Clinical trial NCT00704288: Study of XL184 (Cabozantinib) in Adults With Glioblastoma Multiforme
Official title: A Phase 2 Study of XL184 in Subjects With Progressive or Recurrent Glioblastoma Multiforme in First or Second Relapse
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Glioblastoma Multiforme
Keywords: GBM
Malignant gliomas
Lead sponsor: Exelixis
Sponsor class: INDUSTRY
First posted: 2008-06-24
Enrollment: 222
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the objective response rate and 6-month progression-free survival rate of XL184 in subjects with recurrent or progressive glioblastoma multiforme. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration.


Eligibility criteria: Inclusion Criteria:

* The subject has locally determined histologically confirmed diagnosis of Grade 4 astrocytic tumor.
* The subject has received prior standard radiation for Grade 3 or 4 astrocytic tumor.
* The subject has received prior temozolomide therapy for Grade 3 or 4 astrocytic tumor (if in first relapse, the subject must have received temozolomide until progression, intolerance, or completion of planned therapy; if in second relapse, the subject must have received temozolomide until progression, intolerance, or completion of planned therapy either for first-line treatment or for treatment after first relapse).
* The subject is in first or second Grade 4 relapse, defined as having one or two progressions as Grade 4 astrocytic tumor since the original diagnosis of any grade glioma.
* The subject must have a baseline brain MRI scan within 14 days prior to first dose of XL184 while either not receiving glucocorticoids during the 5 days prior to the baseline MRI scan or on a stable dose of glucocorticoids during the 5 days prior to the baseline MRI scan.
* Subjects having undergone recent resection or biopsy of tumor will be eligible as long as all of the following conditions apply: First dose of XL184 occurs at least 28 days after surgery, the subject has recovered from the effects of surgery, and the subject has measurable residual disease.
* The subject is at least 18 years old.
* The subject has a KPS (Karnofsky Performance Scale) of ≥ 70%.
* The subject is capable of understanding the protocol and has signed the informed consent document.
* The subject has adequate organ and marrow function.
* Sexually active subjects (male and female) must agree to use medically accepted methods of contraception during the course of the study and for 3 months following discontinuation of study drug.
* Female subjects of childbearing potential must have a negative pregnancy test at enrollment.

Exclusion Criteria:

* The subject has received non-standard radiation therapy for glioblastoma, non-anti-angiogenic therapy (including investigational agents, small-molecule kinase inhibitors, and biologic agents) or non-cytotoxic hormonal agent within 28 days of the first scheduled dose of XL184 or mitomycin C within 42 days of the first scheduled dose of XL184, other investigational therapy (including agents not specified above) within 28 days of the first scheduled dose of XL184, or prior treatment with nitrosoureas (including carmustine wafer) at any time.
* Some subjects may not have had any prior VEGF- or VEGFR2-based anti-angiogenic therapy (such as bevacizumab, cediranib, or pazopanib).
* Some subjects may not have had bevacizumab within 14 days of the first scheduled dose of XL184.
* The subject is receiving warfarin (or other coumarin derivatives) at study entry and unable to switch to low molecular weight heparin.
* The subject has evidence of acute intracranial or intratumoral hemorrhage either by MRI or computerized tomography (CT) scan. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin may enter the study.
* The subject is unable to undergo MRI scan (eg, has pacemaker).
* The subject has received enzyme-inducing anti-epileptic agents within 2 weeks before the first dose of XL184 (eg, carbamazepine, phenytoin, phenobarbital, primidone).
* The subject has not recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Grade ≤ 1 from adverse events (AEs) due to surgery, antineoplastic agents, investigational drugs, or other medications that were administered before study enrollment.
* The subject has evidence of wound dehiscence.
* The subject is pregnant or breast-feeding.
* The subject has serious intercurrent illness, such as uncontrolled hypertension, unhealed wounds from recent surgery or cardiac arrhythmias or a recent history of significant disease such as either symptomatic congestive heart failure or unstable angina pectoris within the past 3 months, myocardial infarction within the past 6 months, or active infection requiring systemic treatment/hospitalization within 2 weeks of the first scheduled dose of XL184
* The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.
* The subject has received any live virus vaccine within 28 days or any inactivated vaccine within 7 days prior to first dose of XL184.
* The subject has had another diagnosis of malignancy (unless nonmelanoma skin cancer, in situ carcinoma of the cervix, or a malignancy diagnosed ≥ 2 years previously) or currently has evidence of malignancy (unless non-melanoma skin cancer or in situ carcinoma of the cervix).
* The subject has a known allergy or hypersensitivity to any of the components of the XL184 formulations.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 8 weeks until progressive disease
Secondary outcomes:
measure: Duration of Objective Response (Months)
timeFrame: Assessed during periodically scheduled visits until progressive disease
measure: Progression Free Survival (PFS)
timeFrame: Assessed during periodically scheduled visits until progressive disease
measure: Overall Survival (OS)
timeFrame: Assessed during periodically scheduled visits until progressive disease
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Durham
country: United States
facility: Duke University, The Preston Robert Tisch Brain Tumor Center
state: North Carolina
city: Houston
country: United States
facility: University of Texas M.D. Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
References:
citation: Ellingson BM, Aftab DT, Schwab GM, Hessel C, Harris RJ, Woodworth DC, Leu K, Chakhoyan A, Raymond C, Drappatz J, de Groot J, Prados MD, Reardon DA, Schiff D, Chamberlain M, Mikkelsen T, Desjardins A, Holland J, Ping J, Weitzman R, Wen PY, Cloughesy TF. Volumetric response quantified using T1 subtraction predicts long-term survival benefit from cabozantinib monotherapy in recurrent glioblastoma. Neuro Oncol. 2018 Sep 3;20(10):1411-1418. doi: 10.1093/neuonc/noy054.
citation: Cloughesy TF, Drappatz J, de Groot J, Prados MD, Reardon DA, Schiff D, Chamberlain M, Mikkelsen T, Desjardins A, Ping J, Holland J, Weitzman R, Wen PY. Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy. Neuro Oncol. 2018 Jan 22;20(2):259-267. doi: 10.1093/neuonc/nox151.
citation: Wen PY, Drappatz J, de Groot J, Prados MD, Reardon DA, Schiff D, Chamberlain M, Mikkelsen T, Desjardins A, Holland J, Ping J, Weitzman R, Cloughesy TF. Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy. Neuro Oncol. 2018 Jan 22;20(2):249-258. doi: 10.1093/neuonc/nox154.
citation: Ellingson BM, Harris RJ, Woodworth DC, Leu K, Zaw O, Mason WP, Sahebjam S, Abrey LE, Aftab DT, Schwab GM, Hessel C, Lai A, Nghiemphu PL, Pope WB, Wen PY, Cloughesy TF. Baseline pretreatment contrast enhancing tumor volume including central necrosis is a prognostic factor in recurrent glioblastoma: evidence from single and multicenter trials. Neuro Oncol. 2017 Jan;19(1):89-98. doi: 10.1093/neuonc/now187. Epub 2016 Aug 31.