Gastrointestinal Stromal Tumors
Conditions
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
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.
Interventions
DRUGRAD001
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.
DRUGImatinib 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.
DRUGImatinib 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.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
Belgium, France, Germany, United States
Participant flow
Recruitment details
This trial was a Phase I/II study, following a sequential 2-part design. The 1st part was designed to assess whether there was a pharmacokinetic interaction between Glivec/Gleevec and RAD001. The 2nd part was designed to assess the potential efficacy of the combination in Glivec/Gleevec-resistant GIST patients in 2 strata of patients.
Pre-assignment details
An estimated maximum of 130 patients was planned to be enrolled into the study. In Phase I, there were 42 patients enrolled. In Phase II, there were 75 patients enrolled. 3 patients were excluded from all analyses due to a major protocol violation.
Participants by arm
| Arm | Count |
|---|---|
| Phase l: RAD001 20mg/Week RAD001 20 mg was given once a week. | 13 |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day RAD001 2.5 mg was given in combination with Glivec/Gleevec 600mg/day. | 13 |
| Phase l: RAD001 5mg/Day + Glivec 600mg/Day RAD001 5 mg was given in combination with Glivec/Gleevec 600mg/day. | 5 |
| Phase l: RAD001 2.5mg/Day + Glivec 800mg/Day RAD001 2.5 mg was given in combination with Glivec/Gleevec 800mg/day. | 11 |
| Phase ll - Stratum l (First-line Resistant/Refractory): RAD001 2.5mg/Day + Glivec 600mg/Day All first-line resistant/refractory patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day. | 28 |
| Phase ll: Stratum ll (Post Second-line Therapy) All post second-line therapy patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day. | 47 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Phase l by Treatment | Abnormal laboratory value(s) | 0 | 0 | 1 | 0 | 0 | 0 |
| Phase l by Treatment | Abnormal test procedure result(s) | 0 | 0 | 0 | 1 | 0 | 0 |
| Phase l by Treatment | Adverse Event | 1 | 4 | 2 | 3 | 0 | 0 |
| Phase l by Treatment | Death | 0 | 1 | 0 | 1 | 0 | 0 |
| Phase l by Treatment | Disease progression | 12 | 8 | 2 | 5 | 0 | 0 |
| Phase l by Treatment | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
| Phase ll by Stratum | Abnormal laboratory values | 0 | 0 | 0 | 0 | 0 | 1 |
| Phase ll by Stratum | Adverse Event | 0 | 0 | 0 | 0 | 2 | 10 |
| Phase ll by Stratum | Death | 0 | 0 | 0 | 0 | 1 | 1 |
| Phase ll by Stratum | Disease progression | 0 | 0 | 0 | 0 | 23 | 31 |
| Phase ll by Stratum | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 3 |
Baseline characteristics
| Characteristic | Phase ll - Stratum l (First-line Resistant/Refractory): RAD001 2.5mg/Day + Glivec 600mg/Day | Phase ll: Stratum ll (Post Second-line Therapy) | Total | 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 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 55.6 Years STANDARD_DEVIATION 13.16 | 59.3 Years STANDARD_DEVIATION 12.54 | 55.3 Years STANDARD_DEVIATION 11.8 | 53.5 Years STANDARD_DEVIATION 5.25 | 52.2 Years STANDARD_DEVIATION 14.11 | 53.8 Years STANDARD_DEVIATION 11.95 | 61.9 Years STANDARD_DEVIATION 13.25 |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 27 Participants | 47 Participants | 115 Participants | 13 Participants | 12 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Female | 7 Participants | 16 Participants | 34 Participants | 2 Participants | 3 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 21 Participants | 31 Participants | 83 Participants | 11 Participants | 10 Participants | 1 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 13 | 12 / 13 | 5 / 5 | 11 / 11 | 27 / 28 | 47 / 47 |
| serious Total, serious adverse events | 4 / 13 | 7 / 13 | 3 / 5 | 7 / 11 | 11 / 28 | 25 / 47 |
Outcome results
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.
Time frame: about 4 months
Population: Per Protocol population: The per-protocol population included 82% of Stratum I patients and 75% of Stratum II patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase l: RAD001 20mg/Week | 4-Month Progression-free Survival (PFS) Rate - Phase II | 17.4 Percentage of participants |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | 4-Month Progression-free Survival (PFS) Rate - Phase II | 37.1 Percentage of participants |
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).
