Study of XL184 (Cabozantinib) in Adults With Glioblastoma Multiforme
Condition: Glioblastoma Multiforme
MeSH terms: Glioblastoma
Intervention: XL184
Intervention description: Gelatin capsules supplied in 25-mg and 100-mg strengths; continuous daily dosing
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 222.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GBM; Malignant gliomas

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.