Conditions: Colorectal Cancer
Keywords: colorectal cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 47
Healthy volunteers: no

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 mg/kg 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 2.5 mg PO qd Cohort 2: 5 mg/ kg Q 2weeks Standard Dose FOLFOX-6 5 mg PO qd Cohort 3: 5mg/kg 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 2.5mg 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 mg/d. Based on the PK/PD model, a daily dose of 10mg RAD001 is assumed to provide a persistently high degree of target inhibition in the tumor \[Investigators' Brochure-Section 4.1.1.3\]. 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 mg/d were investigated, confirm the pharmacodynamic activity predicted previously by PK/PD modeling \[Investigators' Brochure-Section 4.1.1.3\]. Therefore, a dose of 10 mg/d 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 2.5 mg which is the lowest dose that can be administered on a daily basis. If the dose is tolerable (\<1/6 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 0/3 DLTs, we would be able to escalate the dose level. If 1/3 DLTs are observed, 3 additional patients will be enrolled on the same dose level. The intent is to escalate dose levels only if \< 1/6 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 \< 1/6 DLTs.

FOLFOX/ Bevacizumab: FOLFOX6 and Bevacizumab will be given as previously described 28. mFOLFOX6 (oxaliplatin 85 mg/m2 IV with LV 350 mg IV over 2 hours plus FU 400 mg/m2 IV bolus and 2,400 mg/m2continuous infusion over 46 hours every 2 weeks) will be combined with Bevacizumab given at 5 mg/kg every 2 weeks. Dose modifications will be carried out for chemotherapy as per the label for oxaliplatin, fluorouracil and bevacizumab.

Arms:
arm 1: All participants enrolled.

Interventions: intervention 1: RAD001 intervention 2: FOLFOX intervention 3: Bevacizumab
Intervention descriptions: intervention 1: RAD001 (everolimus) is a novel oral derivative of rapamycin.

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. intervention 2: FOLFOX regimens combine oxaliplatin and leucovorin with bolus and infusional 5-fluorouracil (5-FU). 1 Oxaliplatin is a DNA cross-linking agent consisting of a platinum ion chelated with1, 2-diaminocyclohexane (DACH) and an oxalate ligand. It undergoes spontaneous activation in aqueous solutions via displacement of the labile oxalate ligand by water. The activated compounds bind with DNA, resulting in inter- and intra-strand platinum-DNA crosslinks. 5-FU is an anti-metabolite that blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, causing thymidine-less cell death in rapidly growing cells. Leucovorin is reduced folic acid that modulates the activity of 5-FU by stabilizing the ternary 5-FdUMP/ thymidylate synthetase complex. Side effects associated with FOLFOX include neuropathy including pharyngo-laryngodysesthesia, diarrhea, nausea, vomiting, and mild myelosuppression. intervention 3: Bevacizumab, a monoclonal antibody directed against VEGF (vascular endothelial growth factor) has been studied in a multitude of Phase I, II, and III clinical trials in more than 5000 patients in multiple tumor types. Phase III data in metastatic cancers

Protocol document: