RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma
Status:
Completed
Trial end date:
2015-08-01
Target enrollment:
Participant gender:
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.