RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma

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.

Conditions

• Colorectal Cancer

Interventions

DRUG

RAD001

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.

DRUG

FOLFOX

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.

DRUG

Bevacizumab

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

Sponsors & Collaborators

• Novartis

  collaborator INDUSTRY

• University of Utah

  lead OTHER

Principal Investigators

• Sunil Sharma, MD · Huntsman Cancer Institute

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2010-05-31

Primary Completion

2015-08-31

Completion

2015-08-31

Countries

• United States

Study Locations