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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01735968
First received: November 15, 2012
Last updated: May 19, 2014
Last verified: May 2014
  Purpose

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 Intervention Phase
3rd Line GIST
Drug: ST571 + BYL719
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Frequency of dose limiting toxicities (DLTs) [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: Yes ]
    Dose limiting toxicity (DLT) will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) (v4.0.3), unless otherwise specified in the protocol.

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

  • Imatinib and BYL719 plasma concentrations vs time profile [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: No ]
  • Clinical benefit rate (CBR) [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: No ]
    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.

  • Type of adverse drug reactions [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: Yes ]
  • Frequency of adverse drug reactions [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: Yes ]
  • Severity of adverse drug reactions [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: Yes ]
  • Effect of basic Pharmacokinetics (PK) parameter: AUC0-24 [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: No ]
  • Effect of basic PK parameter: Cmax [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: No ]
  • Effect of basic PK parameter: Tmax [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: No ]
  • Effect of basic PK parameter: CL/F [ Time Frame: 28 days (1st cycle) ] [ Designated as safety issue: No ]

Estimated Enrollment: 50
Study Start Date: February 2013
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01735968

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

Locations
United States, Florida
University of Miami Dept Onc Recruiting
Miami, Florida, United States, 33136
Contact: Zuzel Rodriguez    305-243-5601    Z.Rodriquez1@med.miami.edu   
Principal Investigator: Jonathan C. Trent         
United States, New Hampshire
Dartmouth Hitchcock Medical Center Dept Oncology Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Nancy Birkrem    603-650-0566    Nancy.P.Birkrem@Dartmouth.edu   
Principal Investigator: Lionel Lewis         
United States, Oregon
Oregon Health & Science University Dept. of OHSU (3) Recruiting
Portland, Oregon, United States, 97239
Contact: Dan Hansen    503-346-0792    hansedan@ohsu.edu   
Principal Investigator: Michael Mauro         
Belgium
Novartis Investigative Site Recruiting
Leuven, Belgium, 3000
France
Novartis Investigative Site Recruiting
Bordeaux, France, 33076
Novartis Investigative Site Not yet recruiting
Lyon Cedex, France, 69373
Germany
Novartis Investigative Site Recruiting
Berlin, Germany, 13125
Novartis Investigative Site Recruiting
Essen, Germany, 45122
Italy
Novartis Investigative Site Recruiting
Bologna, BO, Italy, 40138
Novartis Investigative Site Not yet recruiting
Milano, MI, Italy, 20133
Novartis Investigative Site Recruiting
Candiolo, TO, Italy, 10060
Korea, Republic of
Novartis Investigative Site Withdrawn
Seoul, Korea, Republic of, 738-736
Netherlands
Novartis Investigative Site Recruiting
Groningen, Netherlands, 9713 GZ
Novartis Investigative Site Recruiting
Leiden, Netherlands, 2300 RC
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
United Kingdom
Novartis Investigative Site Not yet recruiting
Leeds, United Kingdom, LS9 7TF
Novartis Investigative Site Not yet recruiting
Manchester, United Kingdom, M20 9BX
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01735968     History of Changes
Other Study ID Numbers: CSTI571X2103, 2012-003273-25
Study First Received: November 15, 2012
Last Updated: May 19, 2014
Health Authority: United States: Food and Drug Administration
Belgium: Federal Agency for Medicinal Products and Health Products
France: Haute Autorit? de Sant? Transparency Commission
Germany: Federal Institute for Drugs and Medical Devices
Italy: National Institute of Health
Netherlands: Medicines Evaluation Board (MEB)
United Kingdom: Medicines and Healthcare Products Regulatory Agency
South Korea: Korea Food and Drug Administration (KFDA)
Spain: Agencia Espa?ola de Medicamentos y Productos Sanitarios

Keywords provided by Novartis:
Imatinib mesylate
BYL719
GIST

Additional relevant MeSH terms:
Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Imatinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 18, 2014