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

Primary Purpose

Gastrointestinal Stromal Tumors

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
RAD001
Imatinib 600mg/day (Glevec is the brand name for imatinib)
Imatinib 800mg/day (Glevec is the brand name for imatinib)
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gastrointestinal Stromal Tumors focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Dana Farber Cancer Institute Dept of Sarcoma Oncology
  • College of Physicians and Surgeons of Columbia University
  • Fox Chase Cancer Center
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Phase l: RAD001 20mg/week

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

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

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

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

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

Arm Description

RAD001 20 mg was given once a week.

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

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

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

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

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

Outcomes

Primary Outcome Measures

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.
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).
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.
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.
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.
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.

Secondary Outcome Measures

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.
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).
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.

Full Information

First Posted
January 10, 2011
Last Updated
June 3, 2021
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01275222
Brief Title
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

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
November 13, 2002 (Actual)
Primary Completion Date
September 3, 2008 (Actual)
Study Completion Date
September 3, 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
117 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Phase l: RAD001 20mg/week
Arm Type
Experimental
Arm Description
RAD001 20 mg was given once a week.
Arm Title
Phase l: RAD001 2.5mg/day + Glivec 600mg/day
Arm Type
Experimental
Arm Description
RAD001 2.5 mg was given in combination with Glivec/Gleevec 600mg/day.
Arm Title
Phase l: RAD001 5mg/day + Glivec 600mg/day
Arm Type
Experimental
Arm Description
RAD001 5 mg was given in combination with Glivec/Gleevec 600mg/day.
Arm Title
Phase l: RAD001 2.5mg/day + Glivec 800mg/day
Arm Type
Experimental
Arm Description
RAD001 2.5 mg was given in combination with Glivec/Gleevec 800mg/day.
Arm Title
Phase ll - Stratum l (first-line resistant/refractory): RAD001 2.5mg/day + Glivec 600mg/day
Arm Type
Experimental
Arm Description
All first-line resistant/refractory patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day.
Arm Title
Phase ll - Stratum ll: (post second-line therapy): RAD001 2.5mg/day + Glivec 600mg/day
Arm Type
Experimental
Arm Description
All post-second-line patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day
Intervention Type
Drug
Intervention Name(s)
RAD001
Other Intervention Name(s)
everolimus
Intervention Description
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
Intervention Name(s)
Imatinib 600mg/day (Glevec is the brand name for imatinib)
Other Intervention Name(s)
STI571
Intervention Description
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
Intervention Name(s)
Imatinib 800mg/day (Glevec is the brand name for imatinib)
Other Intervention Name(s)
STI571
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Events (AEs): Phase I & II
Description
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.
Time Frame
4 - 8 weeks
Title
Best Overall Response (BOR) as Assessed by Overall Response (Complete Response (CR) & Partial Response (PR)) - Phase I & II
Description
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).
Time Frame
6 - 8 weeks
Title
Trough Concentrations for RAD001 and for Imatinib - Phase II
Description
Assessed the pharmacokinetics (PK) of the combination administration of RAD001 and imatinib in this patient population.
Time Frame
Part II Daily regimen: Baseline, Days 8, 15 and thereafter approximately every two months starting at month 3 whenever possible
Title
Overall Survival (OS) - Phase I & II
Description
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.
Time Frame
about 60 months
Title
4-Month Progression-free Survival (PFS) Rate - Phase II
Description
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.
Time Frame
about 4 months
Title
Progression-free Survival (PFS) - Phase II
Description
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.
Time Frame
about 60 months
Secondary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
about 60 months
Title
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).
Description
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).
Time Frame
about 60 months
Title
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.
Description
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.
Time Frame
about 60 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Dana Farber Cancer Institute Dept of Sarcoma Oncology
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
College of Physicians and Surgeons of Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Fox Chase Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111
Country
United States
Facility Name
Novartis Investigative Site
City
Edegem
State/Province
Antwerpen
ZIP/Postal Code
2650
Country
Belgium
Facility Name
Novartis Investigative Site
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Bordeaux
ZIP/Postal Code
33076
Country
France
Facility Name
Novartis Investigative Site
City
Lille Cedex
ZIP/Postal Code
59020
Country
France
Facility Name
Novartis Investigative Site
City
Lyon
ZIP/Postal Code
F-69373
Country
France
Facility Name
Novartis Investigative Site
City
Marseille Cedex 05
ZIP/Postal Code
13385
Country
France
Facility Name
Novartis Investigative Site
City
Villejuif Cedex
ZIP/Postal Code
94805
Country
France
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
13125
Country
Germany
Facility Name
Novartis Investigative Site
City
Frankfurt
ZIP/Postal Code
60488
Country
Germany
Facility Name
Novartis Investigative Site
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Novartis Investigative Site
City
Koeln
ZIP/Postal Code
50937
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenchen
ZIP/Postal Code
81377
Country
Germany
Facility Name
Novartis Investigative Site
City
Tübingen
ZIP/Postal Code
72076
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
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.
IPD Sharing URL
https://www.clinicalstudydatarequest.com

Learn more about this trial

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

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