Safety and Efficacy of INC280 and Buparlisib (BKM120) in Patients With Recurrent Glioblastoma

This is an interventional treatment trial for c-MET Inhibitor; PI3K Inhibitor, PTEN Mutations, Homozygous Del. of PTEN or PTEN Neg. by IHC, c-Met Ampli. by FISH, INC280, BKM120, Buparlisib; Recurrent GBM focused on measuring Glioblastoma multiforme (GBM), glioblastoma, Grade IV Astrocytoma, brain tumor, brain cancer, giant cell glioblastoma, gliosarcoma Read More

Inclusion Criteria:

• ≥ 18 years of age.
• Histologically confirmed diagnosis of glioblastoma (after initial tumor resection or biopsy) with radiographic evidence of recurrent tumor per RANO criteria.
• Phase Ib: Documented evidence of PTEN mutations, homozygous deletion of PTEN or PTEN negative (H Score <10) by IHC confirmed by local or central assessment.
• Phase II: Documented evidence of c-Met amplification (GCN>5) (fusion transcripts or mutant c-Met may be eligible after discussion with Novartis) or PTEN mutations, homozygous deletion of PTEN or PTEN negative (H Score <10) by central assessment.

• Must have received the following treatment for glioblastoma:

  •Prior treatment with radiotherapy and temozolomide; Note: A maximum of two prior chemotherapy/antibody regimens (including bevacizumab or other direct VEFG/VEGFR inhibitors) for recurrent disease are permitted.

• Representative archival tumor sample from glioblastoma (formalin-fixed paraffine embedded tissue) must be available.
• ECOG performance status ≤ 2.
• Able to swallow and retain oral medication.
• Patients in the surgical arm only: patients with recurrent glioblastoma must be eligible for surgical resection as deemed by the site Investigator.

Exclusion Criteria:

• Prior or current treatment with a c-MET inhibitor or HGF-targeting therapy
• Prior treatment with a PI3K and/or mTOR inhibitors for glioblastoma or for pre-existing neoplasm transformed to glioblastoma (applicable for combination treatment arm only)
• Received radiation (including therapeutic radioisotopes such as strontium 89) therapy ≤ 3 months prior to the first dose of study treatment and have not recovered from side effects of such therapy (≤ Grade 1) prior to the first dose of study treatment, except for alopecia.
• Receiving treatment with medications that are known strong inhibitors or inducers of CYP3A, and cannot be discontinued 7 days prior to the start of the treatment and during the course of the study.
• Receiving treatment with medications that are known CYP3A, CYP1A2, CYP2C8, CYP2C9 or CYP2C19 substrates with narrow therapeutic index, and cannot be discontinued during the course of the study.
• Receiving treatment with long acting proton pump inhibitors, and cannot be discontinued 3 days prior to the start of INC280 treatment and during the course of the study.
• Currently receiving warfarin or other coumadin-derived anticoagulants for treatment, prophylaxis or otherwise.
• Currently receiving increasing or chronic treatment ( > 5 days) with corticosteroids (e.g. dexamethasone > 4 mg/day or other corticosteroids equivalent dose) or another immunosuppressive agent.
• History of acute or chronic pancreatitis or any risk factors that may increase the risk of pancreatitis.
• Active cardiac disease or a history of cardiac dysfunction.
• Impairment of gastrointestinal (GI) function or GI disease that might significantly alter the absorption of study drug
• Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders (defined according to DSM- IV).
• Anxiety ≥ CTCAE grade 3

• Any of the following baseline laboratory values:

  • Hemoglobin < 9 g/dL
  • Platelet count < 75 x 109/L
  • Absolute neutrophil count (ANC) < 1.0 x 109/L
  • INR > 1.5
  • Serum lipase > normal limits for the institution
  • Asymptomatic serum amylase > grade 2
  • Potassium, magnesium, and calcium (corrected for albumin) > normal limits for the institution
  • Total bilirubin > 1.5 x ULN
  • Serum creatinine >1.5 x ULN or creatinine clearance ≤ 45 mL/min
  • Alanine aminotransferase (AST) or aspartate aminotransferase (ALT) > 3.0 x ULN (or < 5.0 x ULN if liver metastases are present)
  • Fasting plasma glucose > 120mg/dL or > 6.7 mmol/L
  • HbA1c > 8%.