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

NCT01468688 | Completed Phase 1 FDA Drug

• 2 other identifiers: CSTI571X21012011-002938-39
• Study Type: interventional
• Target: 60
• Locations: 8 countries
• Sites: 11

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.

Conditions

3rd Line GIST

Keywords

Imatinib mesylate; BKM120; GIST

Outcome Measures

Primary Outcomes (1)

• Frequency and characteristics of dose limiting toxicities (DLTs) at each dose level during the first cycle of therapy

  Dose limiting toxicity (DLT) will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) (v4.0.3), unless otherwise specified in the protocol.

  28 days (1st cycle)

Secondary Outcomes (3)

• Frequency and characteristics of DLTs at each dose level during the first cycle of therapy. Type, frequency and severity of adverse drug reactions.

  28 days (1st cycle)

• Imatinib and BKM120 plasma concentrations vs time profile, and basic PK parameters, including but not limited to AUC, Cmax, Tmax, CL/F.

  28 days (1st cycle)

• 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.

  28 days (1st cycle)

Study Arms (3)

STI571 (imatinib mesylate) and BKM120

EXPERIMENTAL

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

STI571+BKM120

EXPERIMENTAL

BKM120 Monotherapy 8 day run-in followed by STI571 and BKM120 combination therapy

Drug: STI571; Drug: BKM120

STI571 monotherapy run-in

EXPERIMENTAL

STI571 Monotherapy 8 day run-in followed by STI571 and BKM120 combination therapy

Drug: STI571

Interventions

STI571 DRUG

STI571 (imatinib mesylate) and BKM120; STI571 monotherapy run-in; STI571+BKM120

BKM120 DRUG

BKM120 combination therapy

STI571+BKM120

Eligibility Criteria

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

You may qualify if:

• Male or female patients ≥ 18 years of age
• WHO performance status (PS) of 0-2
• Histologically confirmed diagnosis of GIST that is unresectable or metastatic
• 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.
• 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

You may not qualify if:

• Previous treatment with PI3-K inhibitors
• 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
• 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)
• 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).
• Poorly controlled diabetes mellitus (defined as HbA1c \> 8%)

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (11)

Dana Farber Cancer Institute SC (2)

Boston, Massachusetts, 02215, United States

Location

Seattle Cancer Care Alliance Onc

Seattle, Washington, 98105, United States

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Novartis Investigative Site

Lyon, 69373, France

Location

Novartis Investigative Site

Villejuif, 94805, France

Location

Novartis Investigative Site

Kashiwa, Chiba, 277-8577, Japan

Location

Novartis Investigative Site

Leiden, 2300 RC, Netherlands

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

London, SW3 6JJ, United Kingdom

Location

Novartis Investigative Site

Manchester, M20 9BX, United Kingdom

Location

Related Publications (1)

• Gelderblom H, Jones RL, George S, Valverde Morales C, Benson C, Jean-Yves Blay, Renouf DJ, Doi T, Le Cesne A, Leahy M, Hertle S, Aimone P, Brandt U, Schӧffski P. Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study. Br J Cancer. 2020 Apr;122(8):1158-1165. doi: 10.1038/s41416-020-0769-y. Epub 2020 Mar 9.

  PMID: 32147671 DERIVED

Related Links

• Novartis' results database

MeSH Terms

Interventions

Imatinib Mesylate; NVP-BKM120

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

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: November 6, 2011
• First Posted: November 9, 2011
• Study Start: April 20, 2012
• Primary Completion: July 29, 2016
• Study Completion: July 29, 2016
• Last Updated: December 21, 2020

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1); NL (1); CA (1); FR (2); US (2); ES (1); GB (2); JP (1)