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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01870726
Recruitment Status : Terminated
First Posted : June 6, 2013
Results First Posted : May 24, 2018
Last Update Posted : May 30, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE June 3, 2013
First Posted Date  ICMJE June 6, 2013
Results First Submitted Date  ICMJE December 8, 2017
Results First Posted Date  ICMJE May 24, 2018
Last Update Posted Date May 30, 2018
Actual Study Start Date  ICMJE January 9, 2014
Actual Primary Completion Date December 23, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 25, 2018)
  • Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 [ Time Frame: Cycle 1, 28 days ]
    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.
  • Phase II: Progression Free Survival Rate (PFSR) [ Time Frame: 6 months ]
    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.
  • Phase II Surgical Arm: Concentrations of INC280 and Buparlisib in Tumor. [ Time Frame: 7 days ]
    Concentrations of INC280 and buparlisib in tumor tissue.
Original Primary Outcome Measures  ICMJE
 (submitted: June 5, 2013)
  • Phase II: Progression Free Survival Rate (PFSR) [ Time Frame: 6 months ]
    Estimate anti-tumor activity of INC280 in combiation with buparlisib in patients with recurrent glioblastoma.
  • Phase Ib: Incidence of dose limiting toxicities [ Time Frame: 28 days ]
    Estimate the Maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of INC280 in combination with buparlisib in patients with recurrent glioblastoma.
  • Surgical arm: Concentrations of INC280 and buparlisib in tumor. [ Time Frame: 7 days ]
    Estimate the concentrations of INC280 and buparlisib in tumor tissue.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2018)
  • Number of Participants With Adverse Events [ Time Frame: throughout the duration of the trial, approximately 3 years from FPFV to LPLV ]
    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.
  • Pharmacokinetic Profile of INC280 - AUCtau [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months ]
    Plasma concentration profile of INC280 in combination with Buparlisib. AUCtau is the AUC from time zero to the end of dosing interval.
  • Pharmacokinetic Profile of INC280 - Cmax [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months ]
    Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration.
  • Pharmacokinetic Profile of INC280 - Tmax [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months ]
    Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration
  • Pharmacokinetic Profile of INC280 - T1/2 [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months ]
    Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life
  • Pharmacokinetic Profile of Buparlisib - AUCtau [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months ]
    Plasma concentration profile of Buparlisib in combination with INC280. AUCtau is the AUC from time zero to the end of dosing interval.
  • Pharmacokinetic Profile of Buparlisib - Cmax [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months ]
    Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration.
  • Pharmacokinetic Profile of Buparlisib - Tmax [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months ]
    Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration
  • Pharmacokinetic Profile of Buparlisib - T1/2 [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months ]
    Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life
  • Best Overall Response (BOR) [ Time Frame: throughout the duration of the trial - approximately 3 years (from FPFV to LPLV) ]
    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.
  • Overall Survival (OS) [ Time Frame: throughout the duration of the trial - approximately 3 years (FPFV to LPLV) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2013)
  • Type, frequency, and severity of adverse events and serious adverse events. [ Time Frame: 3 months ]
    To characterize the safety of INC280 in combination with buparlisib.
  • Tolerability: dose interruptions, reductions and dose intensity. [ Time Frame: 3 months ]
    To characterize the tolerability of INC280 in combination with buparlisib.
  • Pharmacokinetic profile of INC280 in combination with buparlisib. [ Time Frame: 3 months ]
    Plasma concentration of INC280 and buparlisib, and PK parameters, including but not limited to Cmax, Tmax, AUCtau, and T1/2.
  • Overall response rate (ORR) [ Time Frame: 12 months ]
    Further assess the anti-tumor activity of INC280 in combination with buparlisib.
  • Concentration of INC280 and buparlisib in cerebrospinal fluid (if available). [ Time Frame: 7 days ]
    To investigate drug level of INC280 and buparlisib in cerebrospinal fluid (if available).
  • Overall Survival (OS) [ Time Frame: 12 months ]
    Further assess the anti-tumor activity of INC280 in combination with buparlisib.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of INC280 and Buparlisib (BKM120) in Patients With Recurrent Glioblastoma
Official Title  ICMJE A Phase Ib/II, Multi-center, Open-label Study of INC280 in Combination With Buparlisib in Patients With Recurrent Glioblastoma
Brief 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE 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  ICMJE
  • 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 Name: BKM120
Study Arms  ICMJE
  • Experimental: Phase Ib
    To estimate the safe dose of the combination INC280 and buparlisib
    Interventions:
    • Drug: INC280
    • Drug: Buparlisib
  • Experimental: Phase II
    To estimate anti-tumor efficacy of INC280 single agent and in combination with buparlisib
    Intervention: Drug: INC280
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: April 25, 2018)
43
Original Estimated Enrollment  ICMJE
 (submitted: June 5, 2013)
60
Actual Study Completion Date  ICMJE December 23, 2016
Actual Primary Completion Date December 23, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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%.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   Netherlands,   Spain,   Switzerland,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01870726
Other Study ID Numbers  ICMJE CINC280X2204
2013-000699-14 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
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

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP