Efficacy and Safety of Everolimus in Patients With Metastatic Colorectal Cancer Who Have Failed Prior Targeted Therapy and Chemotherapy

Study Overview
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Brief Summary
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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.

Official Title
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A Single Arm, Multicenter Phase II Study of Everolimus in Patients With Metastatic Colorectal Adenocarcinoma Whose Cancer Has Progressed Despite Prior Therapy With an Anti-EGFR Antibody (if Appropriate), Bevacizumab, Fluoropyrimidine, Oxaliplatin, and Irinotecan-based Regimens

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Everolimus (RAD001)


Participation Criteria
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Eligibility Criteria
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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/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus (RAD001) 70 mg/week<br> | Drug: Everolimus (RAD001)<br>* Everolimus was supplied in 5 mg tablets in blister packs.<br>* Other names: Certican;|
| Experimental: Everolimus (RAD001) 10 mg/day<br> | Drug: Everolimus (RAD001)<br>* Everolimus was supplied in 5 mg tablets in blister packs.<br>* Other names: Certican;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Imaging every 8 weeks | 
| 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) | Imaging every 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Imaging every 8 weeks | 
| Overall Survival (OS) | Overall survival defined as the time from date of first study treatment to the date of death due to any cause. | Every 3 months | 
| 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. | From the first day of treatment until 28 days after discontinuation of study treatment | 
| 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. | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | 
| 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. | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | 
| 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. | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | 
| 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. | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | 
| 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. | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | 
| 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. | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | 
| 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. | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | 
| 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. | Screening and Day 1 of cycles 2, 3, 4 and end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, metastatic colorectal adenocarcinoma, anti-EGFR antibody