Clinical Trials /

INC280 Combined With Bevacizumab in Patients With Glioblastoma Multiforme

NCT02386826

Description:

The purpose of this study is to determine whether the combination of two agents, INC280 and bevacizumab, is safe and effective when administered to patients with Glioblastoma Multiforme (GBM) who have progressed after receiving prior therapy or who have unresectable GBM.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: INC280 Combined With Bevacizumab in Patients With Glioblastoma Multiforme
  • Official Title: Phase Ib Study Evaluating the c-Met Inhibitor INC280 in Combination With Bevacizumab in Patients With Glioblastoma Multiforme (GBM)

Clinical Trial IDs

  • ORG STUDY ID: SCRI REFMAL 365
  • NCT ID: NCT02386826

Conditions

  • Glioblastoma Multiforme
  • Gliosarcoma
  • Colorectal Cancer
  • Renal Cell Carcinoma

Interventions

DrugSynonymsArms
INC280INCB28060INC280 + Bevacizumab
bevacizumabAvastinINC280 + Bevacizumab

Purpose

The purpose of this study is to determine whether the combination of two agents, INC280 and bevacizumab, is safe and effective when administered to patients with Glioblastoma Multiforme (GBM) who have progressed after receiving prior therapy or who have unresectable GBM.

Detailed Description

      Despite recent advances, glioblastoma multiforme (GBM) remains an incurable malignancy with a
      short expected survival. c-MET signalling promotes invasive growth and has been described in
      various cancers. INC280 is a highly potent and selective c-MET inhibitor which also
      penetrates the blood-brain barrier. In this open-label, multicenter Phase 1b study,
      investigators determined the optimal dose of the INC280/bevacizumab combination to administer
      to patients. Enrollment has now expanded in order to treat 3 cohorts of GBM patients: those
      who progressed after ≥ first-line standard therapy, those who progressed after ≥ second-line
      therapy with INC280/bevacizumab, and those with unresectable GBM.
    

Trial Arms

NameTypeDescriptionInterventions
INC280 + BevacizumabExperimentalDose Escalation: 18 GBM patients received bevacizumab 10 mg/kg intravenously (IV) once every 2 weeks in combination with INC280 given by mouth (PO) starting at 100 mg twice daily and escalating on a 3+3 escalation pattern until the maximum tolerated dose (MTD) was determined. Dose Expansion: Up to 45 GBM patients enrolled in 3 Cohorts: Cohort A: 20 GBM patients - progressed during or after standard 1st-line therapy; Cohort B: 15 GBM patients - progressed during or after 2nd-line bevacizumab therapy; Cohort C: 10 unresectable GBM patients. INC280: PO twice daily at the MTD. Bevacizumab: 10 mg/kg IV once every 2 weeks for Cohorts A and B; 15 mg/kg IV every 4 weeks for Cohort C Treatment cycles will be repeated every 28 days (4 weeks).
  • INC280
  • bevacizumab

Eligibility Criteria

        Inclusion Criteria:

        KEY POINTS:

          1. Dose Escalation Phase: Histologic diagnosis of GBM or gliosarcoma. Progressed during
             or after standard 1st-line therapy for GBM. Patients scheduled to undergo a repeat
             primary surgical resection are also eligible. Measurable disease as measured by RANO
             (Response Assessment in Neuro-Oncology) criteria.

          2. Dose Expansion Phase:

             Cohort A: Histologic diagnosis of GBM. Patients should have progressed during or after
             standard 1st-line therapy. Patients scheduled to undergo a repeat primary surgical
             resection are also eligible. Measurable disease as measured by RANO criteria.

             At least 5 patients must have an alteration of MET [as assessed by fluorescence in
             situ hybridization (FISH) (c-MET/centromere ratio ≥2, or c-MET gene copy number ≥ 5)
             or RT-PCR or Met immunohistochemistry (IHC) score of 2-3+ or a mutation].

