Bench to Bedside: From the Laboratory to the Pharmacy
OSU-09067 – Phase II Trial of Temsirolimus and Bevacizumab in Patients with Carcinoid Cancer
Hypothesis: Temsirolimus (CCI-779) and bevacizumab (Avastin) combined will induce stable disease in patients with carcinoid cancer.
Rationale: Carcinoid tumors arise from diffuse neuroendocrine cells, most often those in the GI tract, the pulmonary bronchi and pancreas. GI sites are primarily the stomach, ileum and appendix. The tumors may be benign or malignant and cause pain, obstruction and bleeding. Carcinoid tumors may be endocrinologically active, producing a variety of hormones, which may cause carcinoid syndrome. The syndrome is often marked by striking skin color changes, abdominal cramps and diarrhea, right-side endocardial fibrosis and increased excretion of the serotonin metabolite 5-HIAA.
Although curative resection of carcinoid tumors is possible, no effective chemotherapeutic regimen is available for systemic spread, but targeted agents hold promise. VEGF is a critical proangiogenic factor in these hypervascular tumors. In one study of 50 cases of human gastrointestinal neuroendocrine tumors, VEGF expression was associated with poor progression-free survival. Neutralization of VEGF by bevacizumab has been shown to inhibit the VEGF-induced proliferation of human endothelial cells in vitro, and decrease microvessel density and interstitial pressure in tumor xenografts in vivo.
In patients, preliminary results from a neoadjuvant trial in rectal cancer demonstrated a decrease in blood perfusion/permeability and interstitial fluid pressure in tumors after one dose of bevacizumab. Bevacizumab has shown promising antitumor activity in preclinical and clinical studies of patients with carcinoid tumors.
Temsirolimus is a cytostatic cell-cycle inhibitor with antitumor properties. The agent specifically inhibits the mammalian target of rapamycin (mTOR), a Ser/Thr kinase involved in the initiation of mRNA translation. Temsirolimus inhibits the growth of a histologically diverse range of tumor cells, with the greatest sensitivity shown by cells derived from central nervous system cancers, leukemia (T-cell), breast cancer, prostate cancer and melanoma. Key features of this agent include its tolerability, unique mechanism of action, ability to arrest cells in the G1 phase, and ability to induce apoptosis.
A phase II study of single agent temsirolimus and a phase II study of bevacizumab plus octreotide in patients with advanced progressive neuroendocrine carcinoma also showed moderate antitumor activity. This study evaluates bevacizumab and temsirolimus as combined therapy in patients with metastatic carcinoid tumors.
Note: OSU-09067 is part of NCI Protocol #8233, a single study that examines the same therapy in five diseases using five parallel phase II clinical trials.
The overall purpose of NCI # 8233 is to evaluate the safety and effectiveness of temsirolimus and bevacizumab in patients with endometrial, ovarian, hepatocellular carcinoma, carcinoid or islet cell cancer. Each of the two drugs individually has shown some benefit in each of these malignancies.
NCI # 8233 is supported by the NCI Cancer Trials Support Unit, and participation is restricted to centers with an NCI-supported phase II contract. The study chair is Charles Erlichman, MD, professor and chairman of Oncology at Mayo Clinic.
At a Glance
Clinical trial OSU-09067
PI: Manisha Shah, MD, director, Neuroendocrine Tumor Clinic Program
Eligibility: Histologically/ cytologically confirmed carcinoid (neuroendocrine) cancer that is locally advanced, recurrent, metastatic or progressing; Age 18 years or older; Must have measurable disease; Radiation therapy must be completed four weeks or more prior to registration if applicable; ECOG 0-1; Must have tissue available from the primary tumor or metastases for tumor studies.