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

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. Identifier: NCT01468688
Recruitment Status : Completed
First Posted : November 9, 2011
Last Update Posted : December 21, 2020
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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 or disease Intervention/treatment Phase
3rd Line GIST Drug: STI571 Drug: BKM120 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (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
Actual Study Start Date : April 20, 2012
Actual Primary Completion Date : July 29, 2016
Actual Study Completion Date : July 29, 2016

Arm Intervention/treatment
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
Experimental: STI571+BKM120
BKM120 Monotherapy 8 day run-in followed by STI571 and BKM120 combination therapy
Drug: STI571
Drug: BKM120
BKM120 combination therapy

Experimental: STI571 monotherapy run-in
STI571 Monotherapy 8 day run-in followed by STI571 and BKM120 combination therapy
Drug: STI571

Primary Outcome Measures :
  1. Frequency and characteristics of dose limiting toxicities (DLTs) at each dose level during the first cycle of therapy [ Time Frame: 28 days (1st cycle) ]
    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 :
  1. 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) ]
    Dose limiting toxicity (DLT) will be assessed using CTCAE (v4.0.3), unless otherwise specified in the protocol.

  2. 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) ]
  3. 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) ]
    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.

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01468688

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United States, Massachusetts
Dana Farber Cancer Institute SC (2)
Boston, Massachusetts, United States, 02215
United States, Washington
Seattle Cancer Care Alliance Onc
Seattle, Washington, United States, 98105
Novartis Investigative Site
Leuven, Belgium, 3000
Canada, British Columbia
Novartis Investigative Site
Vancouver, British Columbia, Canada, V5Z 4E6
Novartis Investigative Site
Lyon Cedex, France, 69373
Novartis Investigative Site
Villejuif Cedex, France, 94805
Novartis Investigative Site
Kashiwa, Chiba, Japan, 277-8577
Novartis Investigative Site
Leiden, Netherlands, 2300 RC
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
United Kingdom
Novartis Investigative Site
London, United Kingdom, SW3 6JJ
Novartis Investigative Site
Manchester, United Kingdom, M20 9BX
Sponsors and Collaborators
Novartis Pharmaceuticals
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals Identifier: NCT01468688    
Other Study ID Numbers: CSTI571X2101
2011-002938-39 ( EudraCT Number )
First Posted: November 9, 2011    Key Record Dates
Last Update Posted: December 21, 2020
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Imatinib mesylate
Additional relevant MeSH terms:
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Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action