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

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

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.

Study Overview

• Status: Completed
• Conditions: 3rd Line GIST
• Intervention / Treatment: Drug: STI571; Drug: BKM120

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Novartis Investigative Site
• France
  • Lyon Cedex, France, 69373
    • Novartis Investigative Site
  • Villejuif Cedex, France, 94805
    • Novartis Investigative Site
• Japan
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • Novartis Investigative Site
• Netherlands
  • Leiden, Netherlands, 2300 RC
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 9BX
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute SC (2)
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Cancer Care Alliance Onc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency and characteristics of DLTs at each dose level during the first cycle of therapy. Type, frequency and severity of adverse drug reactions.	Dose limiting toxicity (DLT) will be assessed using CTCAE (v4.0.3), unless otherwise specified in the protocol.	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.	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.	28 days (1st cycle)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.

Helpful Links

• Novartis' results database

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2012
• Primary Completion (Actual): July 29, 2016
• Study Completion (Actual): July 29, 2016

Study Registration Dates

• First Submitted: November 6, 2011
• First Submitted That Met QC Criteria: November 8, 2011
• First Posted (Estimate): November 9, 2011

Study Record Updates

• Last Update Posted (Actual): December 21, 2020
• Last Update Submitted That Met QC Criteria: December 17, 2020
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: GIST; Imatinib mesylate; BKM120
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Neoplasms, Connective Tissue; Gastrointestinal Stromal Tumors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: CSTI571X2101; 2011-002938-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No