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

NCT01870726 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: CINC280X22042013-000699-14
• Study Type: interventional
• Target: 43
• Locations: 5 countries
• Sites: 13

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.

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

Keywords

Glioblastoma multiforme (GBM), glioblastoma, Grade IV Astrocytoma, brain tumor, brain cancer, giant cell glioblastoma, gliosarcoma

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (11)

• Number of Participants With Adverse Events

  throughout the duration of the trial, approximately 3 years from FPFV to LPLV

• Pharmacokinetic Profile of INC280 - AUCtau

  Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

• Pharmacokinetic Profile of INC280 - Cmax

  Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

• Pharmacokinetic Profile of INC280 - Tmax

  Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

• Pharmacokinetic Profile of INC280 - T1/2

  Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

Study Arms (2)

Phase Ib

EXPERIMENTAL

To estimate the safe dose of the combination INC280 and buparlisib

Drug: INC280; Drug: Buparlisib

Phase II

EXPERIMENTAL

To estimate anti-tumor efficacy of INC280 single agent and in combination with buparlisib

Drug: INC280

Interventions

INC280 DRUG

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.

Phase II; Phase Ib

Buparlisib DRUG

Buparlisib was given at the starting dose of 50mg once daily with escalation to higher strengths.

Also known as: BKM120

Phase Ib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (13)

Dana Farber Cancer Institute SC

Boston, Massachusetts, 02215, United States

Location

Columbia University Medical Center- New York Presbyterian Dept of Oncology

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center Neurology

New York, New York, 90033, United States

Location

Duke University Medical Center Duke - Baker

Durham, North Carolina, 27710, United States

Location

University of Texas MD Anderson Cancer Center SC-3

Houston, Texas, 77030, United States

Location

Novartis Investigative Site

Bonn, 53105, Germany

Location

Novartis Investigative Site

Heidelberg, 69120, Germany

Location

Novartis Investigative Site

Tübingen, 72076, Germany

Location

ErasmusMC Cancer Institute - Neurooncology, RM G3-55

Rotterdam, 3075EA, Netherlands

Location

University Medical Center Utrecht, Rm Q05.4.300, P.O. Box 85500

Utrecht, 3508 GA, Netherlands

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Madrid, 28041, Spain

Location

Novartis Investigative Site

Sankt Gallen, 9007, Switzerland

Location

Related Publications (1)

• 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.

  PMID: 31776899 DERIVED

MeSH Terms

Conditions

Glioblastoma; Brain Neoplasms; Gliosarcoma

Interventions

capmatinib; NVP-BKM120

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Limitations and Caveats

At the end of Phase Ib, it was decided not to enroll patients in the two Phase II arms evaluating INC280 with buparlisib. The phase II INC280 single agent arm was halted before it reached target enrollment.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 3, 2013
• First Posted: June 6, 2013
• Study Start: January 9, 2014
• Primary Completion: December 23, 2016
• Study Completion: December 23, 2016
• Last Updated: May 30, 2018
• Results First Posted: May 24, 2018

Record last verified: 2018-05

Locations

US (5); DE (3); CH (1); NL (2); ES (2)