Colorectal Cancer
Conditions
Keywords
Colorectal cancer, metastatic colorectal adenocarcinoma, anti-EGFR antibody
Brief summary
To assess the safety and efficacy of weekly (70 mg per week) and daily (10 mg per day) everolimus in patients with metastatic colorectal cancer whose cancer has progressed despite prior treatment with targeted therapy and chemotherapy.
Interventions
DRUGEverolimus (RAD001)
Everolimus was supplied in 5 mg tablets in blister packs.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years old. * Patients with metastatic colorectal cancer (CRC). * Patients must have sufficient and obtainable tumor tissue for biomarker analysis from original surgical resection. * Patients with documented disease progression within 6 months of their most recent dose of chemotherapeutic regimens. * Patients with at least one measurable lesion. * Adequate bone marrow function. * Adequate liver function. * Adequate renal function. * Patients with a life expectancy of \> 3 months. * Patients with a World Health Organization (WHO) performance status of 0, 1, or 2. * Women of childbearing potential must have had a negative serum pregnancy test 72 hours prior to the administration of the first study treatment. * Patients who give a written informed consent obtained according to local guidelines.
Exclusion criteria
* Patients currently receiving anti-cancer agents or who have received these within 4 weeks prior to study entry. * Patients who have previously received RAD001. * Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients. * Chronic treatment with steroids or another immunosuppressive agent. * Patients with untreated central nervous system (CNS) metastases or neurologically unstable CNS metastases. * HIV seropositivity. * Patients with an active, bleeding diathesis. Patients may use enoxaparin. * Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study. * Patients who have a history of another primary malignancy \< 3 years, with the exceptions of non-melanoma skin cancer, and carcinoma in situ of uterine cervix. * Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. * Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to first study treatment. * Patients unwilling to or unable to comply with the protocol. Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) and Objective Response Rate (ORR) According to the Response Evaluation Criteria in Solid Tumors (RECIST) | Imaging every 8 weeks | RECIST (Response Evaluation Criteria In Solid Tumors) is a set of published rules that define when cancer patients improve (respond), stay the same (stable) or worsen (progression) during treatments. Disease Control Rate (DCR) defined as the percentage of participants with Disease Control best overall response (complete response, partial response or stable disease)and Objective Response Rate (ORR) defined as the percentage of participants with best overall Objective Response (complete response or partial response). |
| The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Imaging every 8 weeks | RECIST (Response Evaluation Criteria In Solid Tumors) is a set of published rules that define when cancer patients improve (respond), stay the same (stable) or worsen (progression) during treatments. Best Over Response (BOR): Complete Response (CR, No lesions), Partial Response (PR, 30% decrease in lesions), and Stable Disease (SD, none of the above) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | From the first day of treatment until 28 days after discontinuation of study treatment | Toxicity assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAEv3.0). On treatment death defined as deaths occurring no more than 28 days after the discontinuation of study treatment. |
| Biomarker Predictive of Clinical Benefit (DCR by KRAS) on Everolimus (RAD001) 70 mg/Week | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | The efficacy variable compared in this biomarker analysis is disease control rate (DCR) within the 70mg/week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF. |
| Biomarker Predictive of Clinical Benefit (DCR by KRAS) on Everolimus (RAD001) 10 mg/Day | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | The efficacy variable compared in this biomarker analysis is disease control rate (DCR) within the 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF. |
| Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS ) on Everolimus (RAD001) 70mg/Week | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | The efficacy variable that was compared in the biomarker analysis are Median progression free survival (PFS) and overall survival (OS) within the Everolimus (RAD001) 70mg/week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF. |
| Progression-free Survival (PFS) | Imaging every 8 weeks | Duration in months from the date of first study treatment to the date of the first documented disease progression or death due to any cause. |
| Biomarkers Predictive of Clinical Benefit (DCR by PTEN ) on Everolimus (RAD001) 70mg/Week | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | The efficacy variable that was compared in the biomarker analysis is DCR within the Everolimus (RAD001) 70mg/week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF. |
| Biomarkers Predictive of Clinical Benefit (DCR by PTEN ) on Everolimus (RAD001) 10mg/Day | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | The efficacy variable that was compared in the biomarker analysis is DCR within the Everolimus (RAD001) 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF. |
| Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 70mg/Week | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | The efficacy variable that was compared in the biomarker analysis are PFS & OS within the Everolimus (RAD001) 70mg/Week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF. |
| Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 10mg/Day | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | The efficacy variable that was compared in the biomarker analysis are PFS & OS within the Everolimus (RAD001) 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF. |
| Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS) on Everolimus (RAD001) 10mg/Day | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | The efficacy variable that was compared in the biomarker analysis are Median progression free survival (PFS) and overall survival (OS) within the Everolimus (RAD001) 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF. |
| Overall Survival (OS) | Every 3 months | Overall survival defined as the time from date of first study treatment to the date of death due to any cause. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Everolimus (RAD001) 70 mg/Week Participants self-administered weekly oral dose of Everolimus (RAD001). Drug supplied as 5 mg tablets in blister packs. | 99 |
| Everolimus (RAD001) 10 mg/Day Participants self-administered daily oral dose of Everolimus (RAD001). Drug supplied as 5 mg tablets in blister packs. | 100 |
| Total | 199 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 0 | 2 |
| Overall Study | Adverse Event | 7 | 15 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Disease progression | 79 | 76 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Subject's no longer requires study drug | 0 | 1 |
| Overall Study | Withdrawal by Subject | 10 | 3 |
Baseline characteristics
| Characteristic | Everolimus (RAD001) 10 mg/Day | Everolimus (RAD001) 70 mg/Week | Total |
|---|---|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 12.1 | 60.0 years STANDARD_DEVIATION 11.5 | 60.2 years STANDARD_DEVIATION 11.8 |
| Age, Customized 45 to <55 Years | 17 Participants | 22 Participants | 39 Participants |
| Age, Customized <45 Years | 10 Participants | 10 Participants | 20 Participants |
| Age, Customized 55 to <65 Years | 33 Participants | 29 Participants | 62 Participants |
| Age, Customized > or = to 65 Years | 40 Participants | 38 Participants | 78 Participants |
| Sex: Female, Male Female | 48 Participants | 47 Participants | 95 Participants |
| Sex: Female, Male Male | 52 Participants | 52 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 99 / 99 | 98 / 100 |
| serious Total, serious adverse events | 34 / 99 | 22 / 100 |
Outcome results
Primary
Disease Control Rate (DCR) and Objective Response Rate (ORR) According to the Response Evaluation Criteria in Solid Tumors (RECIST)
RECIST (Response Evaluation Criteria In Solid Tumors) is a set of published rules that define when cancer patients improve (respond), stay the same (stable) or worsen (progression) during treatments. Disease Control Rate (DCR) defined as the percentage of participants with Disease Control best overall response (complete response, partial response or stable disease)and Objective Response Rate (ORR) defined as the percentage of participants with best overall Objective Response (complete response or partial response).
Time frame: Imaging every 8 weeks
Population: Per Protocol Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Disease Control Rate (DCR) and Objective Response Rate (ORR) According to the Response Evaluation Criteria in Solid Tumors (RECIST) | Disease Control Rate (DCR) | 31.0 Percentage of participants |
| Everolimus (RAD001) 70 mg/Week | Disease Control Rate (DCR) and Objective Response Rate (ORR) According to the Response Evaluation Criteria in Solid Tumors (RECIST) | Objective Response Rate (ORR) | 0 Percentage of participants |
| Everolimus (RAD001) 10 mg/Day | Disease Control Rate (DCR) and Objective Response Rate (ORR) According to the Response Evaluation Criteria in Solid Tumors (RECIST) | Disease Control Rate (DCR) | 32.4 Percentage of participants |
| Everolimus (RAD001) 10 mg/Day | Disease Control Rate (DCR) and Objective Response Rate (ORR) According to the Response Evaluation Criteria in Solid Tumors (RECIST) | Objective Response Rate (ORR) | 0 Percentage of participants |
Primary
The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST)
RECIST (Response Evaluation Criteria In Solid Tumors) is a set of published rules that define when cancer patients improve (respond), stay the same (stable) or worsen (progression) during treatments. Best Over Response (BOR): Complete Response (CR, No lesions), Partial Response (PR, 30% decrease in lesions), and Stable Disease (SD, none of the above)
Time frame: Imaging every 8 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus (RAD001) 70 mg/Week | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Stable Disease (SD) | 25 Participants |
| Everolimus (RAD001) 70 mg/Week | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Disease Control (CR or PR or SD) | 25 Participants |
| Everolimus (RAD001) 70 mg/Week | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response (PR) | 0 Participants |
| Everolimus (RAD001) 70 mg/Week | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Objective Response (CR or PR) | 0 Participants |
| Everolimus (RAD001) 70 mg/Week | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Progressive Disease (PD) | 58 Participants |
| Everolimus (RAD001) 70 mg/Week | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Unknown | 16 Participants |
| Everolimus (RAD001) 70 mg/Week | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response (CR) | 0 Participants |
| Everolimus (RAD001) 10 mg/Day | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Unknown | 19 Participants |
| Everolimus (RAD001) 10 mg/Day | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response (CR) | 0 Participants |
| Everolimus (RAD001) 10 mg/Day | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response (PR) | 0 Participants |
| Everolimus (RAD001) 10 mg/Day | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Stable Disease (SD) | 26 Participants |
| Everolimus (RAD001) 10 mg/Day | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Progressive Disease (PD) | 55 Participants |
| Everolimus (RAD001) 10 mg/Day | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Disease Control (CR or PR or SD) | 26 Participants |
| Everolimus (RAD001) 10 mg/Day | The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) | Objective Response (CR or PR) | 0 Participants |
Secondary
Biomarker Predictive of Clinical Benefit (DCR by KRAS) on Everolimus (RAD001) 10 mg/Day
The efficacy variable compared in this biomarker analysis is disease control rate (DCR) within the 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.
