Patient case: 68-year-old male with non-small cell carcinoma; genetic feature: MET

Clinical trial: INC280 Combined With Bevacizumab to Evaluate Glioblastoma Multiforme, Metastatic Colorectal Cancer, and Metastatic Renal Cell Carcinoma Patients

Summary: The purpose of this study is to determine whether the combination of two agents, INC280 and bevacizumab, are safe and effective when administered to patients who have received prior therapy for Glioblastoma Multiforme (GBM), metastatic colorectal cancer (mCRC), or metastatic renal cell carcinoma (mRCC) and who have progressed after therapy.

Detailed description: Despite recent advances, glioblastoma multiforme (GBM) remains an incurable malignancy with a short expected survival. Treatment options are also limited for patients with metastatic colorectal cancer (mCRC) or metastatic renal cell carcinoma (mRCC) who have progressed after prior therapies. Novel targeted therapies are being studied to treat these patient populations. 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 will first determine the optimal dose of INC280 combined with bevacizumab to administer as ≥ second-line therapy for GBM/gliosarcoma patients. After the optimal dose of the drug combination is determined, enrollment will be expanded to include both GBM and mRCC patients who have progressed after ≥ first-line therapy, and mCRC patients who have progressed as ≥ second-line therapy. The study will provide a preliminary safety and pharmacokinetic (PK) assessment of the INC280/bevacizumab combination.

Eligibility: 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 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 criteria
  Cohort B: Metastatic colorectal cancer (mCRC) patients after progression on ≥ 2nd-line therapy for advanced disease. Measurable disease as measured by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1
  Cohort C: Metastatic renal cell carcinoma (mRCC) (with clear cell component) patients after progression on ≥ 1st-line therapy for advanced disease. Measurable disease as measured by RECIST v 1.1
  At least 5 patients in each of the above 3 cohorts must have 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].
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-2 or Karnofsky Performance Scale (KPS) >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 or any other VEGF or VEGFR inhibitors for GBM patients; prior treatment with bevacizumab for mRCC patients. (Prior treatment with bevacizumab is permitted for mCRC patients)
  2. 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.)
  3. History of uncontrolled hereditary or acquired bleeding or thrombotic disorders.
  4. A serious non healing wound, ulcer, or bone fracture ≤ 28 days to the start of treatment
  5. 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.
  6. Leptomeningeal metastases or spinal cord compression due to disease. (mRCC and mCRC patients with stable treated metastases will be allowed to enroll.)
  7. Women of child-bearing potential.
  8. 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.
  9. Treatment with proton pump inhibitors within three days prior to study entry.
  10. Cardiac disease currently or less than 6 months from baseline screening
  11. 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).
  12. Currently receiving treatment with therapeutic doses of warfarin sodium. Low molecular weight heparin is allowed.

Relevance to patient case: not relevant