A Dose-finding Study of a Combination of Imatinib and BKM120 in the Treatment of 3rd Line GIST Patients

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01468688
First received: November 6, 2011
Last updated: May 27, 2014
Last verified: May 2014
  Purpose

The purpose of this study is to determine a maximum tolerated dose and/or recommended phase 2 dose of a combination of imatinib and BKM120 in the treatment of 3rd line GIST patients.


Condition Intervention Phase
3rd Line GIST
Drug: STI571 + BKM120
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multi-arm Dose-finding Phase Ib Multicenter Study of Imatinib in Combination With the Oral Phosphatidyl-inositol 3-kinase (PI3-K) Inhibitor BKM120 in Patients With Gastrointestinal Stromal Tumor (GIST) Who Failed Prior Therapy With Imatinib and Sunitinib

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Frequency and characteristics of dose limiting toxicities (DLTs) at each dose level during the first cycle of therapy [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: Yes ]
    Dose limiting toxicity (DLT) will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) (v4.0.3), unless otherwise specified in the protocol.


Secondary Outcome Measures:
  • Frequency and characteristics of DLTs at each dose level during the first cycle of therapy. Type, frequency and severity of adverse drug reactions. [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: Yes ]
    Dose limiting toxicity (DLT) will be assessed using CTCAE (v4.0.3), unless otherwise specified in the protocol.

  • Imatinib and BKM120 plasma concentrations vs time profile, and basic PK parameters, including but not limited to AUC, Cmax, Tmax, CL/F. [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: No ]
  • Clinical benefit rate (CBR) defined as the rate of confirmed complete response (CR) or partial response (PR), or stable disease (SD) which lasts for at least 16 weeks. [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: No ]
    Tumor response will be determined locally by the investigator sites according to Novartis guideline on the Response Evaluation Criteria in Solid Tumors, based on RECIST Version 1.1.


Estimated Enrollment: 50
Study Start Date: April 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: STI571 (imatinib mesylate) and BKM120
The study will comprise of 2 parts. A dose escalation and a dose expansion part. Patients will receive increasing doses of BKM120 (40, 60, 80, 100 mg) in combination with 400mg imatinib daily until maximum tolerated dose (MTD) and rapid phase 2 dose (RP2D) is determined. 35 patients will enter the expansion phase with 18 patients having a pharmacokinetic (PK) run-in period of 8 days receiving imatinib monotherapy or BKM120 monotherapy.
Drug: STI571 + BKM120
Evaluable patients must meet the minimum treatment and safety evaluation requirements of the study. Patients will be treated until they experience progression of disease, withdraw consent, or experience unacceptable toxicity. One study cycle equals 28 days.
Experimental: STI571+BKM120
BKM120 Monotherapy 8 day run-in followed by STI571 and BKM120 combination therapy
Drug: STI571 + BKM120
BKM120 Monotherapy 8 day run-in followed by STI571 and BKM120 combination therapy
Experimental: STI571 monotherapy run-in
STI571 Monotherapy 8 day run-in followed by STI571 and BKM120 combination therapy
Drug: STI571 + BKM120
STI571 Monotherapy 8 day run-in followed by STI571 and BKM120 combination therapy

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. Male or female patients ≥ 18 years of age
  2. WHO performance status (PS) of 0-2
  3. Histologically confirmed diagnosis of GIST that is unresectable or metastatic
  4. Available tissue specimen:

    • Dose-escalation cohorts: patients must have available archival tumor tissue which can be shipped during the course of the study
    • Dose-expansion cohort: patients must have available archival tumor tissue which can be shipped during the course of the study and must agree to a fresh pre-treatment biopsy.
  5. Failed prior therapy with imatinib followed by sunitinib for the treatment of unresectable or metastatic GIST. Note the following specific criteria for the two phases of the trial:

