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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT01468688

Collaborator

(none)

Enrollment

Locations

Arms

51.3

Actual Duration (Months)

5.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

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 :

Apr 20, 2012

Actual Primary Completion Date :

Jul 29, 2016

Actual Study Completion Date :

Jul 29, 2016

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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)]
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. [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)]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

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

Exclusion Criteria:

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%)

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

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