Time frame: 6 - 8 weeks
Population: Intent-to-treat (ITT) population: All patients (except for the 3 patients who did not meet the protocol inclusion/exclusion criteria) were included in the ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase l: RAD001 20mg/Week | Best Overall Response (BOR) as Assessed by Overall Response (Complete Response (CR) & Partial Response (PR)) - Phase I & II | 0 Percentage of Participants |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Best Overall Response (BOR) as Assessed by Overall Response (Complete Response (CR) & Partial Response (PR)) - Phase I & II | 1 Percentage of Participants |
| Phase l: RAD001 5mg/Day + Glivec 600mg/Day | Best Overall Response (BOR) as Assessed by Overall Response (Complete Response (CR) & Partial Response (PR)) - Phase I & II | 0 Percentage of Participants |
| Phase l: RAD001 2.5mg/Day + Glivec 800mg/Day | Best Overall Response (BOR) as Assessed by Overall Response (Complete Response (CR) & Partial Response (PR)) - Phase I & II | 0.0 Percentage of Participants |
| Phase ll - Stratum l (First-line Resistant/Refractory): RAD001 2.5mg/Day + Glivec 600mg/Day | Best Overall Response (BOR) as Assessed by Overall Response (Complete Response (CR) & Partial Response (PR)) - Phase I & II | 0 Percentage of Participants |
| Phase ll: Stratum ll (Post Second-line Therapy) | Best Overall Response (BOR) as Assessed by Overall Response (Complete Response (CR) & Partial Response (PR)) - Phase I & II | 1 Percentage of Participants |
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.
Time frame: 4 - 8 weeks
Population: Safety Population: All patients (except for the 3 patients who did not meet the protocol inclusion/exclusion criteria) were included in the Safety population for Phase I. All patients were included in the Safety population for Phase II.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase l: RAD001 20mg/Week | Number of Participants With Adverse Events (AEs): Phase I & II | 13 Participants |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Number of Participants With Adverse Events (AEs): Phase I & II | 13 Participants |
| Phase l: RAD001 5mg/Day + Glivec 600mg/Day | Number of Participants With Adverse Events (AEs): Phase I & II | 5 Participants |
| Phase l: RAD001 2.5mg/Day + Glivec 800mg/Day | Number of Participants With Adverse Events (AEs): Phase I & II | 11 Participants |
| Phase ll - Stratum l (First-line Resistant/Refractory): RAD001 2.5mg/Day + Glivec 600mg/Day | Number of Participants With Adverse Events (AEs): Phase I & II | 27 Participants |
| Phase ll: Stratum ll (Post Second-line Therapy) | Number of Participants With Adverse Events (AEs): Phase I & II | 47 Participants |
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.
Time frame: about 60 months
Population: ITT population: All patients (except for the 3 patients who did not meet the protocol inclusion/exclusion criteria) were included in the ITT population for phase I. All patients were included in the ITT population for phase II.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase l: RAD001 20mg/Week | Overall Survival (OS) - Phase I & II | 9.4 months |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Overall Survival (OS) - Phase I & II | 10.9 months |
| Phase l: RAD001 5mg/Day + Glivec 600mg/Day | Overall Survival (OS) - Phase I & II | 18.7 months |
| Phase l: RAD001 2.5mg/Day + Glivec 800mg/Day | Overall Survival (OS) - Phase I & II | NA months |
| Phase ll - Stratum l (First-line Resistant/Refractory): RAD001 2.5mg/Day + Glivec 600mg/Day | Overall Survival (OS) - Phase I & II | 14.9 months |
| Phase ll: Stratum ll (Post Second-line Therapy) | Overall Survival (OS) - Phase I & II | 10.7 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.
Time frame: about 60 months
Population: ITT population: All patients were included in the ITT population for Phase II.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase l: RAD001 20mg/Week | Progression-free Survival (PFS) - Phase II | 1.9 months |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Progression-free Survival (PFS) - Phase II | 3.5 months |
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.