    • Dose-escalation cohorts: patients who failed prior therapy with imatinib and then have failed therapy with sunitinib. Treatment failure may be due to either disease progression on therapy (both imatinib and sunitinib) or intolerance to therapy (sunitinib). Dose-escalation cohort patients may have had additional lines of therapy not limited to imatinib and sunitinib.
    • Dose-expansion cohort: patients must have documented disease progression on both imatinib and sunitinib. In addition, patients may have had no more than two lines of prior therapy (i.e. treatment with imatinib followed by treatment with sunitinib).
    • Adjuvant imatinib will not count as a prior course of imatinib for the purposes of this criterion

Exclusion Criteria:

  1. Previous treatment with PI3-K inhibitors
  2. A medical history of any of the following mood disorders as judged by the Investigator or a psychiatrist:

    • Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or thoughts, or homicidal thoughts (immediate risk of doing harm to others)
    • ≥ CTCAE grade 3 anxiety
  3. When completing the patient questionnaires at screening:

    • Meets the cut-off score of ≥ 10 in the nine item depression scale of the Patient Health Questionnaire (PHQ-9) or a cut-off of ≥ 15 in the Generalized Anxiety Disorder Assessment (GAD 7) mood scale respectively, or
    • Selects positive response of 1, 2, 3 to question number 9 regarding potential for suicidal thoughts or ideation in the PHQ-9 (independent of the total score of the PHQ-9)
  4. Severe and/or uncontrolled concurrent medical condition that, in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. acute or chronic liver, pancreatic, severe renal disease considered unrelated to study disease, chronic pulmonary disease including dyspnea at rest from any cause).
  5. Poorly controlled diabetes mellitus (defined as HbA1c > 8%)

Other protocol-defined inclusion/exclusion criteria may apply.

  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: NCT01468688

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

Locations
United States, Massachusetts
Dana Farber Cancer Institute SC (2) Active, not recruiting
Boston, Massachusetts, United States, 02115
United States, New York
Memorial Sloan Kettering Cancer Center MSKCC SC Withdrawn
New York, New York, United States, 10021
United States, Washington
Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Onc Completed
Seattle, Washington, United States, 98109-1023
Belgium
Novartis Investigative Site Active, not recruiting
Leuven, Belgium, 3000
Canada, British Columbia
Novartis Investigative Site Recruiting
Vancouver, British Columbia, Canada, V5Z 4E6
France
Novartis Investigative Site Recruiting
Lyon Cedex, France, 69373
Novartis Investigative Site Recruiting
Villejuif Cedex, France, 94805
Germany
Novartis Investigative Site Recruiting
Berlin, Germany, 13125
Novartis Investigative Site Withdrawn
Muenchen, Germany, 81377
Italy
Novartis Investigative Site Withdrawn
Milano, MI, Italy, 20133
Japan
Novartis Investigative Site Completed
Kashiwa, Chiba, Japan, 277-8577
Netherlands
Novartis Investigative Site Active, not recruiting
Leiden, Netherlands, 2300 RC
Spain
Novartis Investigative Site Active, not recruiting
Barcelona, Catalunya, Spain, 08035
United Kingdom
Novartis Investigative Site Recruiting
London, United Kingdom, SW3 6JJ
Novartis Investigative Site Recruiting
Manchester, United Kingdom, M20 9BX
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: NCT01468688     History of Changes
Other Study ID Numbers: CSTI571X2101, 2011-002938-39
Study First Received: November 6, 2011
Last Updated: May 27, 2014
Health Authority: United States: Food and Drug Administration
Belgium: Federal Agency for Medicinal Products and Health Products
Canada: Health Canada
France: Haute Autorité de Santé Transparency Commission
Germany: Federal Institute for Drugs and Medical Devices
Italy: National Institute of Health
Japan: Pharmaceuticals and Medical Devices Agency
Netherlands: Medicines Evaluation Board (MEB)
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Spain: Agencia Espanola de Medicamentos y Productos Sanitarios

Keywords provided by Novartis:
Imatinib mesylate
BKM120
GIST

Additional relevant MeSH terms:
Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Imatinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 19, 2014