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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01870726
First received: June 3, 2013
Last updated: August 7, 2014
Last verified: August 2014
  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.


Condition Intervention Phase
c-MET Inhibitor; PI3K Inhibitor, PTEN Mutations, Homozygous Deletion of PTEN or PTEN Negative by IHC, INC280, BKM120, Buparlisib; Recurrent Glioblastoma
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 Single-agent 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 in combiation 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 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 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 in combination with buparlisib.

  • Concentration of INC280 and buparlisib in cerebrospinal fluid (if available). [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    To investigate drug level of INC280 and buparlisib in cerebrospinal fluid (if available).

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


Estimated Enrollment: 74
Study Start Date: January 2014
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: August 2015 (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
INC280 will be given at the starting dose of 200mg 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 efficaty of the combination INC280 and buparlisib
Drug: INC280
INC280 will be given at the starting dose of 200mg 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 and to further assess the safety of the combination. A maximum of 10 patients, 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
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.
  • Documented evidence of PTEN mutations, homozygous deletion of PTEN or PTEN negative (H Score <10) by IHC confirmed by local (Phase Ib only) or central assessment
  • Must have received the following treatment for glioblastoma:

    •Prior adjuvant treatment with radiotherapy and temozolomide; Note: A maximum of two prior chemotherapy regimens (including bevacizumab or other direct VEFG/VEGFR inhibitors) for recurrent disease are permitted.

  • Representative archival or newly obtained 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
  • Received radiation (including therapeutic radioisotopes such as strontium 89) therapy ≤ 4 weeks 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 > normal limits for the institution
    • Serum creatinine >1.5 x ULN or creatinine clearance ≤ 45 mL/min
    • Alanine aminotransferase (AST) or aspartate aminotransferase (ALT) > normal range (or < 3.0 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

Locations
United States, Massachusetts
Dana Farber Cancer Institute SC Active, not recruiting
Boston, Massachusetts, United States, 02115
United States, New York
Columbia University Medical Center- New York Presbyterian Dept of Oncology Recruiting
New York, New York, United States, 10032
Contact: Jonathan Rivera    212-305-9858    jr3387@cumc.columbia.edu   
Principal Investigator: Andrew B. Lassman         
United States, North Carolina
Duke University Medical Center Duke - Baker Recruiting
Durham, North Carolina, United States, 27710
Contact: Cheryl Morgan-Maxey    919-668-0896    cheryl.morgan@duke.edu   
Principal Investigator: Gordana Vlahovic         
United States, Texas
University of Texas/MD Anderson Cancer Center SC-3 Recruiting
Houston, Texas, United States, 77030-4009
Contact: Jiyuan Ni    713-745-5769    jni@mdanderson.org   
Principal Investigator: W.K. A. Yung         
Germany
Novartis Investigative Site Not yet recruiting
Bonn, Germany, 53105
Novartis Investigative Site Recruiting
Heidelberg, Germany, 69120
Netherlands
Novartis Investigative Site Recruiting
Rotterdam, Netherlands, 3015 GD
Novartis Investigative Site Recruiting
Utrecht, Netherlands, 3584 CX
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Not yet 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

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01870726     History of Changes
Other Study ID Numbers: CINC280X2204
Study First Received: June 3, 2013
Last Updated: August 7, 2014
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)

Keywords provided by Novartis:
c-MET inhibitor
PI3K inhibitor
PTEN mutations
homozygous deletion of PTEN or PTEN negative by IHC
INC280
BKM120
buparlisib

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors

ClinicalTrials.gov processed this record on November 25, 2014