Everolimus in Combination With Imatinib in Patients With Glivec Refractory/Resistant Gastrointestinal Stromal Tumors - Full Text View

Purpose

This trial was a Phase I/II, non-randomized, open label, multi-center study, following a sequential 2- part design. The first part, Phase I, was designed to assess whether there is a pharmacokinetic interaction between Glivec/Gleevec (imatinib) and RAD001(everolimus) as well as to collect safety data when these two drugs are co-administered. The second part, (Phase II), was designed to assess the potential efficacy of the combination in imatinib-resistant GIST patients in two strata of patients:

Patients resistant to imatinib as first-line drug therapy and in whom the maximum tolerated dose was at least 600 mg/d (Stratum 1, first-line resistant/refractory)
Patients resistant to imatinib as well as to post-imatinib drug therapy (Stratum 2, post second-line therapy).

Condition	Intervention	Phase
Gastrointestinal Stromal Tumors	Drug: Everolimus + Imatinib	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase I-II, Open-label Study of RAD001 in Combination With Glivec®/Gleevec™ (Imatinib) in Patients With Glivec/Gleevec-refractory/Resistant Gastrointestinal Stromal Tumors.

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Sirolimus Imatinib Everolimus Temsirolimus Imatinib mesylate

U.S. FDA Resources

Further study details as provided by Novartis:

Primary Outcome Measures:

assess the safety and tolerability of the combination administration of RAD001 and imatinib when given to patients with imatinib-refractory gastro-intestinal stromal tumors (GIST). [ Designated as safety issue: No ]
assess the pharmacokinetics of the combination administration of RAD001 and imatinib in this patient population. [ Designated as safety issue: No ]
assess clinical efficacy of the combination regimen in this patient population. [ Designated as safety issue: No ]

Secondary Outcome Measures:

assess mTOR pathway activity before treatment, and inhibition of mTOR pathway activity during treatment as a predictive factor of response, as shown by molecular pathological examination of the tumor. [ Designated as safety issue: No ]
assess the relationship between drug-induced changes in the principal molecular marker of intratumoral mTOR activity and changes in other molecular markers of tumoral activity (e.g. indicators of pathway activity, cell proliferation and apoptosis). [ Designated as safety issue: No ]
assess the relationship between drug-induced changes in tumoral metabolism, as shown by functional imaging with 18F-fluorodeoxyglucose positron emission tomography (FDC-PET), with clinical outcome and changes in molecular pathology. [ Designated as safety issue: No ]

Enrollment:	120
Study Start Date:	November 2002
Primary Completion Date:	September 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: RAD001 + Glivec	Drug: Everolimus + Imatinib

Eligibility

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

Criteria

Inclusion Criteria:

Phase l:

Patients aged ≥ 18 years
Patients with a histologically proven diagnosis of GIST and clinical evidence of resistance to imatinib despite at least 4 months continuous treatment with imatinib
Patients with at least 2 months at a dosage of ≥ 600 mg/day (progression despite uninterrupted therapy for 2 months at ≥800 mg/d for patients entering the Phase I cohort investigating the 800 mg/d dose)
Patients were to have at least one measurable lesion (longest diameter ≥20 mm on conventional CT or MRI scan
patients were to have ≥10 mm on spiral CT) and were to have a WHO Performance Status Score ≤ 2.
Patients also were to have adequate bone marrow, liver and renal function on imatinib treatment, as specified in the protocol

Phase ll:

• For Phase II (Stratum 2) patients must have progression on other 2nd line drug therapies following prior progression on imatinib (Stratum 2)

Exclusion Criteria:

Women who are pregnant or breast-feeding
Patients presenting with known or symptomatic CNS metastases or leptomeningeal involvement
Patients with any concurrent major medical condition liable to compromise the patient's participation in the study (e.g. known HIV infection, uncontrolled diabetes, serious cardiac dysrhythmia or condition, New York Heart Association classification of III or IV, congestive cardiac failure, myocardial infarction with 6 months, unstable angina, chronic or acute renal or liver disease, uncontrolled infections including abscess or fistulae, etc.)
Patients with a history of another malignancy within 5 years prior to study entry, except curatively treated non-melanotic skin cancer or in-situ cervical cancer
Patients unwilling to or unable to comply with the protocol
Patients who are receiving glucocorticoids (only if the p70s6 kinase1 assay is being performed), since these have been shown to inhibit p70s6 kinase1 activity.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01275222

Locations

United States, Massachusetts
Dana Faber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New York
College of Physicians & Surgeons of Columbia University
New York, New York, United States, 10032
United States, Pennsylvania
Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111-2497
Belgium
Novarts Investigative Site
Edegem, Belgium, 2650
Novarts Investigative Site
Leuven, Belgium, 3000
France
Novartis Investigative Site
Bordeaux Cedex, France, 33076
Novartis Investigative Site
Lille Cedex, France, 59020
Novartis Investigative Site
Lyon Cedex 08, France, 69373
Novartis Investigative Site
Marseille, France, 13005
Novartis Investigative Site
Villejuif, France, 94805
Germany
Novartis Investigative Site
Berlin, Germany, 13125
Novartis Investigative Site
Frankfurt, Germany, 60488
Novartis Investigative Site
Hamburg, Germany, 20246
Novartis Investigative Site
Koln, Germany, 50973
Novartis Investigative Site
Muenchen, Germany, 81377
Novartis Investigative Site
Tubingen, Germany, 72076

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:

Novartis Pharmaceuticals

More Information

No publications provided

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT01275222 History of Changes
Other Study ID Numbers:	CRAD001C2206
Study First Received:	January 10, 2011
Last Updated:	May 31, 2012
Health Authority:	United States: Food and Drug Administration Belgium: Belgium Health Authorities France: afssaps Germany:BfArM

Keywords provided by Novartis:

GIST
everolimus
mTOR
Imatinib resistant
Imatinib-refractory/resistant gastrointestinal stromal tumors

Additional relevant MeSH terms:

Gastrointestinal Stromal Tumors
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Everolimus
Sirolimus
Imatinib
Immunosuppressive Agents
Immunologic Factors

Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on October 18, 2012