Chiron and MMRC initiate PI cancer trials

Unlike many kinase inhibitors that only target vascular endothelial growth factor (VEGF), CHIR-258 inhibits receptors in the fibroblast growth factor (FGF) pathway, as well as VEGF and platelet-derived growth factor (PDGF).

FGF receptor tyrosine kinase inhibition is potentially of therapeutic significance to a group of myeloma patients whose cancer cells express high levels of surface FGF receptors.

Previous preclinical data showed that CHIR-258 inhibited multiple kinases associated with different cancers, including acute myeloid leukemia (AML) and multiple myeloma.

Multiple myeloma, also known as myeloma or plasma cell myeloma, is a progressive hematologic (blood) cancer of the plasma cell, an important part of the immune system that produces immunoglobulins (antibodies) to help fight infection and disease.

Clinical symptoms of multiple myeloma include hypocalcaemia, anaemia, renal damage, increased susceptibility to bacterial infection, and impaired production of normal immunoglobulin. The disease also is characterised by diffuse osteoporosis (bone destruction), usually in the pelvis, spine, ribs and skull.

Multiple myeloma is the second most prevalent blood cancer after non-Hodgkin's lymphoma, representing approximately 1 per cent of all cancers and 2 per cent of all cancer deaths. The median age at diagnosis is about 71 years, and only 2 per cent of cases are diagnosed in individuals under the age of 45.

Statistics indicate both increasing incidence and earlier age of onset of multiple myeloma. Approximately 50,000 Americans currently have multiple myeloma, and the American Cancer Society estimates that approximately 15,980 new cases of multiple myeloma will be diagnosed in 2005.

This Phase I trial of CHIR-258 in multiple myeloma is designed to evaluate the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of CHIR-258 in these patients. The maximum tolerated dose for CHIR-258 has not been reached in current phase I trials, as demonstrated by preliminary data from a phase I trial of CHIR-258 in solid tumours recently presented in an award-winning poster at the recent American Society of Clinical Oncology (ASCO) meeting.

"The MMRC​ model fits well with Chiron's translational medicine approach to oncology drug development, and the multitargeted specificity of CHIR-258 makes it a promising candidate for development in solid and hematologic malignancies, including multiple myeloma."​ said Stephen Dilly, chief medical officer at Chiron BioPharmaceuticals.

Chiron currently has three ongoing Phase I clinical trials for CHIR-258: one in mixed solid tumours, one in AML, and, with the initiation of the MMRC trial, one in multiple myeloma. An additional Phase I trial in multiple myeloma is expected to begin enrolling patients in 2005. Selection of a first indication and dosing regimen for Phase II development is planned for 2005.

In recent years, research focusing on novel targeted approaches in treating myeloma has increased dramatically. The 2003 approval of Velcade, the first new drug of its class, showed that that novel targeted therapies offer great promise in effectively treating patients with multiple myeloma.

Velcade is now widely accepted as one of the most significant recent advances in the treatment of multiple myeloma. Today, Velcade is being explored in several clinical trials as a treatment for myeloma patients at all stages of disease.

Currently, several new therapeutic agents - including immunomodulatory drugs (IMiDs), such as Revlimid - are showing promise in treating myeloma. In addition, there are a number of emerging therapies, including IGF-1 inhibitors, histone deacetylase inhibitors, heat shock proteins-that may serve as new treatment approaches.

Only this week, Kosan Biosciences presented preliminary data on KOS-953, Kosan's proprietary formulation of the Hsp90 inhibitor 17-AAG, showing early signs of anticancer activity and tolerability when administered as single-agent therapy in a Phase I trial in heavily pre-treated patients with relapsed-refractory multiple myeloma.

Other new drugs currently under investigation in clinical trials, as well as the most promising new agents currently being studies in preclinical trials include Novartis' PTK-787/ ZK222584, which is currently in phase II clinical trials. It is an oral angiogenesis inhibitor; inhibiting myeloma cell growth as well as overcoming drug resistance in the lab

AstraZeneca's ZD6474 is currently in phase II. The drug candidate is an inhibitor of that acts by blocking receptors for vascular endothelial growth factor (VEGF).