Clinical Studies in the Pipeline

Newswise — During the past decade, several new drugs have been approved that target specific genes and molecules, increasing survival for many cancer patients. Not only are these drugs often more effective than the current standards of care, they also carry an added benefit of fewer side effects. Many believe that a new generation of targeted therapies will be the first choice for cancer care in the future, with the goal of tailoring treatment to individual tumors and patients.

Clinical studies with several molecularly targeted drugs are being featured at the Annual International Conference on Molecular Targets and Cancer Therapeutics coordinated by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI) and the European Organisation for Research and Treatment of Cancer (EORTC). These include:

1. A Phase III trial, which has found that cetuximab (Erbitux) and radiotherapy improves disease control and survival rates for a specific category of advanced head and neck cancers.

2. A Phase II study, offering encouraging results that temsirolimus, a derivative of the immunosuppressant drug rapamycin, may be effective against recurrent and metastatic endometrial cancer.

Cetuximab Improves Locoregional Control and Survival of Locoregionally Advanced Head and Neck Cancer: Independent Review of Mature Data with a Median Follow-up of 45 Months (Abstract 2628)

Head and neck cancers account for three percent of diagnosed cancers in the United States, and almost 13,000 people will die each year from the disease. A majority of these cancers begin in cells lining the head and neck. Treatment for these patients usually consists of radiation therapy, chemotherapy combined with radiation treatment, or surgery followed by radiation and/or chemotherapy plus radiation for patients whose tumors can be surgically removed.

However, researchers are now finding that many head and neck cancer cells overexpress a protein called the epidermal growth factor receptor (EGFR), which may help cancer cells to grow more aggressively, that should lead to more targeted therapies.

A research group led by investigators from the University of Alabama at Birmingham conducted a phase III trial and found that cetuximab (Erbitux) improves disease control and survival rates when used in conjunction with radiotherapy in locoregionally (restricted to the pharynx/larynx and lymph nodes in the neck) advanced squamous cell carcinoma of the head and neck (SCCHN). The benefits were achieved with minimal increases to the toxicity experienced with radiation.

Cetuximab is a monoclonal antibody that binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor and other ligands, such as transforming growth factor"alpha. It is currently approved for the treatment of EGFR-expressing, metastatic colorectal cancer in patients who are refractory to irinotecan-based chemotherapy.

In the current trial, median survival was 49 months with cetuximab plus radiation and 29 months with radiation alone, coupled with a 26 percent reduction in mortality risk. The three-year survival rates for cetuximab plus radiation were 56 percent compared to 45 percent for radiation alone.

Four hundred and twenty four patients with locoregionally advanced SCCHN were randomized to one of two groups " radiation treatment alone or radiation treatment plus weekly cetuximab at an initial dose of 400 mg/m2 followed by 250 mg/m2 for the duration of radiation treatment. The median age of the patients was 57, and 80 percent were male. Patients were stratified according to Karnofsky performance status (which classifies patients according to their functional impairment and can be used to compare effectiveness of different therapies and assess the prognosis in individual patients), tumor stage, nodal involvement, and radiotherapy treatment fractionation regimen.

"We believe the combination of cetuximab and radiotherapy represents a unique therapeutic option for treating patients with locoregional SCCHN," said James Bonner, M.D., a professor at the University of Alabama, Birmingham and lead investigator of the study. "These results will provide a much needed platform for additional efforts aimed at further improvements in outcomes."

Phase II Biomarker Analysis of Sorafenib (BAY 43-9006) in Patients with Advanced Hepatocellular Carcinoma (Abstract 2979)

More than 17,000 new cases of liver cancer will be diagnosed in the United States this year, with a total of more than 667,000 cases diagnosed worldwide. It is the sixth most common type of cancer in the world. Currently, liver cancer can only be cured when diagnosed at the earliest stage of disease -- when the patient is healthy enough to undergo an operation. Liver cancer is difficult to control with current treatments, so patients are often referred to clinical trials. One such clinical trial is testing the use of sorafenib (BAY-9006) against the most common form of liver cancer, hepatocellular carcinoma (HCC), which accounts for 83 percent of all liver cancers.

Investigators from the Memorial Sloan-Kettering Cancer Center have demonstrated that the pretreatment tumor cell phospho-ERK (pERK, phosphorylated extracellular signal-regulated protein kinases, biomarkers that inhibit neuronal apoptosis) levels may predict liver cancer's response to the drug sorafenib, a novel, oral multi-kinase (enzyme) inhibitor that effects both the tumor and its vasculature (blood vessels). Sorafenib targets Raf kinase (which regulates cell differentiation and supresses cell death) and several receptor tyrosine kinases, including VEGFR-2 and PDGFR-?. Overexpression of the Raf-1 protein is a common feature of HCC.

