A Dose-finding Study of a Combination of Imatinib and BYL719 in the Treatment of 3rd Line GIST Patients

NCT01735968 | Completed Phase 1 FDA Drug

• 2 other identifiers: CSTI571X21032012-003273-25
• Study Type: interventional
• Target: 56
• Locations: 8 countries
• Sites: 11

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.

Conditions

3rd Line GIST

Keywords

Imatinib mesylate; STI571; BYL719; GIST; 3rd line GIST

Outcome Measures

Primary Outcomes (2)

• Frequency of dose limiting toxicities (DLTs)

  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)

• Characteristics of dose limiting toxicities (DLTs)

  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 Outcomes (10)

• Frequency and characteristics of DLTs

  28 days (1st cycle)

• Imatinib and BYL719 plasma concentrations vs time profile

  28 days (1st cycle)

• Clinical benefit rate (CBR)

  28 days (1st cycle)

• Type of adverse drug reactions

  28 days (1st cycle)

• Frequency of adverse drug reactions

  28 days (1st cycle)

Study Arms (1)

STI571 (imatinib mesylate) and BYL719

EXPERIMENTAL

The study will comprise of 2 parts. A dose escalation and a dose expansion part. All patients in the dose escalation part will have a pharmacokinetic (PK) run-in period of 7 days receiving imatinib monotherapy. Patients will receive increasing doses of BYL719 (200, 300, 400 mg) in combination with 400mg imatinib daily until maximum tolerated dose (MTD) and rapid phase 2 dose (RP2D) is determined. Approximately 35 patients will enter the expansion phase.

Drug: ST571 + BYL719

Interventions

ST571 + BYL719 DRUG

Evaluable patients must meet the minimum treatment and safety evaluation requirements of the study. Patients will be treated until they experience progression of disease, withdraw consent, or experience unacceptable toxicity. One study cycle equals 28 days.

STI571 (imatinib mesylate) and BYL719

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (11)

Oregon Health and Science University Dept. of OHSU (3)

Portland, Oregon, 97239, United States

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Bordeaux, 33076, France

Location

Novartis Investigative Site

Berlin, 13125, Germany

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Bologna, BO, 40138, Italy

Location

Novartis Investigative Site

Candiolo, TO, 10060, Italy

Location

Novartis Investigative Site

Groningen, 9713 GZ, Netherlands

Location

Novartis Investigative Site

Leiden, 2300 RC, Netherlands

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Leeds, LS9 7TF, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 35524239 DERIVED

Related Links

• Results for CSTI571X2103 can be found on the Novartis Clinical Trial Results Website

MeSH Terms

Interventions

Alpelisib

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2012
• First Posted: November 28, 2012
• Study Start: February 27, 2013
• Primary Completion: October 19, 2018
• Study Completion: October 19, 2018
• Last Updated: December 21, 2020

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1); ES (1); US (1); BE (1); IT (2); NL (2); GB (1); DE (2)