Clinical trial NCT01468688: A Dose-finding Study of a Combination of Imatinib and BKM120 in the Treatment of 3rd Line GIST Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 3rd Line GIST
Keywords: Imatinib mesylate
BKM120
GIST
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-11-09
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Frequency and characteristics of dose limiting toxicities (DLTs) at each dose level during the first cycle of therapy
timeFrame: 28 days (1st cycle)
Secondary outcomes:
measure: Frequency and characteristics of DLTs at each dose level during the first cycle of therapy. Type, frequency and severity of adverse drug reactions.
timeFrame: 28 days (1st cycle)
measure: Imatinib and BKM120 plasma concentrations vs time profile, and basic PK parameters, including but not limited to AUC, Cmax, Tmax, CL/F.
timeFrame: 28 days (1st cycle)
measure: 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.
timeFrame: 28 days (1st cycle)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute SC (2)
state: Massachusetts
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance Onc
state: Washington
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Lyon Cedex
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.