b/2 Study of Orally Administered PLX3397 in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

Resource links provided by NLM:


Further study details as provided by Plexxikon:

Primary Outcome Measures:
  • Phase 1b dose escalation: Identification of Recommended Phase 2 Dose (RP2D) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    A total of approximately 7 patients will be enrolled in each dose level. The starting dose level of PLX3397 will be 800 mg/day, using a twice daily (BID) dosing regimen. If that dose level is tolerated, the next dose level to be tested will be 1000 mg/day, which is the RP2D for single agent PLX3397 in solid tumors. Lower doses may be explored, if required. These lower doses are planned to be 600 mg/day (if PLX3397 is not tolerated at 800 mg/day) and 400 mg/day (if PLX3397 is not tolerated at 600 mg/day). Conversely, if the dose level of 1000 mg/day is tolerated, higher dose levels of PLX3397 may be investigated, at up to 50% increments, depending on the observed pharmacokinetics (PK) and toxicities.

  • Phase 2: Efficacy, Comparison of median Progression Free Survival (PFS) to historical control (median PFS of 5.5 months from the RTOG 0525 study) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    After discontinuation of PLX3397 for reasons other than progression of disease, patients will be followed as clinically indicated, until progression of disease or death is documented.


Secondary Outcome Measures:
  • Efficacy-Overall Survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    After discontinuation of PLX3397 patients will be followed as clinically indicated, until death is documented.

  • Safety-Subject incidence of adverse events [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

    Subjects will take oral doses of PLX3397 twice a day. Physical examinations, vital signs, 12-lead electrocardiograms (ECG), adverse events, hematology and serum chemistry will be used to assess safety throughout the study. Adverse events will be monitored and reviewed for safety issues/abnormal changes in the above mentioned tests.

    Ongoing safety will be continuously and rigorously monitored by the Sponsor. Additionally, biweekly teleconferences are planned to review in detail the safety across all study sites.


  • Pharmacokinetic profile (PK) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    PLX3397 PK parameters including, but not limited to, maximum observed concentration (Cmax), area under the plasma concentration-time curve and half-life will be measured.


Estimated Enrollment: 65
Study Start Date: August 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase 1b dose escalation - 800mg/day PLX3397 cohort
800mg/day PLX3397, Radiation Therapy, and Temozolomide
Drug: PLX3397 Radiation: Radiation Therapy Drug: Temozolomide
Other Names:
  • TMZ
  • Temodar
Experimental: Phase 1b dose escalation - 1000mg/day PLX3397
1000mg/day PLX3397, Radiation Therapy, and Temozolomide
Drug: PLX3397 Radiation: Radiation Therapy Drug: Temozolomide
Other Names:
  • TMZ
  • Temodar
Experimental: Phase 2 - Recommended phase 2 dose of PLX3397
Recommended phase 2 dose of PLX3397, Radiation therapy, and Temozolomide
Drug: PLX3397 Radiation: Radiation Therapy Drug: Temozolomide
Other Names:
  • TMZ
  • Temodar
Experimental: Phase 1b dose escalation - 600 mg/day PLX3397 cohort
600 mg/day PLX3397, Radiation Therapy, and Temozolomide
Drug: PLX3397 Radiation: Radiation Therapy Drug: Temozolomide
Other Names:
  • TMZ
  • Temodar

Detailed Description:

Study drug will be administered twice daily for 7 days prior to the initiation of RT (radiation therapy)and will continue twice daily during the course of RT. The RT schedule will be once daily for 5 days per week for 6 weeks (total radiation dose of 60 Gy. Oral temozolomide will be administered once daily (7 days per week) for the duration of RT. Four weeks after the completion of the course of RT, patients will be started on once-daily adjuvant temozolomide (Day 1-5 of a 28 day cycle) and PLX3397 twice daily (28 days of a 28 day cycle) for up to 12 cycles in the absence of progressive disease or unacceptable toxicities. After discontinuation of study drug, patients will continue to be followed for OS every 6 months. For patients participating in the run-in Phase 1b of the study, intra patient dose escalation will be permitted after a RP2D has been established. The Phase 2 portion of the study will enroll patients to be treated with PLX3397 at RP2D.

For the Phase 1b portion of the study, 2 cohorts (800 mg/day and 1000 mg/day) are planned to be enrolled at approximately 7-10 sites. Each cohort will consist of approximately 7 patients. Therefore, a minimum of 14 patients are planned to be enrolled in Phase 1b. Additional patients may be required for replacement patients, or if lower dose cohorts (600 mg or 400 mg) are required. For the Phase 2 portion of the study, enrollment is planned to include approximately 44 patients.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01790503

Contacts
Contact: David Karlin, MD 510-647-4100 dkarlin@plexxikon.com

Locations
United States, Illinois
Northwestern Memorial Hospital Recruiting
Chicago, Illinois, United States, 60611
Principal Investigator: Jeffrey Raizer, MD         
United States, Massachusetts
Dana Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Principal Investigator: David Reardon, MD         
United States, Michigan
Henry Ford Hospital Recruiting
Detroit, Michigan, United States, 48202
Principal Investigator: Tom Mikkelsen, MD         
United States, New York
Columbia University Medical Center Not yet recruiting
New York, New York, United States, 10032
Principal Investigator: Andrew Lassman, MD         
United States, Ohio
James Cancer Hospital/Ohio State University Recruiting
Columbia, Ohio, United States, 43210
Principal Investigator: Vinay Puduvalli, MD         
United States, Utah
Huntsman Cancer Institute University of Utah Recruiting
Salt Lake City, Utah, United States, 84132
Principal Investigator: Howard Colman, MD, PhD         
United States, Washington
Seattle Cancer Care Alliance Recruiting
Seattle, Washington, United States, 98109
Principal Investigator: Marc Chamberlain, MD         
Sponsors and Collaborators
Plexxikon
Investigators
Principal Investigator: Howard Colman, MD Huntsman Cancer Institute - Salt Lake City, UT
  More Information

No publications provided

Responsible Party: Plexxikon
ClinicalTrials.gov Identifier: NCT01790503     History of Changes
Other Study ID Numbers: PLX108-08
Study First Received: February 7, 2013
Last Updated: December 10, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Plexxikon:
glioblastoma
GBM

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 20, 2014