Zactima (vandetanib) is a potential new oral anti-cancer therapy, which has a unique profile that fights cancer through two clinically proven mechanisms. It blocks the development of a tumour’s blood supply (anti-VEGFR) and blocks the growth and survival of the tumour itself (anti-EGFR). Zactima also inhibits RET-kinase activity, an important growth driver in certain types of thyroid cancer.
Zactima is being investigated in a number of phase III clinical trials across the world to assess its impact on survival and on the lives of patients with NSCLC and medullary thyroid cancer.
In 2005, promising early data in hereditary medullary thyroid cancer led to orphan drug designation for Zactima by the FDA and the European Medicines Agency, as well as fast-track status for regulatory review by the FDA. Orphan drug designation encourages the development of new products that demonstrate promise for life-threatening or very serious conditions that are rare and affect relatively few people. Fast-track designation potentially facilitates and expedites the process for the review by the FDA of new drugs intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. A randomised phase III study of Zactima versus placebo in medullary thyroid cancer has completed enrolment.
In addition, the anti-cancer activity of Zactima continues to be evaluated in other tumour types, including colorectal, glioma, head and neck, breast and prostate cancers.
Recentin (cediranib) is a highly potent, selective, orally active inhibitor of vascular endothelial cell growth factor (VEGF) receptor signalling in solid tumours. Recentin inhibits all three VEGF receptors irrespective of activating ligand. Following the decision in 2005 to accelerate the development of Recentin, and the subsequent commencement of the pivotal phase II/III NSCLC study that year, the pivotal colorectal cancer (CRC) programme started in 2006. The CRC programme includes a head-to-head study comparing Recentin plus FOLFOX (a combination chemotherapy treatment made up of a number of drugs) with bevacizumab (Avastin™) plus FOLFOX in first-line treatment of CRC. It also includes two other studies in CRC, namely a second-line head-to-head study with bevacizumab and a first-line study involving Recentin with and without standard chemotherapy. Phase II studies of Recentin in gastrointestinal stromal tumours, and renal and breast cancer, are continuing. As well as these programmes, the US National Cancer Institute (NCI) is now recruiting patients for more than 15 studies in a number of different tumour settings. Encouraging data for Recentin from two completed NCI studies to treat renal cancer and glioblastoma were presented in 2007. The data in recurrent glioblastoma were published in the journal ‘Cancer Cell’ in January 2007 and presented at the American Society of Clinical Oncology meeting in June 2007. These data have lead to the commencement of a development programme for Recentin in recurrent glioblastoma.
ZD4054 is a potent and specific endothelin A-receptor antagonist that reduces tumour growth and survival, lessening the potential for invasion and metastasis. ZD4054 entered phase III development in 2007 for patients with hormone-resistant prostate cancer (HRPC), an area of great unmet need with few treatment options.
This move into phase III development is based on promising early data from the EPOC phase II study presented at the European Congress of Clinical Oncology in September 2007. The trial suggests that ZD4054 10mg once-daily has the potential to increase the median overall survival time by approximately seven months in men with asymptomatic or mildly symptomatic metastatic HRPC, with the benefit of a generally well-tolerated side effect profile and the convenience of a once-daily tablet.
The phase III ENTHUSE global trial programme, which consists of three studies, is in the early stage of start-up and began enrolling the first patients in the fourth quarter of 2007. These trials will investigate the efficacy of ZD4054 in metastatic HRPC, both as monotherapy and in combination with docetaxel, and in non-metastatic HRPC.
Our early oncology pipeline includes novel compounds that target signalling pathways believed to be pivotal in cancer cell growth, invasion and survival, with two products in phase II and nine others in phase I development. Phase II data from AZD6244, a potent MEK inhibitor licensed from Array BioPharma, Inc., was reported in December 2007. AZD6244 showed biological activity in lung cancer and melanoma and studies will now focus on its use in combination with standard and other novel therapies, rather than its development as monotherapy. Phase II studies with the poly (ADP-ribose) polymerase (PARP) inhibitor AZD2281 have started and will initially focus on BRCA-mutated breast and ovarian cancer as well as other cancers where DNA repair could be defective.
The dual-specific Src/Abl kinase inhibitor, AZD0530, has shown a dramatic effect on biomarkers of cell motility and bone resorption and is starting phase II studies in a range of malignancies. Among the compounds from the early portfolio continuing in development are AZD4877, a novel inhibitor of cell cycle; AZD7762, a tumour-selective chemo sensitiser; and AZD8931.
MedImmune
MedImmune is developing potential new cancer treatments using biological approaches with highly defined molecular targets for patient populations with unmet medical needs.
In 2007, oncology trials underway included those for IPI-504 (also known as MEDI-561), a drug candidate designed to inhibit heat shock protein 90 (Hsp90). Hsp90 is an emerging cancer target, which is currently being evaluated as a potential treatment for three solid tumour cancers.
Development of MEDI-538, a recombinant single-chain bi-specific T-cell engager (BiTE™) molecule targeting the CD19 antigen is progressing. This candidate drug is the first and only BiTE™-inspired molecule in clinical trials, and is currently in phase I and phase II clinical development for the treatment of various B-cell malignancies. In 2007, preliminary data was released from a continuing phase I study of MEDI-538 in patients with late-stage non-Hodgkin’s lymphoma.
MedImmune is continuing the development of CAT-8015 with four phase I dose escalation studies in progress in chronic lymphocytic leukaemia, hairy cell leukaemia, CD22-positive non-Hodgkin's lymphoma and paediatric acute lymphoblastic leukaemia. CAT-8015 is an immunotoxin that targets CD22, which is expressed on adult cells, B-cell leukaemia and lymphomas.
