Enrolment for the RESILIENCE trial (NCT 01234337)[1], a phase III randomized, double-blind, placebo-controlled for a evaluating sorafenib ( Nexavar?, Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc) in combination with the oral chemotherapeutic agent has started earlier this month. The trial is expected to include 519 patients in more than 20 countries including the United States, Brazil, Japan and Australia.

The study will evaluate sorafenib, an oral multitarget kinase inhibitor with antiproliferative and antiangiogenic activity, in combination with capecitabine (Xeloda) in patients with locally advanced or metastatic HER-2 negative breast cancer who are resistant to or have failed prior taxane and an anthracycline or for whom further anthracycline is not indicated. The primary endpoint of the study is progression-free survival. Secondary endpoints include overall survival, time to progression, and safety.

Patients will receive 600 mg of oral Nexavar or matching placebo daily on a continuous schedule, in addition to 1,000mg/m2 of capecitabine twice daily for 14 days of a 21 day cycle. Dose escalation to 800 mg of oral Nexavar daily and capecitabine 1,250 mg/m2 twice daily will be permitted depending on tolerance.

New breast cancer treatment options
Breast cancer was the most commonly diagnosed cancer among women worldwide in 2007-2008 (approximately 1.3 million cases), and the second leading cause of cancer-related death among women (approximately 465,000 deaths). It is the most commonly diagnosed cancer among women in the United States (1 in 4 cancer diagnoses is breast cancer). There are approximately 200,000 new cases of breast cancer in the United States and 430,000 in Europe each year. More than 40,000 women in the United States and more than 130,000 in Europe die of breast cancer each year. [2, 3, 4]

Sorafenib, which is currently approved by the U.S Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma, inhibits both the tumor cell and tumor vasculature. In preclinical studies, sorafenib has been shown to inhibit members of two classes of kinases thought to be involved in both cell proliferation (growth) and angiogenesis (blood supply) ? two important processes that enable cancer growth. These kinases included Raf kinase, VEGFR 1, 2 and 3, PDGF receptors ? and ?, c-KIT, FLT-3 and RET and the RAF kinase and MAPK pathways.

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Commenting on the commencement of the trial, Ted W. Love, M.D., Executive Vice President and Head of Research and Development and Technical Operations for Onyx Pharmaceuticals said: “Nexavar has demonstrated efficacy in advanced kidney cancer and unresectable liver cancer and we are committed to evaluating Nexavar in a variety of treatment settings and tumor types.”

Sorafenib phase III trials program in Breast Cancer
The new phase III trial was initiated based on the early results from the cooperative group-sponsored Phase II clinical trial evaluating sorafenib in combination with capecitabine in patients with advanced breast cancer.

“This Phase III trial is an important milestone in our development of Nexavar as it provides an opportunity to evaluate Nexavar in this patient population,” said Dr. Dimitris Voliotis, Vice President, Global Clinical Development Oncology, Bayer HealthCare. “We look forward to continuing our breast cancer clinical trial program, which includes two ongoing cooperative group-sponsored Phase II trials.”

Sorafenib TIES Breast Cancer As a single agent, sorafenib has been shown to have activity in patients with breast cancer. The TIES (Trials to Investigate the Effects of Sorafenib in Breast Cancer) program [4], a compilation of investigator-sponsored phase IIb multinational, randomized, double-blind, placebo-controlled studies that aim to determine the optimal sequencing of pharmacologic agents for the treatment of breast cancer, evaluates sorafenib in a variety of treatment settings
In earlier phase II clinical trials, funded by the manufacturer of the drug, the combination of sorafenib with capecitabine significantly improved progression-free survival, compared with capecitabine alone, in locally advanced or metastatic breast cancer.

One of these studies, known as SOLTI0701, compared sorafenib plus capecitabine with capecitabine alone.[5.6] In this trial, which included 229 patients with unresectable locally advanced or metastatic HER-negative breast cancer who had previously undergone only 1 course of chemotherapy or no chemotherapy at all, participants were randomized to receive sorafenib (400 mg twice daily) plus capecitabine (n = 115) or capecitabine (1,000 mg/m2 twice daily for 14 of every 21 days, a dose is similar to the dose normally used in clinical practice but slightly lower than the approved dose of 1,250 mg/m2) alone (n = 114) until disease progression or unacceptable toxicity.

The combination of sorafenib and capecitabine showed a 42% reduction in the risk of disease progression and prolonged progression-free survival by more than 2 months compared with capecitabine alone (6.4 vs. 4.1 months for capecitabine alone; P = .0006, with a hazard ratio (HR) of 0.576 (95% confidence interval [CI 0.410 – 0.809]). The researchers concluded that the difference in progression-free survival was statistically significant in patients who had not received previous chemotherapy (HR, 0.498) and in those who had already received one previous regimen (HR, 0.652).

However, this trial showed that adding sorafenib to capecitabine did not provide an Overall Survival (OS) advantage. The incidence of grade 3 hand-foot syndrome was 45% for the sorafenib plus capecitabine arm compared with 13% in the capecitabine alone arm. Other grade 3 treatment-related adverse events included diarrhea (5%), dyspnea (5%), neutropenia (4%) and mucositis (1%).

Jos? Baselga, MD, PhD, professor of medicine at the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and Director of Hematology & Medical Oncology Division at the Cancer Center of the Massachusetts General Hospital at Harvard Medical School in Boston, one of the principal investigators in of this trial said, said that because the drug are administered orally, this approach, if successful ?? may represent a unique and convenient treatment option for patients with breast cancer?.

The results from the phase II trial were first presented in 2009 at the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress and the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).[5,6]

Other trials included in the TIES program are two ongoing randomized Phase II studies, including a trial to evaluate sorafenib plus gemcitabine or capecitabine in the second-line setting following progression on bevacizumab and a trial to evaluate sorafenib plus docetaxel and/or letrozole in the first-line metastatic breast cancer setting.

[1] Phase III Trial Comparing Capecitabine in Combination With Sorafenib or Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer
[2] American Cancer Society, 2007 Global Cancer Facts and Figures Report
[3] American Cancer Society, 2009 Global Cancer Facts and Figures Report
[4] Estimates of the cancer incidence and mortality in
Europe in 2006, Annals of Oncology, 2007 Mar;18(3):581-92
[5] Baselga J, Gianni L, Gradishar WJ, Hudis C, Perez EA, Piccart-Gebhart M, et al. Phase IIb double-blind, randomized, placebo-controlled trials for the efficacy and safety of sorafenib in patients (pts) with metastatic or locally advanced breast cancer (BC): Review of the Trials to Investigate the Effects of Sorafenib in BC (TIES) program. J Clin Oncol 27, 2009 (suppl; abstr e12000)
[6] Baselga J, Roch? H, Costa F, Get? lio Martins Segalla J, Pinczowski H, Ma Ciruelos E, Cabral Filho S, G? mez P, Van Eyll B. SOLTI-0701: A Multinational Double-Blind, Randomized Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo When Administered in Combination with Capecitabine in Patients with Locally Advanced or Metastatic Breast Cancer (BC). 32nd Annual San Antonio Breast Cancer Symposium, General Session IV, Friday December 11, 2009. Abstracts 45,; December 9-13, 2009; San Antonio, Texas.

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