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

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.

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%.