Clinical trial NCT01275222: Everolimus in Combination With Imatinib in Patients With Glivec Refractory/Resistant Gastrointestinal Stromal Tumors
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Gastrointestinal Stromal Tumors
Keywords: RAD001
everolimusGIST
everolimus
mTOR
Imatinib resistant
Imatinib-refractory/resistant
gastrointestinal stromal tumors
Gastrointestinal Stromal Tumors(GIST)
soft tissue sarcoma
stomach tumor
tumor of interstitial cells of Cajal (ICC)
digestive system cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-01-12
Enrollment: 117
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs): Phase I & II
timeFrame: 4 - 8 weeks
measure: Best Overall Response (BOR) as Assessed by Overall Response (Complete Response (CR) & Partial Response (PR)) - Phase I & II
timeFrame: 6 - 8 weeks
measure: Trough Concentrations for RAD001 and for Imatinib - Phase II
timeFrame: Part II Daily regimen: Baseline, Days 8, 15 and thereafter approximately every two months starting at month 3 whenever possible
measure: Overall Survival (OS) - Phase I & II
timeFrame: about 60 months
measure: 4-Month Progression-free Survival (PFS) Rate - Phase II
timeFrame: about 4 months
measure: Progression-free Survival (PFS) - Phase II
timeFrame: about 60 months
Secondary outcomes:
measure: 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.
timeFrame: about 60 months
measure: 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).
timeFrame: about 60 months
measure: 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.
timeFrame: about 60 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute Dept of Sarcoma Oncology
state: Massachusetts
city: New York
country: United States
facility: College of Physicians and Surgeons of Columbia University
state: New York
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Edegem
country: Belgium
facility: Novartis Investigative Site
state: Antwerpen
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Marseille Cedex 05
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Tübingen
country: Germany
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: