Everolimus in Combination With Imatinib in Patients With Glivec Refractory/Resistant Gastrointestinal Stromal Tumors

NCT ID: NCT01275222

Last Updated: 2021-06-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 117 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2002-11-13
• Study Completion Date: 2008-09-03

Brief Summary

This trial was a Phase I/II, non-randomized, open label, multi-center study, following a sequential 2-part design.

Detailed Description

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).

It was decided to discontinue the study and close to further enrollment based on alternative treatment options that became available. Phase 1 and Phase 2 Stratum 1 were ended early on 02-Nov-2006. Investigators were allowed to complete the enrollment in the Phase 2 Stratum 2.

Conditions

Gastrointestinal Stromal Tumors

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase l: RAD001 20mg/week

RAD001 20 mg was given once a week.

Group Type: EXPERIMENTAL

RAD001

Intervention Type: DRUG

RAD001 was in tablets of 0.5 mg, 1.0 mg, 2.5 mg and 5.0 mg strength and was taken by mouth, once a week or once a day depending upon the treatment group the patient was enrolled into.

Phase l: RAD001 2.5mg/day + Glivec 600mg/day

RAD001 2.5 mg was given in combination with Glivec/Gleevec 600mg/day.

Group Type: EXPERIMENTAL

RAD001

Intervention Type: DRUG

RAD001 was in tablets of 0.5 mg, 1.0 mg, 2.5 mg and 5.0 mg strength and was taken by mouth, once a week or once a day depending upon the treatment group the patient was enrolled into.

Imatinib 600mg/day (Glevec is the brand name for imatinib)

Intervention Type: DRUG

Glivec/Gleevec was supplied as commercialized 100 mg and 400 mg tablets. Gleevec/Glivec was provided as capsules of 100 mg strength in bottles containing 60 capsules each. The use of this supply was study center specific. Glivec/Gleevec was taken, by mouth, at a dose of 300 mg twice a day. The Glivec/Gleevec regimen was changed from 600 mg once a day to 300 mg BID, by an amendment since taking too many tablets at once was difficult for patients with gastro-intestinal disease. In the phase II part of the study all patients received Glivec 600 mg/day.

Phase l: RAD001 5mg/day + Glivec 600mg/day

RAD001 5 mg was given in combination with Glivec/Gleevec 600mg/day.

Group Type: EXPERIMENTAL

RAD001

Intervention Type: DRUG

RAD001 was in tablets of 0.5 mg, 1.0 mg, 2.5 mg and 5.0 mg strength and was taken by mouth, once a week or once a day depending upon the treatment group the patient was enrolled into.

Imatinib 600mg/day (Glevec is the brand name for imatinib)

Intervention Type: DRUG

Glivec/Gleevec was supplied as commercialized 100 mg and 400 mg tablets. Gleevec/Glivec was provided as capsules of 100 mg strength in bottles containing 60 capsules each. The use of this supply was study center specific. Glivec/Gleevec was taken, by mouth, at a dose of 300 mg twice a day. The Glivec/Gleevec regimen was changed from 600 mg once a day to 300 mg BID, by an amendment since taking too many tablets at once was difficult for patients with gastro-intestinal disease. In the phase II part of the study all patients received Glivec 600 mg/day.

Phase l: RAD001 2.5mg/day + Glivec 800mg/day

RAD001 2.5 mg was given in combination with Glivec/Gleevec 800mg/day.

Group Type: EXPERIMENTAL

RAD001

Intervention Type: DRUG

RAD001 was in tablets of 0.5 mg, 1.0 mg, 2.5 mg and 5.0 mg strength and was taken by mouth, once a week or once a day depending upon the treatment group the patient was enrolled into.

Imatinib 600mg/day (Glevec is the brand name for imatinib)

Intervention Type: DRUG

Glivec/Gleevec was supplied as commercialized 100 mg and 400 mg tablets. Gleevec/Glivec was provided as capsules of 100 mg strength in bottles containing 60 capsules each. The use of this supply was study center specific. Glivec/Gleevec was taken, by mouth, at a dose of 300 mg twice a day. The Glivec/Gleevec regimen was changed from 600 mg once a day to 300 mg BID, by an amendment since taking too many tablets at once was difficult for patients with gastro-intestinal disease. In the phase II part of the study all patients received Glivec 600 mg/day.

Phase ll - Stratum l (first-line resistant/refractory): RAD001 2.5mg/day + Glivec 600mg/day

All first-line resistant/refractory patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day.

