INC280 Combined With Bevacizumab in Patients With Glioblastoma Multiforme

September 19, 2023 updated by: SCRI Development Innovations, LLC

Phase Ib Study Evaluating the c-Met Inhibitor INC280 in Combination With Bevacizumab in Patients With Glioblastoma Multiforme (GBM)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

65

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Denver, Colorado, United States, 80218
        • Sarah Cannon Research Institute at HealthONE
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Yale School of Medicine
    • Missouri
      • Kansas City, Missouri, United States, 64132
        • HCA Midwest - Kansas City
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Oklahoma University Health Science Center
    • Tennessee
      • Nashville, Tennessee, United States, 37203
        • Tennessee Oncology PLLC

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: INC280 + Bevacizumab
  1. Dose 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.
  2. 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).
Drug: INC280

Dose Escalation: INC280 by mouth (PO) twice daily for 28 days according to the following schedule until the maximum tolerated dose (MTD) is determined:

Dose Level 1 (starting dose): 200 mg (divided dose of 100 mg twice per day) Dose Level 2: 400 mg (divided dose of 200 mg twice per day) Dose Level 3: 800 mg (divided dose of 400 mg twice per day)

Dose Expansion: INC280 PO twice daily at the MTD determined in the dose escalation phase

Other Names:
  • INCB28060
Biological: bevacizumab
bevacizumab: 10 mg/kg IV every 2 weeks. Patients with unresectable GBM will be given 15 mg/kg IV every 4 weeks.
Other Names:
  • Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose (MTD) of INC280
Time Frame: weekly for 4 weeks
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
weekly for 4 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free Survival
Time Frame: every 8 weeks until treatment discontinuation, expected average of 6 months
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.
every 8 weeks until treatment discontinuation, expected average of 6 months
Overall Response Rate
Time Frame: Every 8 weeks up to 6 months
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.
Every 8 weeks up to 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

SCRI Development Innovations, LLC

Collaborators

Novartis

Investigators

  • Study Chair: Kent C. Shih, M.D., SCRI Development Innovations, LLC

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 22, 2015

Primary Completion (Actual)

July 31, 2021

Study Completion (Actual)

August 23, 2023

Study Registration Dates

First Submitted

March 6, 2015

First Submitted That Met QC Criteria

March 6, 2015

First Posted (Estimated)

March 12, 2015

Study Record Updates

Last Update Posted (Actual)

September 21, 2023

Last Update Submitted That Met QC Criteria

September 19, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SCRI REFMAL 365

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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