INC280 Combined With Bevacizumab in Patients With Glioblastoma Multiforme

NCT02386826 | Completed Phase 1

• 1 other identifier: SCRI REFMAL 365
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Glioblastoma Multiforme; Gliosarcoma; Colorectal Cancer; Renal Cell Carcinoma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) of INC280

  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 Outcomes (2)

• Progression-free Survival

  every 8 weeks until treatment discontinuation, expected average of 6 months

• Overall Response Rate

  Every 8 weeks up to 6 months

Study Arms (1)

INC280 + Bevacizumab

EXPERIMENTAL

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; Biological: bevacizumab

Interventions

INC280 DRUG

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

Also known as: INCB28060

INC280 + Bevacizumab

bevacizumab BIOLOGICAL

bevacizumab: 10 mg/kg IV every 2 weeks. Patients with unresectable GBM will be given 15 mg/kg IV every 4 weeks.

Also known as: Avastin

INC280 + Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• KEY POINTS:
• 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.
• 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.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-2 or Karnofsky Performance Scale (KPS) of at least 70%.
• Adequate hematologic, renal and liver function
• Life expectancy ≥ 3 months
• 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.)

You may not qualify if:

• 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.)
• Most recent chemotherapy ≤ 21 days to the start of treatment and ≥ Grade 2 chemotherapy-related side effects with the exception of alopecia.
• 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.
• 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.)
• History of uncontrolled hereditary or acquired bleeding or thrombotic disorders.
• Major surgery ≤ 28 days to the start of treatment, or subcutaneous venous access device placement ≤ 7 days to the start of treatment
• A serious non healing wound, ulcer, or bone fracture ≤ 28 days to the start of treatment
• 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.
• Leptomeningeal metastases or spinal cord compression due to disease.
• Women of child-bearing potential.
• 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.
• Treatment with proton pump inhibitors within three days prior to study entry.
• Cardiac disease currently or less than 6 months from baseline screening
• 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).
• Currently receiving treatment with therapeutic doses of warfarin sodium. Low molecular weight heparin is allowed.

Sponsors & Collaborators

• SCRI Development Innovations, LLC: lead
• Novartis: collaborator

Study Sites (5)

Sarah Cannon Research Institute at HealthONE

Denver, Colorado, 80218, United States

Location

Yale School of Medicine

New Haven, Connecticut, 06520, United States

Location

HCA Midwest - Kansas City

Kansas City, Missouri, 64132, United States

Location

Oklahoma University Health Science Center

Oklahoma City, Oklahoma, 73104, United States

Location

Tennessee Oncology PLLC

Nashville, Tennessee, 37203, United States

Location

MeSH Terms

Conditions

Glioblastoma; Gliosarcoma; Colorectal Neoplasms; Carcinoma, Renal Cell

Interventions

capmatinib; Bevacizumab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Adenocarcinoma; Carcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Kent C. Shih, M.D.

  SCRI Development Innovations, LLC

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 6, 2015
• First Posted: March 12, 2015
• Study Start: September 22, 2015
• Primary Completion: July 31, 2021
• Study Completion: August 23, 2023
• Last Updated: September 21, 2023

Record last verified: 2023-09

Locations

US (5)