Everolimus in Combination With Imatinib in Patients With Glivec Refractory/Resistant Gastrointestinal Stromal Tumors
- Conditions
- Gastrointestinal Stromal Tumors
- Interventions
- Registration Number
- NCT01275222
- Lead Sponsor
- Novartis Pharmaceuticals
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 117
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)
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase l: RAD001 5mg/day + Glivec 600mg/day Imatinib 600mg/day (Glevec is the brand name for imatinib) RAD001 5 mg was given in combination with Glivec/Gleevec 600mg/day. Phase l: RAD001 2.5mg/day + Glivec 800mg/day Imatinib 600mg/day (Glevec is the brand name for imatinib) RAD001 2.5 mg was given in combination with Glivec/Gleevec 800mg/day. Phase l: RAD001 2.5mg/day + Glivec 600mg/day Imatinib 600mg/day (Glevec is the brand name for imatinib) RAD001 2.5 mg was given in combination with Glivec/Gleevec 600mg/day. Phase l: RAD001 2.5mg/day + Glivec 800mg/day RAD001 RAD001 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 Imatinib 800mg/day (Glevec is the brand name for imatinib) All 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 Imatinib 800mg/day (Glevec is the brand name for imatinib) All post-second-line patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day Phase l: RAD001 20mg/week RAD001 RAD001 20 mg was given once a week. Phase ll - Stratum ll: (post second-line therapy): RAD001 2.5mg/day + Glivec 600mg/day RAD001 All post-second-line patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day Phase l: RAD001 2.5mg/day + Glivec 600mg/day RAD001 RAD001 2.5 mg was given in combination with Glivec/Gleevec 600mg/day. Phase l: RAD001 5mg/day + Glivec 600mg/day RAD001 RAD001 5 mg was given in combination with Glivec/Gleevec 600mg/day. Phase ll - Stratum l (first-line resistant/refractory): RAD001 2.5mg/day + Glivec 600mg/day RAD001 All first-line resistant/refractory patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day.
- Primary Outcome Measures
Name Time Method Number of Participants With Adverse Events (AEs): Phase I & II 4 - 8 weeks 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.
Best Overall Response (BOR) as Assessed by Overall Response (Complete Response (CR) & Partial Response (PR)) - Phase I & II 6 - 8 weeks 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).
Trough Concentrations for RAD001 and for Imatinib - Phase II Part II Daily regimen: Baseline, Days 8, 15 and thereafter approximately every two months starting at month 3 whenever possible Assessed the pharmacokinetics (PK) of the combination administration of RAD001 and imatinib in this patient population.
Progression-free Survival (PFS) - Phase II about 60 months 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.Overall Survival (OS) - Phase I & II about 60 months 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.
4-Month Progression-free Survival (PFS) Rate - Phase II about 4 months 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.
- Secondary Outcome Measures
Name Time Method 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 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.
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 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).
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 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.
Trial Locations
- Locations (4)
Novartis Investigative Site
🇩🇪Tübingen, Germany
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