Time frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Biomarker Predictive of Clinical Benefit (DCR by KRAS) on Everolimus (RAD001) 10 mg/Day | 17.1 percentage of participants |
| Everolimus (RAD001) 10 mg/Day | Biomarker Predictive of Clinical Benefit (DCR by KRAS) on Everolimus (RAD001) 10 mg/Day | 35.0 percentage of participants |
p-value: 0.0795% CI: [0.135, 1.083]Unadjusted Logistic Regression
Secondary
Biomarker Predictive of Clinical Benefit (DCR by KRAS) on Everolimus (RAD001) 70 mg/Week
The efficacy variable compared in this biomarker analysis is disease control rate (DCR) within the 70mg/week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.
Time frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Biomarker Predictive of Clinical Benefit (DCR by KRAS) on Everolimus (RAD001) 70 mg/Week | 33.3 percentage of participants |
| Everolimus (RAD001) 10 mg/Day | Biomarker Predictive of Clinical Benefit (DCR by KRAS) on Everolimus (RAD001) 70 mg/Week | 21.7 percentage of participants |
p-value: 0.25395% CI: [0.657, 4.929]Unadjusted Logistic Regression
Secondary
Biomarkers Predictive of Clinical Benefit (DCR by PTEN ) on Everolimus (RAD001) 10mg/Day
The efficacy variable that was compared in the biomarker analysis is DCR within the Everolimus (RAD001) 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.
Time frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Biomarkers Predictive of Clinical Benefit (DCR by PTEN ) on Everolimus (RAD001) 10mg/Day | 26.9 percentage of participants |
| Everolimus (RAD001) 10 mg/Day | Biomarkers Predictive of Clinical Benefit (DCR by PTEN ) on Everolimus (RAD001) 10mg/Day | 26.1 percentage of participants |
p-value: 0.93895% CI: [0.352, 3.099]Unadjusted Logistic Regression
Secondary
Biomarkers Predictive of Clinical Benefit (DCR by PTEN ) on Everolimus (RAD001) 70mg/Week
The efficacy variable that was compared in the biomarker analysis is DCR within the Everolimus (RAD001) 70mg/week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.
Time frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Biomarkers Predictive of Clinical Benefit (DCR by PTEN ) on Everolimus (RAD001) 70mg/Week | 20.9 percentage of participants |
| Everolimus (RAD001) 10 mg/Day | Biomarkers Predictive of Clinical Benefit (DCR by PTEN ) on Everolimus (RAD001) 70mg/Week | 33.3 percentage of participants |
p-value: 0.23895% CI: [0.184, 1.523]Unadjusted Logistic Regression
Secondary
Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS) on Everolimus (RAD001) 10mg/Day
The efficacy variable that was compared in the biomarker analysis are Median progression free survival (PFS) and overall survival (OS) within the Everolimus (RAD001) 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.
Time frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment
Population: FAS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS) on Everolimus (RAD001) 10mg/Day | Median PFS | 1.71 months |
| Everolimus (RAD001) 70 mg/Week | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS) on Everolimus (RAD001) 10mg/Day | Median OS | 5.59 months |
| Everolimus (RAD001) 10 mg/Day | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS) on Everolimus (RAD001) 10mg/Day | Median PFS | 1.77 months |
| Everolimus (RAD001) 10 mg/Day | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS) on Everolimus (RAD001) 10mg/Day | Median OS | 7.06 months |
p-value: 0.44195% CI: [0.752, 1.923]Unadjusted Logistic Regression
p-value: 0.12695% CI: [0.884, 2.708]Unadjusted Logistic Regression
Secondary
Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS ) on Everolimus (RAD001) 70mg/Week
The efficacy variable that was compared in the biomarker analysis are Median progression free survival (PFS) and overall survival (OS) within the Everolimus (RAD001) 70mg/week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.
