Glioblastoma Multiforme
Conditions
Keywords
GBM, Malignant gliomas
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.
Interventions
DRUGXL184
Gelatin capsules supplied in 25-mg and 100-mg strengths; continuous daily dosing
Sponsors
Exelixis
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 8 weeks until progressive disease | Response and progression were determined per modified MacDonald Criteria and modified RANO criteria for GBM using imaging and clinical features |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Objective Response (Months) | Assessed during periodically scheduled visits until progressive disease | Duration of response is defined as the time from the first documentation of objective response that was subsequently confirmed at a visit that was ≥ 28 days later to disease progression or death due to any cause. |
| Progression Free Survival (PFS) | Assessed during periodically scheduled visits until progressive disease | Response and progression were determined per modified MacDonald Criteria and modified RANO criteria for GBM using imaging and clinical features |
| Overall Survival (OS) | Assessed during periodically scheduled visits until progressive disease | Overall survival (OS) is defined as the time from first dose to death due to any cause. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group A (175 mg) Cabozantinib 175 mg (L-malate salt weight; 140 mg freebase equivalent) taken orally once per day (qd) | 46 |
| Treatment Group B + Group C (125 mg) Cabozantinib 125 mg (L-malate salt weight; 100 mg freebase equivalent) taken orally once per day (qd) | 176 |
| Total | 222 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extended Post Treatment Follow Up Period | Death | 41 | 50 | 93 |
| Extended Post Treatment Follow Up Period | Lost to Follow-up | 0 | 2 | 1 |
| Extended Post Treatment Follow Up Period | Various reasons | 5 | 5 | 21 |
| Extended Post Treatment Follow Up Period | Withdrawal by Subject | 0 | 2 | 2 |
| Overall Treatment Period | Adverse Event | 11 | 8 | 22 |
| Overall Treatment Period | Death | 0 | 0 | 1 |
| Overall Treatment Period | Disease Progression--Clinical Deterioration | 3 | 6 | 11 |
| Overall Treatment Period | Disease progression--per Modified MacDonald Criteria (Group A) | 30 | 0 | 0 |
| Overall Treatment Period | Disease Progression--Radiologic Progression (Group B and C) | 0 | 42 | 76 |
| Overall Treatment Period | Other--Subject had intracranial hemorrhage | 1 | 0 | 0 |
| Overall Treatment Period | Physician Decision | 0 | 2 | 0 |
| Overall Treatment Period | Roll-over to another study | 1 | 0 | 4 |
| Overall Treatment Period | Withdrawal by Subject | 0 | 1 | 3 |
Baseline characteristics
| Characteristic | Treatment Group A (175 mg) | Treatment Group B + Group C (125 mg) | Total |
|---|---|---|---|
| Age, Customized 18 to <45 | 11 Participants | 33 Participants | 44 Participants |
| Age, Customized 45 to <55 | 11 Participants | 53 Participants | 64 Participants |
| Age, Customized 55 to <65 | 18 Participants | 61 Participants | 79 Participants |
| Age, Customized 65 to <75 | 6 Participants | 28 Participants | 34 Participants |
| Age, Customized >= 75 | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) White | 40 Participants | 158 Participants | 198 Participants |
| Sex: Female, Male Female | 15 Participants | 68 Participants | 83 Participants |
| Sex: Female, Male Male | 31 Participants | 108 Participants | 139 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 46 | 144 / 176 |
| other Total, other adverse events | 46 / 46 | 176 / 176 |
| serious Total, serious adverse events | 24 / 46 | 90 / 176 |
Outcome results
Primary
Objective Response Rate (ORR)
Response and progression were determined per modified MacDonald Criteria and modified RANO criteria for GBM using imaging and clinical features
Time frame: 8 weeks until progressive disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Group A1 (175 mg) - Naive | Objective Response Rate (ORR) | 17.6 percentage of participants |
| Treatment Group B1 (125 mg) - Naive | Objective Response Rate (ORR) | 27.0 percentage of participants |
| Treatment Group C1 (125 mg) - Naive | Objective Response Rate (ORR) | 8.8 percentage of participants |
| Treatment Group A2 (175 mg) - Pre-Treated | Objective Response Rate (ORR) | 8.3 percentage of participants |
| Treatment Group B2 (125 mg) - Pre-Treated | Objective Response Rate (ORR) | 0 percentage of participants |
| Treatment Group C2 (125 mg) - Pre-Treated | Objective Response Rate (ORR) | 5.6 percentage of participants |
Secondary
Duration of Objective Response (Months)
Duration of response is defined as the time from the first documentation of objective response that was subsequently confirmed at a visit that was ≥ 28 days later to disease progression or death due to any cause.
Time frame: Assessed during periodically scheduled visits until progressive disease
Population: Insufficient number of participants with events
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Group A1 (175 mg) - Naive | Duration of Objective Response (Months) | 5.913 Months |
| Treatment Group B1 (125 mg) - Naive | Duration of Objective Response (Months) | 8.541 Months |
| Treatment Group C1 (125 mg) - Naive | Duration of Objective Response (Months) | NA Months |
| Treatment Group A2 (175 mg) - Pre-Treated | Duration of Objective Response (Months) | NA Months |
| Treatment Group C2 (125 mg) - Pre-Treated | Duration of Objective Response (Months) | 4.172 Months |
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as the time from first dose to death due to any cause.
Time frame: Assessed during periodically scheduled visits until progressive disease
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Group A1 (175 mg) - Naive | Overall Survival (OS) | 7.671 Months |
| Treatment Group B1 (125 mg) - Naive | Overall Survival (OS) | 4.074 Months |
| Treatment Group C1 (125 mg) - Naive | Overall Survival (OS) | 10.381 Months |
| Treatment Group A2 (175 mg) - Pre-Treated | Overall Survival (OS) | 4.221 Months |
| Treatment Group B2 (125 mg) - Pre-Treated | Overall Survival (OS) | 10.217 Months |
| Treatment Group C2 (125 mg) - Pre-Treated | Overall Survival (OS) | 4.583 Months |
Secondary
Progression Free Survival (PFS)
Response and progression were determined per modified MacDonald Criteria and modified RANO criteria for GBM using imaging and clinical features
Time frame: Assessed during periodically scheduled visits until progressive disease
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Group A1 (175 mg) - Naive | Progression Free Survival (PFS) | 3.712 Months |
| Treatment Group B1 (125 mg) - Naive | Progression Free Survival (PFS) | 4.698 Months |
| Treatment Group C1 (125 mg) - Naive | Progression Free Survival (PFS) | 3.712 Months |
| Treatment Group A2 (175 mg) - Pre-Treated | Progression Free Survival (PFS) | 3.285 Months |
| Treatment Group B2 (125 mg) - Pre-Treated | Progression Free Survival (PFS) | 1.807 Months |
| Treatment Group C2 (125 mg) - Pre-Treated | Progression Free Survival (PFS) | 2.300 Months |