Everolimus in Combination With Imatinib in Patients With Glivec Refractory/Resistant Gastrointestinal Stromal Tumors
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.
1 other identifier
interventional
117
4 countries
16
Brief Summary
This trial was a Phase I/II, non-randomized, open label, multi-center study, following a sequential 2-part design.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Nov 2002
Longer than P75 for phase_1
16 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
November 13, 2002
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 3, 2008
CompletedStudy Completion
Last participant's last visit for all outcomes
September 3, 2008
CompletedFirst Submitted
Initial submission to the registry
January 10, 2011
CompletedFirst Posted
Study publicly available on registry
January 12, 2011
CompletedResults Posted
Study results publicly available
June 25, 2021
CompletedJune 25, 2021
June 1, 2021
5.8 years
January 10, 2011
May 7, 2021
June 3, 2021
Conditions
Keywords
Outcome Measures
Primary Outcomes (6)
Number of Participants With Adverse Events (AEs): Phase I & II
Assessed safety and tolerability of the combination administration of RAD001 and imatinib when given to patients with imatinib-refractory gastro-intestinal stromal tumors (GIST) by number of participants with adverse events.
4 - 8 weeks
Best Overall Response (BOR) as Assessed by Overall Response (Complete Response (CR) & Partial Response (PR)) - Phase I & II
Assessed clinical efficacy of the combination regimen in this patient population per BOR by Overall response (CR + PR). Complete response: Disappearance of all target lesions; Partial response: ≥ 30% decrease in the sum of the longest diameter of target lesions compared to baseline (and not ≥20% increase compared to smallest sum).
6 - 8 weeks
Trough Concentrations for RAD001 and for Imatinib - Phase II
Assessed the pharmacokinetics (PK) of the combination administration of RAD001 and imatinib in this patient population.
Part II Daily regimen: Baseline, Days 8, 15 and thereafter approximately every two months starting at month 3 whenever possible
Overall Survival (OS) - Phase I & II
Assessed clinical efficacy of the combination regimen in this patient population per Overall Survival (OS). Overall survival was defined as the time from date of start of treatment to date of death due to any cause. For patients still receiving study medication at the time of the analysis, survival was censored at the date of last examination. If a patient was not known to have died but was no longer continuing with study medication, survival was censored at the date of last contact.
about 60 months
4-Month Progression-free Survival (PFS) Rate - Phase II
Assessed clinical efficacy of the combination regimen in this patient population per Progression-free survival (PFS). Progression-free survival (PFS) was the time from date of start of treatment to the date of first documented progression or death due to any cause. Per protocol (PP) population includes patients with no known overall lesion response during 4 months +/- 2 weeks, or who later had response of CR/PR/stable disease (SD). PP population excludes patients with no known response during 4 months + / -2 weeks and no subsequent CR/PR/SD.
about 4 months
Progression-free Survival (PFS) - Phase II
Assessed clinical efficacy of the combination regimen in this patient population per Progression-free survival (PFS). Progression-free survival (PFS) was the time from date of start of treatment to the date of first documented progression or death due to any cause. If a patient had not progressed or died, progression-free survival was censored at the time of last adequate tumor assessment. According to the study protocol no tumor assessments were performed after discontinuation of treatment with study drug. Therefore, for all patients who discontinued treatment without a documented progression but died thereafter, death was considered as PFS event only if it occurred within the regular safety follow-up of 28 days after discontinuation. Otherwise, the PFS time was censored at the last adequate tumor assessment.
about 60 months
Secondary Outcomes (3)
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.
about 60 months
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).
about 60 months
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.
about 60 months
Study Arms (6)
Phase l: RAD001 20mg/week
EXPERIMENTALRAD001 20 mg was given once a week.
Phase l: RAD001 2.5mg/day + Glivec 600mg/day
EXPERIMENTALRAD001 2.5 mg was given in combination with Glivec/Gleevec 600mg/day.
Phase l: RAD001 5mg/day + Glivec 600mg/day
EXPERIMENTALRAD001 5 mg was given in combination with Glivec/Gleevec 600mg/day.
Phase l: RAD001 2.5mg/day + Glivec 800mg/day
EXPERIMENTALRAD001 2.5 mg was given in combination with Glivec/Gleevec 800mg/day.
Phase ll - Stratum l (first-line resistant/refractory): RAD001 2.5mg/day + Glivec 600mg/day
EXPERIMENTALAll first-line resistant/refractory patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day.
Phase ll - Stratum ll: (post second-line therapy): RAD001 2.5mg/day + Glivec 600mg/day
EXPERIMENTALAll post-second-line patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day
Interventions
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.
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.
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.
Eligibility Criteria
You may qualify if:
- 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)
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (16)
Dana Farber Cancer Institute Dept of Sarcoma Oncology
Boston, Massachusetts, 02215, United States
College of Physicians and Surgeons of Columbia University
New York, New York, 10032, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, 19111, United States
Novartis Investigative Site
Edegem, Antwerpen, 2650, Belgium
Novartis Investigative Site
Leuven, 3000, Belgium
Novartis Investigative Site
Bordeaux, 33076, France
Novartis Investigative Site
Lille, 59020, France
Novartis Investigative Site
Lyon, F-69373, France
Novartis Investigative Site
Marseille, 13385, France
Novartis Investigative Site
Villejuif, 94805, France
Novartis Investigative Site
Berlin, 13125, Germany
Novartis Investigative Site
Cologne, 50937, Germany
Novartis Investigative Site
Frankfurt, 60488, Germany
Novartis Investigative Site
Hamburg, 20246, Germany
Novartis Investigative Site
München, 81377, Germany
Novartis Investigative Site
Tübingen, 72076, Germany
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Study Director
- Organization
- Novartis Pharmaceuticals
Study Officials
- STUDY DIRECTOR
Novartis Pharmaceuticals
Novartis Pharmaceuticals
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
January 10, 2011
First Posted
January 12, 2011
Study Start
November 13, 2002
Primary Completion
September 3, 2008
Study Completion
September 3, 2008
Last Updated
June 25, 2021
Results First Posted
June 25, 2021
Record last verified: 2021-06
Data Sharing
- IPD Sharing
- Will share
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the triasl in line with applicable laws and regulations. This trial data will be available according to the process described on www.clinicalstudydatarequest.com.