Clinical trial NCT01735968: A Dose-finding Study of a Combination of Imatinib and BYL719 in the Treatment of 3rd Line GIST Patients
Official title: A Dose-finding Phase Ib Multicenter Study of Imatinib in Combination With the Oral Phosphatidyl-inositol 3-kinase (PI3K) Inhibitor BYL719 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
STI571
BYL719
GIST
3rd line GIST
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-11-28
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
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 BYL719 in the treatment of 3rd line GIST patients.


Eligibility criteria: 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 part: patients must have available archival tumor tissue which can be shipped during the course of the study. In the absence of archival tumor tissue, patients must agree to a fresh pre-treatment biopsy at screening. • Dose-expansion part: 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 parts of the trial: • Dose-escalation part: 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 part patients may have had additional lines of therapy than imatinib and sunitinib dose-expansion part: 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). • Note: Adjuvant imatinib will not count as a prior course of imatinib for the purposes of this criterion 6. Radiological (CT/MRI) confirmation of disease progression (RECIST criteria) during prior therapy with imatinib and sunitinib will be required for patients entering the Dose-expansion part

Exclusion Criteria:

-Previous treatment with PI3K inhibitors -Patient has active uncontrolled or symptomatic central nervous system (CNS) metastases Note: A patient with controlled and asymptomatic CNS metastases may participate in this trial. As such, the patient must have completed any prior treatment for CNS metastases \> 28 days (including radiotherapy and/or surgery) prior to start of treatment in this study and should not be receiving chronic corticosteroid therapy for the CNS metastases -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 disease, severe renal disease considered unrelated to study disease, chronic pulmonary disease including dyspnea at rest from any cause) -Patients with diabetes mellitus requiring insulin treatment and/or with clinical signs or with FPG \>120mg/dL / 6.7mmol/L, or history of documented steroid-induced diabetes mellitus -Patient who has not recovered to grade 1 or better from any adverse events related to previous imatinib and/or sunitinib therapy before screening procedures are initiated

Primary outcomes:
measure: Frequency of dose limiting toxicities (DLTs)
timeFrame: 28 days (1st cycle)
measure: Characteristics of dose limiting toxicities (DLTs)
timeFrame: 28 days (1st cycle)
Secondary outcomes:
measure: Frequency and characteristics of DLTs
timeFrame: 28 days (1st cycle)
measure: Imatinib and BYL719 plasma concentrations vs time profile
timeFrame: 28 days (1st cycle)
measure: Clinical benefit rate (CBR)
timeFrame: 28 days (1st cycle)
measure: Type of adverse drug reactions
timeFrame: 28 days (1st cycle)
measure: Frequency of adverse drug reactions
timeFrame: 28 days (1st cycle)
measure: Severity of adverse drug reactions
timeFrame: 28 days (1st cycle)
measure: Effect of basic Pharmacokinetics (PK) parameter: AUC0-24
timeFrame: 28 days (1st cycle)
measure: Effect of basic PK parameter: Cmax
timeFrame: 28 days (1st cycle)
measure: Effect of basic PK parameter: Tmax
timeFrame: 28 days (1st cycle)
measure: Effect of basic PK parameter: CL/F
timeFrame: 28 days (1st cycle)
Other outcomes:
Locations:
city: Portland
country: United States
facility: Oregon Health and Science University Dept. of OHSU (3)
state: Oregon
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Candiolo
country: Italy
facility: Novartis Investigative Site
state: TO
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Pantaleo MA, Heinrich MC, Italiano A, Valverde C, Schoffski P, Grignani G, Reyners AKL, Bauer S, Reichardt P, Stark D, Berhanu G, Brandt U, Stefanelli T, Gelderblom H. A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor. BMC Cancer. 2022 May 6;22(1):511. doi: 10.1186/s12885-022-09610-4.