Ignite Creation Date:
2024-05-05 @ 10:10 PM
Last Modification Date:
2024-10-26 @ 10:14 AM
Study NCT ID:
NCT01047293
Status:
COMPLETED
Last Update Posted:
2017-04-04
First Post:
2010-01-08
Brief Title:
RAD001 FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma
Sponsor:
University of Utah
Organization:
University of Utah
Study Overview
Official Title:
A Phase III Study of RAD001 FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma
Status:
COMPLETED
Status Verified Date:
2017-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
RAD001 everolimus is a novel oral derivative of rapamycin RAD001 has been in clinical development since 1996 as an immunosuppressant in solid organ transplantation and has obtained marketing authorization Certican for prophylaxis of rejection in renal and cardiac transplantation in a number of countries including the majority of the European Union RAD001 has been in development for patients with various malignancies since 2002
RAD001 is being investigated as an anticancer agent based on its potential to act
Directly on the tumor cells by inhibiting tumor cell growth and proliferation
Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity via potent inhibition of tumor cell HIF-1 activity VEGF production and VEGF-induced proliferation of endothelial cells The role of angiogenesis in the maintenance of solid tumor growth is well established and the mTOR pathway has been implicated in the regulation of tumor production of proangiogenic factors as well as modulation of VEGFR signaling in endothelial cells
At weekly and daily schedules and at various doses explored RAD001 is generally well tolerated The most frequent adverse events rash mucositis fatigue and headache associated with RAD001 therapy are manageable Non-infectious pneumonitis has been reported with mTOR inhibitors but is commonly low-grade and reversible
Both FOLFOX and bevacizumab are well established for treatment of metastatic colorectal carcinomas FOLFOX-6 can be combined safely with Bevacizumab and is currently in phase 3 testing for adjuvant therapy and is commonly used as a first line treatment regimen for metastatic colorectal cancers 25 There is an enhanced interest in development of more effective regimens for colorectal cancers RAD001 is a mTOR inhibitor that has preclinical and clinical activity in colorectal cancers RAD001 downregulates the mTOR pathway which can lead to direct antiproliferative effects as well as decreased production of Vascular Endothelial Growth Factor A combination of RAD001 at 10 mg per day in combination with Bevacizumab 10 mgkg every 2 weeks has been shown to be efficacious and safe In another trial RAD001 was shown to have many patients with stable disease and clearly needs to be given in combination therapy
RAD001 is being investigated as an anticancer agent based on its potential to act
Directly on the tumor cells by inhibiting tumor cell growth and proliferation
Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity via potent inhibition of tumor cell HIF-1 activity VEGF production and VEGF-induced proliferation of endothelial cells The role of angiogenesis in the maintenance of solid tumor growth is well established and the mTOR pathway has been implicated in the regulation of tumor production of proangiogenic factors as well as modulation of VEGFR signaling in endothelial cells
At weekly and daily schedules and at various doses explored RAD001 is generally well tolerated The most frequent adverse events rash mucositis fatigue and headache associated with RAD001 therapy are manageable Non-infectious pneumonitis has been reported with mTOR inhibitors but is commonly low-grade and reversible
Both FOLFOX and bevacizumab are well established for treatment of metastatic colorectal carcinomas FOLFOX-6 can be combined safely with Bevacizumab and is currently in phase 3 testing for adjuvant therapy and is commonly used as a first line treatment regimen for metastatic colorectal cancers 25 There is an enhanced interest in development of more effective regimens for colorectal cancers RAD001 is a mTOR inhibitor that has preclinical and clinical activity in colorectal cancers RAD001 downregulates the mTOR pathway which can lead to direct antiproliferative effects as well as decreased production of Vascular Endothelial Growth Factor A combination of RAD001 at 10 mg per day in combination with Bevacizumab 10 mgkg every 2 weeks has been shown to be efficacious and safe In another trial RAD001 was shown to have many patients with stable disease and clearly needs to be given in combination therapy
Detailed Description:
Patient population Phase I portion Metastatic colorectal cancer A total of 3 patients on each cohort Additional 3 patients on the tolerable cohort Total patient number Minimum 6 Maximum 12 Phase II portion Metastatic colorectal cancer A total of 33 patients will be treated in this portion This will include the patients treated on the tolerable dose level from the phase I trial The statistical justification is indicated in the Statistics section 7
Overall study design Phase I Study A three cohort dose escalation will be used Cycle length will be 28 days
Bevacizumab FOLFOX-6 RAD001 Cohort 1 5 mg kg Q 2weeks Standard Dose FOLFOX-6 25 mg PO qd Cohort 2 5 mg kg Q 2weeks Standard Dose FOLFOX-6 5 mg PO qd Cohort 3 5mgkg Q 2 weeks Standard Dose FOLFOX-6 10 mg PO qd
Phase II Study
For the Phase II portion the primary endpoint is Progression Free Survival at 6 months
Study Objectives Primary
1 To evaluate the progression free survival PFS for a combination of FOLFOX Bevacizumab RAD001 in previously untreated metastatic or advanced colorectal cancers