Group Type: EXPERIMENTAL

RAD001

Intervention Type: DRUG

RAD001 was in tablets of 0.5 mg, 1.0 mg, 2.5 mg and 5.0 mg strength and was taken by mouth, once a week or once a day depending upon the treatment group the patient was enrolled into.

Imatinib 800mg/day (Glevec is the brand name for imatinib)

Intervention Type: DRUG

Glivec/Gleevec was supplied as commercialized 100 mg and 400 mg tablets. Gleevec/Glivec was provided as capsules of 100 mg strength in bottles containing 60 capsules each. The use of this supply was study center specific. Glivec/Gleevec was taken, by mouth. In the phase II part of the study all patients received Glivec 600 mg/day, except for 2 patients who received Glivec at a dose of 800 mg/day. This dose was permitted in Phase II as it was found to be safe in Phase I.

Phase ll - Stratum ll: (post second-line therapy): RAD001 2.5mg/day + Glivec 600mg/day

All post-second-line patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day

Group Type: EXPERIMENTAL

RAD001

Intervention Type: DRUG

RAD001 was in tablets of 0.5 mg, 1.0 mg, 2.5 mg and 5.0 mg strength and was taken by mouth, once a week or once a day depending upon the treatment group the patient was enrolled into.

Imatinib 800mg/day (Glevec is the brand name for imatinib)

Intervention Type: DRUG

Glivec/Gleevec was supplied as commercialized 100 mg and 400 mg tablets. Gleevec/Glivec was provided as capsules of 100 mg strength in bottles containing 60 capsules each. The use of this supply was study center specific. Glivec/Gleevec was taken, by mouth. In the phase II part of the study all patients received Glivec 600 mg/day, except for 2 patients who received Glivec at a dose of 800 mg/day. This dose was permitted in Phase II as it was found to be safe in Phase I.

Interventions

RAD001

RAD001 was in tablets of 0.5 mg, 1.0 mg, 2.5 mg and 5.0 mg strength and was taken by mouth, once a week or once a day depending upon the treatment group the patient was enrolled into.

Intervention Type: DRUG

Imatinib 600mg/day (Glevec is the brand name for imatinib)

Glivec/Gleevec was supplied as commercialized 100 mg and 400 mg tablets. Gleevec/Glivec was provided as capsules of 100 mg strength in bottles containing 60 capsules each. The use of this supply was study center specific. Glivec/Gleevec was taken, by mouth, at a dose of 300 mg twice a day. The Glivec/Gleevec regimen was changed from 600 mg once a day to 300 mg BID, by an amendment since taking too many tablets at once was difficult for patients with gastro-intestinal disease. In the phase II part of the study all patients received Glivec 600 mg/day.

Intervention Type: DRUG

Imatinib 800mg/day (Glevec is the brand name for imatinib)

Glivec/Gleevec was supplied as commercialized 100 mg and 400 mg tablets. Gleevec/Glivec was provided as capsules of 100 mg strength in bottles containing 60 capsules each. The use of this supply was study center specific. Glivec/Gleevec was taken, by mouth. In the phase II part of the study all patients received Glivec 600 mg/day, except for 2 patients who received Glivec at a dose of 800 mg/day. This dose was permitted in Phase II as it was found to be safe in Phase I.

Intervention Type: DRUG

Other Intervention Names

everolimus; STI571; STI571

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Dana Farber Cancer Institute Dept of Sarcoma Oncology

Boston, Massachusetts, United States

College of Physicians and Surgeons of Columbia University

New York, New York, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Novartis Investigative Site

Edegem, Antwerpen, Belgium

Novartis Investigative Site

Leuven, , Belgium

Novartis Investigative Site

Bordeaux, , France

Novartis Investigative Site

Lille, , France

Novartis Investigative Site

Lyon, , France

Novartis Investigative Site

Marseille, , France

Novartis Investigative Site

Villejuif, , France

Novartis Investigative Site

Berlin, , Germany

Novartis Investigative Site

Cologne, , Germany

Novartis Investigative Site

Frankfurt, , Germany

Novartis Investigative Site

Hamburg, , Germany

Novartis Investigative Site

München, , Germany

Novartis Investigative Site

Tübingen, , Germany

Countries

United States; Belgium; France; Germany

Other Identifiers

CRAD001C2206

Identifier Type: -

Identifier Source: org_study_id