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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase Ib/II, Multi-center, Open-label Study of INC280 in Combination With Buparlisib in Patients With Recurrent Glioblastoma

Conditions
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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

Intervention / Treatment
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* Drug: INC280
* Drug: Buparlisib


Participation Criteria
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Eligibility Criteria
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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%.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ib<br>To estimate the safe dose of the combination INC280 and buparlisib | Drug: INC280<br>* Phase Ib: INC280 was given at the starting dose of 200mg capsules twice daily with escalation to higher strengths. Phase II: INC280 was given at the dose of 400mg (tablets) twice daily.<br>Drug: Buparlisib<br>* Buparlisib was given at the starting dose of 50mg once daily with escalation to higher strengths.<br>* Other names: BKM120;|
| Experimental: Phase II<br>To estimate anti-tumor efficacy of INC280 single agent and in combination with buparlisib | Drug: INC280<br>* Phase Ib: INC280 was given at the starting dose of 200mg capsules twice daily with escalation to higher strengths. Phase II: INC280 was given at the dose of 400mg (tablets) twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | A DLT is defined as an adverse event or abnormal laboratory value where the relationship to study treatment cannot be ruled out, and is not primarily related to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment (28 days) with INC280 in combination with buparlisib and meets any of the pre-defined criteria. The maximum tolerated dose was identified as INC280 300 mg BID + buparlisib 80 mg QD. | Cycle 1, 28 days | 
| Phase II: Progression Free Survival Rate (PFSR) | Estimated rate of patients treated during 6 months without experiencing disease progression. The Progression Free Survival Rate at 6 months was to be estimated using a Bayesian model described in the protocol. The models operating characteristics were evaluated based on the enrollment of at least 30 patients enrolled. Patients did not reach the milestone for the PFSR analysis (trial terminated); as such no analysis was performed. | 6 months | 
| Phase II Surgical Arm: Concentrations of INC280 and Buparlisib in Tumor. | Concentrations of INC280 and buparlisib in tumor tissue. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | To characterize the safety of INC280 single agent and in combination with buparlisib including type, frequency, severity of adverse events, serious adverse events, and dose interruptions and adjustments. Adverse events will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, unless otherwise specified. If CTCAE grading did not exist for an AE, the severity of mild, moderate, severe, and lifethreatening, corresponding to Grades 1 - 4, were used. CTCAE Grade 5 (death) was not used in this study but was collected as a seriousness criterion; rather, information about deaths was collected though a Death form. | throughout the duration of the trial, approximately 3 years from FPFV to LPLV | 
| Pharmacokinetic Profile of INC280 - AUCtau | Plasma concentration profile of INC280 in combination with Buparlisib. AUCtau is the AUC from time zero to the end of dosing interval. | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months | 
| Pharmacokinetic Profile of INC280 - Cmax | Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration. | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months | 
| Pharmacokinetic Profile of INC280 - Tmax | Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months | 
| Pharmacokinetic Profile of INC280 - T1/2 | Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months | 
| Pharmacokinetic Profile of Buparlisib - AUCtau | Plasma concentration profile of Buparlisib in combination with INC280. AUCtau is the AUC from time zero to the end of dosing interval. | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months | 
| Pharmacokinetic Profile of Buparlisib - Cmax | Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration. | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months | 
| Pharmacokinetic Profile of Buparlisib - Tmax | Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months | 
| Pharmacokinetic Profile of Buparlisib - T1/2 | Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life | Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months | 
| Best Overall Response (BOR) | Best Overall Response (BOR) observed in the study population of INC280 Single Agent and in Combination with Buparlisib. Responses will be assessed by the investigators following the RANO criteria with MRI or CT scans scheduled every 8 weeks. Summary of the RANO response criteria: CR has no T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; PR has ≥50% decrease T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; SD has ≥50% decrease but <25% increase T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; PD has ≥25% increase in T1-Gd+ (enhancing lesion), increase T2/FLAIR (non-enhancing lesion), presence of new lesion, deterioration in clinical status. | throughout the duration of the trial - approximately 3 years (from FPFV to LPLV) | 
| Overall Survival (OS) | Survival rate of patients from start of treatment to date of death due to any cause. Patients did not reach the milestone for the survival data analysis (terminated early); as such no analysis was done. | throughout the duration of the trial - approximately 3 years (FPFV to LPLV) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma multiforme (GBM), glioblastoma, Grade IV Astrocytoma, brain tumor, brain cancer, giant cell glioblastoma, gliosarcoma