2 To evaluate the safety of the combination at a daily dosing of 25mg RAD001 5 mg RAD001 or 10 mg RAD001 Phase 1 part Secondary
1 To study the toxicity profile of the combination 2 To study the Response Rate RR of the combination 3 To determine the serum proteomic profiles of patients treated with combination therapy Both phase I and II portions
Dose selection for RAD001 In phase 1 clinical studies of RAD001 as a monotherapy agent in oncology patients the side-effect profile is essentially mild to moderate adverse events with a low frequency of DLT at the daily dose of 10 mgd Based on the PKPD model a daily dose of 10mg RAD001 is assumed to provide a persistently high degree of target inhibition in the tumor Investigators Brochure-Section 4113 In addition preliminary data from phase 1 studies in which changes in molecular characteristics of tumor induced by treatment with RAD001 at the doses of 5 and 10 mgd were investigated confirm the pharmacodynamic activity predicted previously by PKPD modeling Investigators Brochure-Section 4113 Therefore a dose of 10 mgd should ensure adequate drug target inhibition for most patients taking into consideration the known inter-patient variability in drug levels CV of approx 50 In this study we will begin with a RAD001 dose of 25 mg which is the lowest dose that can be administered on a daily basis If the dose is tolerable 16 DLTs we will escalate to the dose of RAD001 5 mg and a third cohort of 10 mg If cohort 1 is intolerable study will be closed without any further expansion On any dose level 3 patients would be enrolled If there are 03 DLTs we would be able to escalate the dose level If 13 DLTs are observed 3 additional patients will be enrolled on the same dose level The intent is to escalate dose levels only if 16 DLTs are observed In case 2 or more DLTs are observed on a particular dose level no further dose escalation is possible This dose level would be deemed intolerable and the lower dose level would be expanded The definition of the Maximum Tolerated Dose MTD is the highest dose level at which RAD001 can be combined with FOLFOX Bevacizumab with 16 DLTs
FOLFOX Bevacizumab FOLFOX6 and Bevacizumab will be given as previously described 28 mFOLFOX6 oxaliplatin 85 mgm2 IV with LV 350 mg IV over 2 hours plus FU 400 mgm2 IV bolus and 2400 mgm2continuous infusion over 46 hours every 2 weeks will be combined with Bevacizumab given at 5 mgkg every 2 weeks Dose modifications will be carried out for chemotherapy as per the label for oxaliplatin fluorouracil and bevacizumab
Overall study design Phase I Study A three cohort dose escalation will be used Cycle length will be 28 days
Bevacizumab FOLFOX-6 RAD001 Cohort 1 5 mg kg Q 2weeks Standard Dose FOLFOX-6 25 mg PO qd Cohort 2 5 mg kg Q 2weeks Standard Dose FOLFOX-6 5 mg PO qd Cohort 3 5mgkg Q 2 weeks Standard Dose FOLFOX-6 10 mg PO qd
Phase II Study
For the Phase II portion the primary endpoint is Progression Free Survival at 6 months
Study Objectives Primary
1 To evaluate the progression free survival PFS for a combination of FOLFOX Bevacizumab RAD001 in previously untreated metastatic or advanced colorectal cancers
2 To evaluate the safety of the combination at a daily dosing of 25mg RAD001 5 mg RAD001 or 10 mg RAD001 Phase 1 part Secondary
1 To study the toxicity profile of the combination 2 To study the Response Rate RR of the combination 3 To determine the serum proteomic profiles of patients treated with combination therapy Both phase I and II portions
Dose selection for RAD001 In phase 1 clinical studies of RAD001 as a monotherapy agent in oncology patients the side-effect profile is essentially mild to moderate adverse events with a low frequency of DLT at the daily dose of 10 mgd Based on the PKPD model a daily dose of 10mg RAD001 is assumed to provide a persistently high degree of target inhibition in the tumor Investigators Brochure-Section 4113 In addition preliminary data from phase 1 studies in which changes in molecular characteristics of tumor induced by treatment with RAD001 at the doses of 5 and 10 mgd were investigated confirm the pharmacodynamic activity predicted previously by PKPD modeling Investigators Brochure-Section 4113 Therefore a dose of 10 mgd should ensure adequate drug target inhibition for most patients taking into consideration the known inter-patient variability in drug levels CV of approx 50 In this study we will begin with a RAD001 dose of 25 mg which is the lowest dose that can be administered on a daily basis If the dose is tolerable 16 DLTs we will escalate to the dose of RAD001 5 mg and a third cohort of 10 mg If cohort 1 is intolerable study will be closed without any further expansion On any dose level 3 patients would be enrolled If there are 03 DLTs we would be able to escalate the dose level If 13 DLTs are observed 3 additional patients will be enrolled on the same dose level The intent is to escalate dose levels only if 16 DLTs are observed In case 2 or more DLTs are observed on a particular dose level no further dose escalation is possible This dose level would be deemed intolerable and the lower dose level would be expanded The definition of the Maximum Tolerated Dose MTD is the highest dose level at which RAD001 can be combined with FOLFOX Bevacizumab with 16 DLTs
FOLFOX Bevacizumab FOLFOX6 and Bevacizumab will be given as previously described 28 mFOLFOX6 oxaliplatin 85 mgm2 IV with LV 350 mg IV over 2 hours plus FU 400 mgm2 IV bolus and 2400 mgm2continuous infusion over 46 hours every 2 weeks will be combined with Bevacizumab given at 5 mgkg every 2 weeks Dose modifications will be carried out for chemotherapy as per the label for oxaliplatin fluorouracil and bevacizumab
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None