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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01735968
Recruitment Status : Completed
First Posted : November 28, 2012
Last Update Posted : December 21, 2020
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
3rd Line GIST Drug: ST571 + BYL719 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 56 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 27, 2013
Actual Primary Completion Date : October 19, 2018
Actual Study Completion Date : October 19, 2018

Arm Intervention/treatment
Experimental: STI571 (imatinib mesylate) and BYL719
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
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.

Primary Outcome Measures :
  1. Frequency of dose limiting toxicities (DLTs) [ Time Frame: 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.

  2. Characteristics of dose limiting toxicities (DLTs) [ Time Frame: 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 :
  1. Frequency and characteristics of DLTs [ Time Frame: 28 days (1st cycle) ]
    Dose limiting toxicity (DLT) will be assessed using CTCAE (v4.0.3), unless otherwise specified in the protocol.

  2. Imatinib and BYL719 plasma concentrations vs time profile [ Time Frame: 28 days (1st cycle) ]
  3. Clinical benefit rate (CBR) [ Time Frame: 28 days (1st cycle) ]
    Clinical benefit rate is defined as the rate of confirmed complete response (CR) or partial response (PR), or stable disease (SD) which lasts for at least 16 weeks.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.

  4. Type of adverse drug reactions [ Time Frame: 28 days (1st cycle) ]
  5. Frequency of adverse drug reactions [ Time Frame: 28 days (1st cycle) ]
  6. Severity of adverse drug reactions [ Time Frame: 28 days (1st cycle) ]
  7. Effect of basic Pharmacokinetics (PK) parameter: AUC0-24 [ Time Frame: 28 days (1st cycle) ]
  8. Effect of basic PK parameter: Cmax [ Time Frame: 28 days (1st cycle) ]
  9. Effect of basic PK parameter: Tmax [ Time Frame: 28 days (1st cycle) ]
  10. Effect of basic PK parameter: CL/F [ Time Frame: 28 days (1st cycle) ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01735968

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United States, Oregon
Oregon Health and Science University Dept. of OHSU (3)
Portland, Oregon, United States, 97239
Novartis Investigative Site
Leuven, Belgium, 3000
Novartis Investigative Site
Bordeaux, France, 33076
Novartis Investigative Site
Berlin, Germany, 13125
Novartis Investigative Site
Essen, Germany, 45147
Novartis Investigative Site
Bologna, BO, Italy, 40138
Novartis Investigative Site
Candiolo, TO, Italy, 10060
Novartis Investigative Site
Groningen, Netherlands, 9713 GZ
Novartis Investigative Site
Leiden, Netherlands, 2300 RC
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
United Kingdom
Novartis Investigative Site
Leeds, United Kingdom, LS9 7TF
Sponsors and Collaborators
Novartis Pharmaceuticals
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01735968    
Other Study ID Numbers: CSTI571X2103
2012-003273-25 ( EudraCT Number )
First Posted: November 28, 2012    Key Record Dates
Last Update Posted: December 21, 2020
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Imatinib mesylate
3rd line GIST
Additional relevant MeSH terms:
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Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases