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

Gastrointestinal Stromal Tumors Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01275222
• Other study ID #: CRAD001C2206
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 13, 2002
• Est. completion date: September 3, 2008

Study information

• Verified date: June 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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 information / eligibility

• Status: Completed
• Enrollment: 117
• Est. completion date: September 3, 2008
• Est. primary completion date: September 3, 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Gastrointestinal Stromal Tumors

Intervention

Drug:
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Belgium	Novartis Investigative Site	Leuven
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Lille Cedex
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Marseille Cedex 05
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Tübingen
United States	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

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  France,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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.	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.	about 60 months
Secondary	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).	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).	about 60 months
Secondary	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.	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.	about 60 months