Safety Study of XL184 (Cabozantinib) in Combination With Temozolomide and Radiation Therapy in the Initial Treatment of Adults With Glioblastoma

A Phase 1 Dose Finding Study of the Safety and Pharmacokinetics of XL184 Administered Orally in Combination With Temozolomide and Radiation Therapy in the First Line Treatment of Subjects With Glioblastoma

The purpose of this study is to determine the highest safe dose of XL184 administered orally in combination with temozolomide (TMZ, Temodar®) and radiation therapy (RT). XL184 is a new chemical entity that inhibits VEGFR2, MET, and RET, kinases implicated in tumor formation, growth and migration. Temozolomide (TMZ, Temodar®) is an orally administered alkylating agent. It is approved by the Food and Drug Administration (FDA) for the treatment of newly diagnosed glioblastoma (GB) patients when given in combination with radiation therapy (RT) followed by maintenance treatment. First-line treatment for patients with GB consists of a concurrent phase (6-7 weeks in duration) during which TMZ is given with RT, followed by a rest phase (4 weeks in duration; to allow for recovery from delayed toxicity, if present), and a maintenance phase, during which patients receive TMZ for approximately twelve 28-day cycles. To determine the highest safe dose, subjects will receive different amounts of XL184 at different times according to the phase of TMZ and radiation therapy. The first group of subjects will receive the lowest dose of XL184. As long as no medically unacceptable side effects are noted, the dose will be increased for the next group. If the dose is not well-tolerated by the first group of subjects, the dose will be lowered for the next group.

Study Overview

• Status: Completed
• Conditions: Glioblastoma; Gliosarcoma; Giant Cell Glioblastoma
• Intervention / Treatment: Drug: XL184; Drug: temozolomide; Drug: temozolomide; Radiation: Radiation Therapy; Drug: temozolomide

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • New York
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center; The Preston Robert Tisch Brain Tumor Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System/Division of Neuro-Oncology
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington

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:

• Histologically confirmed diagnosis of Grade 4 astrocytic tumor, which includes glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components.
• Must have had a partial or complete surgical resection of the Grade 4 astrocytic tumor.
• Subjects in Arm 1 must have had no previous treatment except surgery (ie, no previous RT, local chemotherapy, or systemic therapy). Subjects must meet certain other eligibility requirements.
• Subjects in Arm 2 must have completed a standard first line regimen of concurrent TMZ and RT for newly diagnosed GB, followed by a rest phase, and has not had any other previous treatment except surgery (including any other regimens of RT and local or systemic chemotherapy). Subjects must meet certain other eligibility requirements.
• Subjects must be able to undergo serial MRIs (computerized tomography [CT] may not substitute for magnetic resonance imaging [MRI]).
• Must be ≥ 18 years old.
• Must have a Karnofsky performance status of ≥ 70% and the ability to swallow whole capsules
• Must have no other diagnosis of malignancy (except surgically excised non-melanoma skin cancer or carcinoma in situ of the cervix, treated early stage prostate cancer, or a malignancy diagnosed ≥ 2 years previously with no current evidence of disease and no therapy within two years prior to enrollment on this study).
• Must be capable of understanding and complying with the protocol requirements and has signed the informed consent document.
• Sexually active fertile subjects (male and female) must agree to use accepted methods of contraception during the course of the study and for 3 months after the last dose of study drug(s).
• Female subjects of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

