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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2016 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01870726
First received: June 3, 2013
Last updated: July 18, 2016
Last verified: July 2016
  Purpose
The study will assess 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 will be assessed in patients with recurrent glioblastoma with c-Met alteration.

Condition Intervention Phase
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
Drug: INC280
Drug: Buparlisib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib/II, Multi-center, Open-label Study of INC280 in Combination With Buparlisib in Patients With Recurrent Glioblastoma

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Phase II: Progression free survival rate (PFSR) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Estimate anti-tumor activity of INC280 single agent and in combination with buparlisib in patients with recurrent glioblastoma.

  • Phase Ib: Incidence of dose limiting toxicities [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    Estimate the concentrations of INC280 and buparlisib in tumor tissue.


Secondary Outcome Measures:
  • Type, frequency, and severity of adverse events and serious adverse events. [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
    To characterize the safety of INC280 single agent and in combination with buparlisib.

  • Tolerability: dose interruptions, reductions and dose intensity. [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
    To characterize the tolerability of INC280 single agent and in combination with buparlisib.

  • Pharmacokinetic profile of INC280 in combination with buparlisib. [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    Further assess the anti-tumor activity of INC280 single agent and in combination with buparlisib.

  • Overall survival (OS) [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Further assess the anti-tumor activity of INC280 single agent and in combination with buparlisib.


Estimated Enrollment: 63
Study Start Date: January 2014
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase Ib
To estimate the safe dose of the combination INC280 and buparlisib
Drug: INC280
Phase Ib: INC280 will be given at the starting dose of 200mg twice daily. Phase II: INC280 will be given at the dose of 400mg (tablets) twice daily.
Drug: Buparlisib
Buparlisib will be given at the starting dose of 50mg once daily.
Other Name: BKM120
Experimental: Phase II
To estimate anti-tumor efficacy of INC280 single agent and in combination with buparlisib
Drug: INC280
Phase Ib: INC280 will be given at the starting dose of 200mg twice daily. Phase II: INC280 will be given at the dose of 400mg (tablets) twice daily.
Drug: Buparlisib
Buparlisib will be given at the starting dose of 50mg once daily.
Other Name: BKM120

Detailed Description:
This is a multi-center, open-label, phase Ib/II study. The aim of the phase Ib part is 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. A maximum of 10 patients (in the combination arm) and approx. 5 patients (in the single agent arm), who have received bevacizumab treatment before entering the study, will be enrolled in the phase II part. In addition, a surgical arm will start 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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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%.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01870726

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals +41613241111

Locations
United States, Massachusetts
Dana Farber Cancer Institute SC Completed
Boston, Massachusetts, United States, 02215
United States, New York
Columbia University Medical Center- New York Presbyterian Dept of Oncology Recruiting
New York, New York, United States, 10032
Contact: Jonathan E. Rivera    212-305-9858    jr3387@cumc.columbia.edu   
Principal Investigator: Andrew B. Lassman         
Memorial Sloan Kettering Cancer Center Neurology Not yet recruiting
NY, New York, United States, 90033
Contact: Thomas Kaley    212-639-5122      
Principal Investigator: Thomas Kaley         
United States, North Carolina
Duke University Medical Center Duke - Baker Terminated
Durham, North Carolina, United States, 27710
United States, Texas
University of Texas/MD Anderson Cancer Center SC-3 Active, not recruiting
Houston, Texas, United States, 77030-4009
Germany
Novartis Investigative Site Recruiting
Bonn, Germany, 53105
Novartis Investigative Site Recruiting
Heidelberg, Germany, 69120
Novartis Investigative Site Recruiting
Tübingen, Germany, 72076
Netherlands
ErasmusMC Cancer Institute - Neurooncology, RM G3-55 Recruiting
Rotterdam, Netherlands, 3075EA
Contact: M.J. Van den Bent, M.D.    +31-10-7041415    m.vandenbent@erasmusmc.nl   
Principal Investigator: M.J. Van den Bent, M.D.         
University Medical Center Utrecht, Rm Q05.4.300, P.O. Box 85500 Recruiting
Utrecht, Netherlands, 3508 GA
Contact: Filip Y.F.L. De Vos, M.D.    +31-88-755-55-55      
Contact: Filip Y.F.L. De Vos, M.D.    +31-88-755-55-55    f.devos@umcutrecht.nl   
Principal Investigator: Filip Y.F.L. De Vos, M.D.         
Spain
Novartis Investigative Site Completed
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Active, not recruiting
Madrid, Spain, 28041
Switzerland
Novartis Investigative Site Recruiting
St. Gallen, Switzerland, 9007
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01870726     History of Changes
Other Study ID Numbers: CINC280X2204 
Study First Received: June 3, 2013
Last Updated: July 18, 2016
Health Authority: United States: Food and Drug Administration
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Switzerland: Swissmedic
Germany: German Institute of Medical Documentation and Information
Netherlands: Medical Ethics Review Committee (METC)

ClinicalTrials.gov processed this record on August 23, 2016