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

A Phase Ib/II, Multi-center, Open-label Study of INC280 in Combination With Buparlisib 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.

Study Overview

• Status: Terminated
• Conditions: 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: Drug: INC280; Drug: Buparlisib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany, 53105
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Tübingen, Germany, 72076
    • Novartis Investigative Site
• Netherlands
  • Rotterdam, Netherlands, 3075EA
    • ErasmusMC Cancer Institute - Neurooncology, RM G3-55
  • Utrecht, Netherlands, 3508 GA
    • University Medical Center Utrecht, Rm Q05.4.300, P.O. Box 85500
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Switzerland
  • St. Gallen, Switzerland, 9007
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute SC
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center- New York Presbyterian Dept of Oncology
    • New York, New York, United States, 90033
      • Memorial Sloan Kettering Cancer Center Neurology
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center Duke - Baker
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center SC-3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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%.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase Ib; To estimate the safe dose of the combination INC280 and buparlisib	Drug: INC280; 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.; Drug: Buparlisib; Buparlisib was given at the starting dose of 50mg once daily with escalation to higher strengths.; Other Names: BKM120
Experimental: Phase II; To estimate anti-tumor efficacy of INC280 single agent and in combination with buparlisib	Drug: INC280; 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.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• van den Bent M, Azaro A, De Vos F, Sepulveda J, Yung WKA, Wen PY, Lassman AB, Joerger M, Tabatabai G, Rodon J, Tiedt R, Zhao S, Kirsilae T, Cheng Y, Vicente S, Balbin OA, Zhang H, Wick W. A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma. J Neurooncol. 2020 Jan;146(1):79-89. doi: 10.1007/s11060-019-03337-2. Epub 2019 Nov 27.

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2014
• Primary Completion (Actual): December 23, 2016
• Study Completion (Actual): December 23, 2016

Study Registration Dates

• First Submitted: June 3, 2013
• First Submitted That Met QC Criteria: June 5, 2013
• First Posted (Estimate): June 6, 2013

Study Record Updates

• Last Update Posted (Actual): May 30, 2018
• Last Update Submitted That Met QC Criteria: May 29, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Glioblastoma multiforme (GBM), glioblastoma, Grade IV Astrocytoma, brain tumor, brain cancer, giant cell glioblastoma, gliosarcoma
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence
• Other Study ID Numbers: CINC280X2204; 2013-000699-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No