• Subject has received prior systemic chemotherapy or RT (Arm 1) or prior systemic chemotherapy other than TMZ (Arm 2), biologic agents, or any other type of investigational agent for the treatment of brain tumors. Subjects who have progressed on TMZ are not eligible.
• Subject has evidence of acute intracranial or intratumoral hemorrhage > Grade 1 either by MRI or CT scan. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin may enter the study.
• Subject has serious intercurrent illness such as: hypertension despite optimal treatment, or significant cardiac arrhythmias; or a recent history of serious disease such as symptomatic congestive heart failure, or abdominal fistula or gastrointestinal (GI) perforation within 6 months, prior to starting study treatment.
• Subject has had major surgery within 28 days prior to starting study treatment, or had non water-tight dural closure during previous surgery, or has unhealed wounds from previous surgery.
• Subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.
• Subject is pregnant or breastfeeding.
• Subject is known to be positive for the human immunodeficiency virus (HIV) (a test for HIV at screening is not required).
• Subject has a previously-identified allergy or hypersensitivity to components of either the XL184 or TMZ formulations.
• Subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm 1; XL184 will be initiated at the start of the 6-7 week concurrent phase of RT (+TMZ; some subjects found to have specific gene activity in their tumor tissue may not receive TMZ), given as a single agent during the rest phase (4 weeks), if applicable, and continued subsequently in the maintenance phase.	Drug: XL184; XL184 will be administered daily as a single oral agent supplied as 25- and 100-mg capsules; Drug: temozolomide; TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules. The starting dose will be 75 mg/m2/day given daily with concurrent RT for 6 weeks; Other Names: Temodar®; Drug: temozolomide; TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules. The starting dose will be 200 mg/m2/day given for 5 consecutive days and repeated every 28 days.; Other Names: Temodar®; Radiation: Radiation Therapy; Subjects will receive RT consisting of fractionated focal irradiation administered using 1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total dose of up to 60 Gy.; Drug: temozolomide; TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules.; Other Names: Temodar®
EXPERIMENTAL: Arm 2; XL184 will be initiated during the maintenance phase with TMZ	Drug: XL184; XL184 will be administered daily as a single oral agent supplied as 25- and 100-mg capsules; Drug: temozolomide; TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules. The starting dose will be 75 mg/m2/day given daily with concurrent RT for 6 weeks; Other Names: Temodar®; Drug: temozolomide; TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules. The starting dose will be 200 mg/m2/day given for 5 consecutive days and repeated every 28 days.; Other Names: Temodar®; Drug: temozolomide; TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules.; Other Names: Temodar®
EXPERIMENTAL: MTD Expansion; XL184 will be initiated at the start of the 6-7 week concurrent phase of RT (+TMZ; some subjects found to have specific gene activity in their tumor tissue may not receive TMZ), given as a single agent in the rest phase (4 weeks), if applicable, and continued subsequently in the maintenance phase. Subjects in this group will receive XL184 and TMZ at the maximally tolerated dose levels determined in Arms 1 and 2.	Drug: XL184; XL184 will be administered daily as a single oral agent supplied as 25- and 100-mg capsules; Drug: temozolomide; TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules. The starting dose will be 75 mg/m2/day given daily with concurrent RT for 6 weeks; Other Names: Temodar®; Drug: temozolomide; TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules. The starting dose will be 200 mg/m2/day given for 5 consecutive days and repeated every 28 days.; Other Names: Temodar®; Drug: temozolomide; TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules.; Other Names: Temodar®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Evaluate the safety and tolerability of oral administration of XL184 added to first-line treatment for subjects with newly diagnosed GB	Assessed at every visit to the study clinic
Determine the maximum tolerated dose (MTD) of oral XL184 when added to the concurrent phase of treatment with TMZ and RT and when added to the maintenance phase of treatment with TMZ for subjects with newly diagnosed GB	Assessed periodically as subjects are dose-escalted
Determine the safety and tolerability of XL184 when administered in combination with first-line treatment throughout the concurrent, rest and maintenance phases in an expanded MTD cohort	Assessed at each visit to the study center

Secondary Outcome Measures

Outcome Measure	Time Frame
Evaluate the plasma pharmacokinetics of XL184 and TMZ when XL184 is administered in combination with TMZ, and of XL184 when it is administered alone, in subjects with newly diagnosed GB	Assessed at 4 visits during the concurrent phase, 2 visits during the first maintenance phase cycle, and approximately every 4 weeks thereafter
Evaluate the pharmacodynamic effects of XL184 (with or without TMZ) and RT in the first line treatment of subjects with GB.	Assessed at 4 visits during the concurrent phase, 2 visits during the first maintenance phase cycle, and approximately every 4 weeks thereafter
Evaluate the preliminary efficacy of XL184 (with or without TMZ) and RT in the MTD expansion cohort in the first line treatment of subjects with GB	Assessed at 10 weeks and approximately every 4 weeks thereafter

Collaborators and Investigators

• Sponsor: Exelixis

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (ACTUAL): November 1, 2012
• Study Completion (ACTUAL): October 1, 2013

Study Registration Dates

• First Submitted: August 13, 2009
• First Submitted That Met QC Criteria: August 14, 2009
• First Posted (ESTIMATE): August 17, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): September 22, 2014
• Last Update Submitted That Met QC Criteria: September 19, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Astrocytic tumor; Glioblastoma with oligodendroglial components
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Gliosarcoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: XL184-002