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

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.

This was a multi-center, open-label, phase Ib/II study. The aim of the phase Ib part was to estimate the MTD and/or to identify the recommended phase II dose (RP2D) for the combination of INC280 and buparlisib, followed by the phase II part to assess the clinical efficacy of INC280 single agent and in combination with buparlisib (BKM120), and to further assess the safety of the combination. In addition, a surgical arm should have started concurrently with the phase II part, to determine the PK/PD profile of the study drug combination in patients undergoing tumor resection for recurrent glioblastoma after 7 to 10-days treatment.

RP2D was not declared due to a lack of efficacy of the combination in the phase Ib stage, and phase II was continued with INC280 monotherapy only.

Eligibility 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%.