Time frame: Part II Daily regimen: Baseline, Days 8, 15 and thereafter approximately every two months starting at month 3 whenever possible
Population: Pharmacokinetics (PK) population: The PK population included 18% of Stratum I patients and 47% of Stratum II patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase l: RAD001 20mg/Week | Trough Concentrations for RAD001 and for Imatinib - Phase II | Baseline: Imatinib | 472.00 ng/mL |
| Phase l: RAD001 20mg/Week | Trough Concentrations for RAD001 and for Imatinib - Phase II | Week 3: RAD001 | 19.900 ng/mL |
| Phase l: RAD001 20mg/Week | Trough Concentrations for RAD001 and for Imatinib - Phase II | Month 4: Imatinib | 333.00 ng/mL |
| Phase l: RAD001 20mg/Week | Trough Concentrations for RAD001 and for Imatinib - Phase II | Week 2: Imatinib | 626.50 ng/mL |
| Phase l: RAD001 20mg/Week | Trough Concentrations for RAD001 and for Imatinib - Phase II | Month 6: Imatinib | 181.00 ng/mL |
| Phase l: RAD001 20mg/Week | Trough Concentrations for RAD001 and for Imatinib - Phase II | Week 2: RAD001 | 24.300 ng/mL |
| Phase l: RAD001 20mg/Week | Trough Concentrations for RAD001 and for Imatinib - Phase II | Week 3: Imatinib | 572.00 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Week 3: Imatinib | 718.00 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Week 9: Imatinib | 899.0 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Month 4: Imatinib | 446.00 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Month 6: Imatinib | 2040.00 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Month 12: Imatinib | 324.00 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Month 8: Imatinib | 575.00 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Week 2: RAD001 | 12.100 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Week 3: RAD001 | 12.750 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Week 9: RAD001 | 10.950 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Month 4: RAD001 | 7.840 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Baseline: Imatinib | 501.50 ng/mL |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | Trough Concentrations for RAD001 and for Imatinib - Phase II | Week 2: Imatinib | 540.00 ng/mL |
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.
Time frame: about 60 months
Population: Pharmacodynamic population: Molecular pathology and pharmacogenomic assessments were planned, but not carried out due to an alternative therapy that became available after the initiation of this study.
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).
Time frame: about 60 months
Population: Pharmacodynamic population: Molecular pathology and pharmacogenomic assessments were planned, but not carried out due to an alternative therapy that became available after the initiation of this study.
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.
Time frame: about 60 months
Population: PET scans at baseline and as follow-up were planned to assess functional changes in tumors for patients on treatment. This analysis was not carried out due to alternative therapy that became available after the initiation of this study.
Post Hoc
All Collected Deaths
On treatment deaths were collected from FPFT up to 28 days after study drug discontinuation, for a maximum duration of 35.52 months (treatment duration ranged from 0.36 to to 35.52 months for the phase I part) and a maximum duration of 21.88 months (treatment duration of 0.16 to 21.88 months for the phase II part). Deaths post treatment survival follow up were collected after the on treatment period, up to 70 months.
Time frame: approx. 35.52 months, approx. 70 months
Population: ITT population: All patients (except for the 3 patients who did not meet the protocol inclusion/exclusion criteria) were included in the ITT population for phase I. All patients were included in the ITT population for phase II.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase l: RAD001 20mg/Week | All Collected Deaths | Total Deaths | 12 Participants |
| Phase l: RAD001 20mg/Week | All Collected Deaths | Deaths on-treatment | 2 Participants |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | All Collected Deaths | Total Deaths | 8 Participants |
| Phase l: RAD001 2.5mg/Day + Glivec 600mg/Day | All Collected Deaths | Deaths on-treatment | 3 Participants |
| Phase l: RAD001 5mg/Day + Glivec 600mg/Day | All Collected Deaths | Total Deaths | 3 Participants |
| Phase l: RAD001 5mg/Day + Glivec 600mg/Day | All Collected Deaths | Deaths on-treatment | 0 Participants |
| Phase l: RAD001 2.5mg/Day + Glivec 800mg/Day | All Collected Deaths | Total Deaths | 3 Participants |
| Phase l: RAD001 2.5mg/Day + Glivec 800mg/Day | All Collected Deaths | Deaths on-treatment | 2 Participants |
| Phase ll - Stratum l (First-line Resistant/Refractory): RAD001 2.5mg/Day + Glivec 600mg/Day | All Collected Deaths | Total Deaths | 9 Participants |
| Phase ll - Stratum l (First-line Resistant/Refractory): RAD001 2.5mg/Day + Glivec 600mg/Day | All Collected Deaths | Deaths on-treatment | 3 Participants |
| Phase ll: Stratum ll (Post Second-line Therapy) | All Collected Deaths | Total Deaths | 22 Participants |
| Phase ll: Stratum ll (Post Second-line Therapy) | All Collected Deaths | Deaths on-treatment | 6 Participants |