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

• Status: Terminated
• Trial end date: 2016-12-23
• Target enrollment: 0
• Participant gender: All

Summary

The study assessed the safety and the dose of the combination of INC280 and buparlisib (BKM120), as well as the anti-tumor activity of the combination, in patients with recurrent glioblastoma with PTEN mutations, homozygous deletion of PTEN or PTEN negative by IHC. In addition, the anti-tumor activity of INC280 single agent should have been assessed in patients with recurrent glioblastoma with c-Met alteration.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Novartis Pharmaceuticals

Criteria

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%.