Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals, Inc. announced new preclinical data on the proposed anti-tumour activity of the investigational drug Bay 43-9006, indicating that the novel signal transduction inhibitor exhibits a dual mechanism of action targeting both cell proliferation and angiogenesis (the formation of new blood vessels to support cancer cell growth). The data were presented at the American Association for Cancer Research-National Cancer Institute-European Organization for Research and Treatment of Cancer (AACR-NCI-EORTC) meeting in Boston, USA.
Bay 43-9006 is the first compound that is known to target both Raf kinase and Vegfr2 to inhibit two essential mechanisms involved in tumour growth. Raf kinase is a key enzyme in an important growth signaling pathway associated with the proliferation of tumour cells. Vegfr2 is a main receptor of the vascular endothelial growth factor (VEGF), which plays a key role in angiogenesis.
Additionally, updated Phase II clinical data was presented at the meeting, evaluating Bay 43-9006 as a potential treatment of advanced renal cell carcinoma (RCC, or kidney cancer).
"Bay 43-9006 exhibits dual activity in important mechanisms that inhibit cancer progression. These findings suggest that Bay 43-9006 may have a potential role in the treatment of a range of cancers," said Susan Kelley, MD, vice president, oncology, Bayer Pharmaceuticals Corporation. "Besides kidney cancer, Bayer and Onyx are also evaluating this novel compound as a treatment for melanoma, liver, pancreatic and other cancers."
Interim Phase II Study Results
Bayer and Onyx also released an updated data analysis of Phase II clinical results that were first presented in October 2003. The updated data analysis included 50 participants with advanced and progressive RCC who were evaluable after 12 weeks of treatment. Of the evaluable patients, 42 per cent (21 patients) had tumour shrinkage of at least 25 per cent at the week 12 assessment. Twenty-six per cent (13 patients) had their tumours stabilized within 25 per cent of pretreatment size. Overall, 68 per cent (34 patients) of this cohort of study participants did not demonstrate tumour progression by the 12-week evaluation point, as assessed by the physicians conducting the clinical trial. The remaining 32 per cent (16 patients) discontinued study treatment either because of progressive disease or adverse effects. These early data are subject to confirmation and to a final independent review at the conclusion of the study, at which time the final results will be released.
The five-center, Phase II randomized discontinuation study incorporates a study design that consists of two phases: a 12-week induction phase followed by a randomization phase. During the induction phase, all study participants received Bay 43-9006 orally at 400mg twice a day, administered as a single agent.
"BAY 43-9006 continues to demonstrate potential as a treatment for patients with progressive renal cell carcinoma, with a frequency of tumour shrinkage and disease stabilization rates that remain encouraging as we analyze additional patient experience from this clinical trial," said Mark J Ratain, MD, the Phase II study's lead investigator and professor of medicine and associate director for Clinical Sciences, Cancer Research Center, University of Chicago, USA.
All patients with RCC who participated in the trial had progressive disease on study entry. In the study, the most commonly reported drug-related events include: mild-to-moderate hand-foot syndrome, rash, diarrhea, and hypertension, which were shown to be manageable and reversible.
The participants in this study with RCC are part of a larger study population, which totals 342 participants, with advanced refractory solid tumours of multiple types, including RCC (73), melanoma (31), colorectal (115) and others (123) including pancreas, ovarian and breast carcinoma.
Based on the results observed in kidney cancer, Bayer and Onyx have begun an international, multi-center Phase III trial to further evaluate the safety and efficacy of Bay 43-9006. More than 800 people with advanced renal cell carcinoma will participate in the Phase III study at sites worldwide. The primary objective of this randomized study is to confirm the early suggestions of clinical activity of Bay 43-9006 in RCC, using improvement in survival as the primary endpoint for assessment of clinical benefit. The study also will assess time-to-tumour progression, overall response rate, quality of life and the pharmacokinetics of Bay 43-9006.
In other clinical studies, Bay 43-9006 is being evaluated in a Phase II study in participants who have advanced hepatocellular carcinoma (liver cancer), as well as in eight ongoing Phase Ib studies where Bay 43-9006 is combined with standard cytotoxic chemotherapeutic agents. In preliminary findings reported to date, preliminary anti-cancer activity has been observed across a number of tumour types.