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

NCT ID: NCT00960492

Last Updated: 2014-09-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-09-30
• Study Completion Date: 2013-10-31

Brief Summary

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.

Conditions

Glioblastoma; Giant Cell Glioblastoma; Gliosarcoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

XL184

Intervention Type: DRUG

XL184 will be administered daily as a single oral agent supplied as 25- and 100-mg capsules

temozolomide

Intervention Type: DRUG

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

Radiation Therapy

Intervention Type: RADIATION

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.

Arm 2

XL184 will be initiated during the maintenance phase with TMZ

Group Type: EXPERIMENTAL

XL184

Intervention Type: DRUG

XL184 will be administered daily as a single oral agent supplied as 25- and 100-mg capsules

temozolomide

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

XL184

Intervention Type: DRUG

XL184 will be administered daily as a single oral agent supplied as 25- and 100-mg capsules

temozolomide

Intervention Type: DRUG

TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules.

Interventions

XL184

XL184 will be administered daily as a single oral agent supplied as 25- and 100-mg capsules

Intervention Type: 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

Intervention Type: 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.

Intervention Type: DRUG

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.

Intervention Type: RADIATION

temozolomide

TMZ will be supplied as 5-, 20-, 100-, 250-, 140-, and 180-mg capsules.

Intervention Type: DRUG

Other Intervention Names

Temodar®; Temodar®; Temodar®

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Exelixis

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

UCLA

Los Angeles, California, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Henry Ford Health System

Detroit, Michigan, United States

Beth Israel Medical Center

New York, New York, United States

Duke University Medical Center; The Preston Robert Tisch Brain Tumor Center

Durham, North Carolina, United States

MD Anderson Cancer Center

Houston, Texas, United States

University of Virginia Health System/Division of Neuro-Oncology

Charlottesville, Virginia, United States

University of Washington

Seattle, Washington, United States

Countries

United States

Other Identifiers

XL184-002

Identifier Type: -

Identifier Source: org_study_id