The study enrolled 137 patients with advanced, inoperable HCC who had not received prior systemic treatment and who received continuous orally administered sorafenib 400 mg twice a day. Patients with tumors that expressed higher baseline staining intensity of pERK had a significantly longer time to progression than those with a lower staining intensity. In 75 assessed patients, there was no correlation between plasma HER-2/neu levels (human epidermal growth factor receptor 2, a gene that helps control how cells grow, divide and repair themselves) before or during sorafenib treatment, and best response, time to progression or time to death.

A Phase II Study of Temsirolimus (CCI-779) in Patients with Metastatic and/or Locally Recurrent Endometrial Cancer " NCIC CTG IND 160 (Abstract 3125)

Endometrial cancer (uterine corpus) affects an estimated 40,000 women, and more than 7,000 deaths are expected this year in the United States. As with all cancers, early diagnosis of the disease is essential to survival for diagnosed women. Most cases are diagnosed at the early stage because of post-menopausal bleeding. PTEN (phosphatase and tensin homolog) is a tumor suppressor gene that is mutated at high frequency in a large number of cancers. The mutations lead to loss of protein expression and function that appear to play a significant role in the development of endometrial cancer. This loss has been reported in 26 to 80 percent of endometrial cancers.

Researchers led by the National Cancer Institute of Canada Clinical Trials Group have found that the drug temsirolimus is effective against recurring and metastatic endometrial cancer.

Temsirolimus is a derivative of rapamycin (helps the body refrain from rejecting organ and bone marrow transplants) that inhibits mTOR, a protein kinase (enzyme). In laboratory studies with mice, inhibition of mTOR has led to fewer endometrial carcinoma cell lines and decreased endometrial peoplasia (abnormal, uncontrolled cell growth), including carcinomas. Additionally, loss of PTEN protein function provides neoplastic cells (cells that are part of tumors) with a selective survival advantage by enhancing angiogenesis (development of new blood vessels), protein translation and cell cycle progression.

Due to the frequent loss of PTEN in human endometrial carcinomas and the anti-tumor activity induced with mTOR inhibition, temsirolimus was examined in a stage 2, phase II study. Women with recurrent or metastatic endometrial cancer who had not received chemotherapy but had received up to one prior line of hormonal therapy were evaluated. Eighteen patients were given 25 mg of temsirolimus weekly for a median of 24 weeks. Of the 16 evaluable patients, 31 percent had a confirmed partial response; 63 percent had stable disease as best response; and six percent had progressive disease.

A Phase II Trial of AP23573, a Novel mTOR Inhibitor, in Patients with Advanced Soft Tissue or Bone Sarcoma (Abstract 2503)

Soft tissue sarcomas are relatively rare cancers that begin in the muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. They are grouped together because they share certain microscopic characteristics, produce similar symptoms, and are generally treated in similar ways. Bone tumors (osteosarcomas) are also called sarcomas, but are in a separate category due to its different clinical and microscopic characteristics and are treated differently. Sarcomas can invade surrounding tissue and can metastasize (spread) to other organs of the body, forming secondary tumors. The most common treatments for sarcomas are surgery, radiation and chemotherapy, although the use chemotherapy to prevent the spread of soft tissue sarcomas has not been proven to be effective.

Researchers at the Century City Doctor's Hospital & John Wayne Cancer Institute have conducted a phase II clinical trial on a new drug, AP23573, that has been shown to be well tolerated with promising anti-tumor activity in patients with advanced sarcomas. AP23573 is a rapamycin analog (modeled after drugs that help the body refrain from rejecting organ and bone marrow transplants) that kills mTOR, a protein kinase (enzyme). Overall, 35 percent of the evaluable patients have achieved clinical benefit responses, including four partial responses.

The phase II clinical trial is being conducted in two stages, with 200 patients enrolled to date. In stage one, 95 percent of the patients were evaluated for response in four histologic groups, each showing clinical benefit " bone sarcomas (38 percent), leiomyosarcoma (40 percent, sarcoma composed in part of smooth muscle cells), liposarcoma (22 percent, sarcoma arising from immature fat cells of the bone marrow), and other soft tissue sarcomas. Nineteen percent of these patients remained progression free after six months of treatment. Three patients with osteosarcoma and one with malignant fibrous histiocytoma (tumor that consists predominantly of immune cell tissues) achieved confirmed partial responses, 46 percent had stable disease, and 29 patients have progressed.

Founded in 1907, the American Association for Cancer Research is a professional society of more than 24,000 laboratory, translational, and clinical scientists engaged in cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. This work is carried out through five major peer-reviewed scientific journals and high-quality scientific programs focusing on the latest developments in all areas of cancer research. The National Cancer Institute, founded in 1971, is the principal United States government agency charged with coordinating the National Cancer Program. It facilitates international cooperation in clinical trials involving U.S. and foreign collaborating institutions.

The European Organisation for Research and Treatment of Cancer was organized in 1962 to conduct, develop, coordinate and stimulate laboratory and clinical research in Europe, and to improve the management of cancer and related problems by increasing the survival and quality of life for patients.