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

Novartis

Status and phase: Completed; Phase 1

Conditions: 3rd Line GIST

Treatments: Drug: BKM120; Drug: STI571

Study type: Interventional

Funder types: Industry

Identifiers

NCT01468688

CSTI571X2101

2011-002938-39 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 60 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

---

60 participants in 3 patient groups

STI571 (imatinib mesylate) and BKM120

Experimental group

Description:

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.

Treatment:

Drug: STI571

STI571+BKM120

Experimental group

Description:

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

Treatment:

Drug: BKM120

Drug: STI571

STI571 monotherapy run-in

Experimental group

Description:

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

Treatment:

Drug: STI571