             Cohort B: Histologic diagnosis of GBM patients who have progressed during or after
             2nd-line therapy with bevacizumab or a bevacizumab-based regimen. Measurable disease
             according to RANO criteria.

             Cohort C: Histologic diagnosis of GBM by stereotactic biopsy in patients with
             unresectable brain tumors.

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-2 or Karnofsky
             Performance Scale (KPS) of at least 70%.

          4. Adequate hematologic, renal and liver function

          5. Life expectancy ≥ 3 months

          6. Availability of archived tumor samples and/or willingness to provide tissue samples if
             resection is done. (Fresh tissue biopsy is not required if archival tissue is not
             available.)

        Exclusion Criteria:

          1. Prior treatment with bevacizumab for GBM patients eligible for Cohorts A and C. (Prior
             treatment with bevacizumab is permitted for GBM patients eligible for Cohort B only.)

          2. Most recent chemotherapy ≤ 21 days to the start of treatment and ≥ Grade 2
             chemotherapy-related side effects with the exception of alopecia.

          3. Use of any investigational drug ≤ 21 days to the start of treatment or 5 half-lives
             (whichever is shorter) prior to the first dose of INC280 with bevacizumab. For study
             drugs for which 5 half-lives is ≤ 21 days, a minimum of 10 days between termination of
             the study drug and the start of treatment is required.

          4. Uncontrolled seizures (Patients with a history of seizures are eligible if they are
             currently without seizures on a stable dose of anti-epileptic drugs for 14 days prior
             to enrollment.)

          5. History of uncontrolled hereditary or acquired bleeding or thrombotic disorders.

          6. Major surgery ≤ 28 days to the start of treatment, or subcutaneous venous access
             device placement ≤ 7 days to the start of treatment

          7. A serious non healing wound, ulcer, or bone fracture ≤ 28 days to the start of
             treatment

          8. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89)
             administered ≤ 28 days or limited field radiation for palliation ≤ 7 days prior to
             starting study drug or has not recovered from side effects of such therapy.

          9. Leptomeningeal metastases or spinal cord compression due to disease.

         10. Women of child-bearing potential.

         11. Receiving drugs known to be strong inhibitors or inducers of CYP3A4 and cannot be
             discontinued 7 days prior to the start of INC280 treatment and during the course of
             the study, or medications that are known CYP3A4, CYP1A2, CYP2C8, CYP2C9 or CYP2C19
             substrates with narrow therapeutic index, and cannot be discontinued during the course
             of the study.

         12. Treatment with proton pump inhibitors within three days prior to study entry.

         13. Cardiac disease currently or less than 6 months from baseline screening

         14. Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] >180 mmHg or
             diastolic blood pressure (DBP) >100 mmHg) (patients with values above these levels
             must have their blood pressure (BP) controlled with medication prior to starting
             treatment).

         15. Currently receiving treatment with therapeutic doses of warfarin sodium. Low molecular
             weight heparin is allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of INC280
Time Frame:weekly for 4 weeks
Safety Issue:
Description:The MTD of INC280 to be administered with standard dose bevacizumab is determined as the highest dose at which ≤1 of 6 patients experiences a dose limiting toxicity (DLT) during one cycle (28 days) of therapy, assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v. 4.0.3

Secondary Outcome Measures

Measure:Progression-free Survival
Time Frame:every 8 weeks until treatment discontinuation, expected average of 6 months
Safety Issue:
Description:Progression-free survival is measured from Day 1 of study drug administration to disease progression or death on study. Disease progression is assessed by Response Assessment in Neuro-Oncology (RANO) criteria.
Measure:Overall Response Rate
Time Frame:Every 8 weeks up to 6 months
Safety Issue:
Description:Defined as the proportion of patients with confirmed complete response or partial response (CR or PR) assessed according to RANO criteria. CR=complete disappearance of all measurable and non-measurable disease sustained for at least 4 weeks. PR=≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:SCRI Development Innovations, LLC

Trial Keywords

  • INC280
  • c-MET Inhibitors
  • bevacizumab
  • Avastin
  • C-Met proto-oncogene

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