Time frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment
Population: FAS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS ) on Everolimus (RAD001) 70mg/Week | Median PFS | 1.77 months |
| Everolimus (RAD001) 70 mg/Week | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS ) on Everolimus (RAD001) 70mg/Week | Median OS | 6.18 months |
| Everolimus (RAD001) 10 mg/Day | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS ) on Everolimus (RAD001) 70mg/Week | Median PFS | 1.71 months |
| Everolimus (RAD001) 10 mg/Day | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS ) on Everolimus (RAD001) 70mg/Week | Median OS | 4.90 months |
p-value: 0.39995% CI: [0.505, 1.312]Unadjusted Logistic Regression
p-value: 0.99595% CI: [0.62, 1.617]Unadjusted Logistic Regression
Secondary
Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 10mg/Day
The efficacy variable that was compared in the biomarker analysis are PFS & OS within the Everolimus (RAD001) 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.
Time frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment
Population: FAS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 10mg/Day | Median PFS | 1.81 months |
| Everolimus (RAD001) 70 mg/Week | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 10mg/Day | Median OS | 10.38 months |
| Everolimus (RAD001) 10 mg/Day | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 10mg/Day | Median PFS | 1.68 months |
| Everolimus (RAD001) 10 mg/Day | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 10mg/Day | Median OS | 6.34 months |
p-value: 0.58895% CI: [0.521, 1.447]Unadjusted Cox Model
p-value: 0.14895% CI: [0.314, 1.191]Unadjusted Cox Model
Secondary
Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 70mg/Week
The efficacy variable that was compared in the biomarker analysis are PFS & OS within the Everolimus (RAD001) 70mg/Week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.
Time frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment
Population: FAS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 70mg/Week | Median PFS | 1.71 months |
| Everolimus (RAD001) 70 mg/Week | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 70mg/Week | Median OS | 5.98 months |
| Everolimus (RAD001) 10 mg/Day | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 70mg/Week | Median PFS | 1.77 months |
| Everolimus (RAD001) 10 mg/Day | Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 70mg/Week | Median OS | 4.37 months |
p-value: 0.14595% CI: [0.875, 2.484]Unadjusted Cox Model
p-value: 0.58395% CI: [0.696, 1.903]Unadjusted Cox Model
Secondary
Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr).
Toxicity assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAEv3.0). On treatment death defined as deaths occurring no more than 28 days after the discontinuation of study treatment.
Time frame: From the first day of treatment until 28 days after discontinuation of study treatment
Population: Safety set analysis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | Deaths | 86 Participants |
| Everolimus (RAD001) 70 mg/Week | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | On-treatment Death | 11 Participants |
| Everolimus (RAD001) 70 mg/Week | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | SAE regardless of relationship to study treatment | 34 Participants |
| Everolimus (RAD001) 70 mg/Week | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | SAE with suspected relationship to study treatment | 7 Participants |
| Everolimus (RAD001) 70 mg/Week | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | AE Grade 3-4, regardless of relationship to study | 58 Participants |
| Everolimus (RAD001) 70 mg/Week | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | AE Grade 3-4, suspected relationship to study tr | 31 Participants |
| Everolimus (RAD001) 70 mg/Week | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | AE leading to discontinuation | 9 Participants |
| Everolimus (RAD001) 70 mg/Week | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | Clinically notable adverse event | 85 Participants |
| Everolimus (RAD001) 10 mg/Day | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | Clinically notable adverse event | 76 Participants |
| Everolimus (RAD001) 10 mg/Day | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | Deaths | 65 Participants |
| Everolimus (RAD001) 10 mg/Day | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | AE Grade 3-4, regardless of relationship to study | 50 Participants |
| Everolimus (RAD001) 10 mg/Day | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | On-treatment Death | 14 Participants |
| Everolimus (RAD001) 10 mg/Day | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | AE leading to discontinuation | 20 Participants |
| Everolimus (RAD001) 10 mg/Day | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | SAE regardless of relationship to study treatment | 22 Participants |
| Everolimus (RAD001) 10 mg/Day | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | AE Grade 3-4, suspected relationship to study tr | 26 Participants |
| Everolimus (RAD001) 10 mg/Day | Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). | SAE with suspected relationship to study treatment | 6 Participants |
Secondary
Overall Survival (OS)
Overall survival defined as the time from date of first study treatment to the date of death due to any cause.
Time frame: Every 3 months
Population: Overall Survival \[OS\] was analyzed in Full Analysis Set \[FAS\].
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Overall Survival (OS) | 4.90 Months |
| Everolimus (RAD001) 10 mg/Day | Overall Survival (OS) | 5.88 Months |
Secondary
Progression-free Survival (PFS)
Duration in months from the date of first study treatment to the date of the first documented disease progression or death due to any cause.
Time frame: Imaging every 8 weeks
Population: Progression- Free Survival (PFS) was analyzed in Full Analysis Set \[FAS\].
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus (RAD001) 70 mg/Week | Progression-free Survival (PFS) | 1.77 Months |
| Everolimus (RAD001) 10 mg/Day | Progression-free Survival (PFS) | 1.77 Months |