Newswise — AstraZeneca has reached important milestones on the clinical development timelines for the company's investigational cancer drugs vandetanib (ZACTIMA®) and cediranib (RECENTINâ„¢, AZD2171). In March, the company announced the completion of patient enrollment in three of four pivotal Phase III studies for vandetanib for the second-line treatment of non-small cell lung cancer (NSCLC). AstraZeneca announced in February that a Phase II/III study of cediranib for the first-line treatment of patients with advanced colorectal cancer (CRC) will be progressing directly into Phase III.
Once-daily oral vandetanib reaches investigational milestone for NSCLC, an area of high unmet medical need. As of March 2008, AstraZeneca has completed patient enrollment in three of four pivotal Phase III studies for the second-line treatment of NSCLC. Data from the studies are expected later this year and the broad development program is on track for a first regulatory submission in 2008.
- The ZEST (ZACTIMA Efficacy Study versus Tarceva) study, which is investigating vandetanib versus erlotinib, was the first Phase III study of vandetanib to complete enrollment in November 2007. ZEST is a randomized, double-blind, multi-center Phase III study to assess the efficacy of vandetanib versus erlotinib in overall survival (OS) and progression-free survival (PFS) in more than 1,150 patients with locally-advanced or metastatic non-small cell lung cancer (NSCLC) after failure of first-line anti-cancer therapy.
- The ZODIAC (ZACTIMA in cOmbination with Docetaxel In non-smAll cell lung Cancer) and ZEAL (ZACTIMA Efficacy with Alimta in Lung cancer) studies completed enrollment in March 2008.
- ZODIAC is a randomized, double-blind, international, multi-center Phase III study to assess the efficacy of vandetanib 100 mg once-daily plus the standard docetaxel chemotherapy versus docetaxel alone in 1,380 patients with locally advanced or metastatic NSCLC after failure of first-line anti-cancer therapy.
- ZEAL is a Phase III parallel group, randomized, double-blind study evaluating vandetanib 100 mg once daily plus pemetrexed 500 mg/m2 (every 3 weeks) compared with placebo plus pemetrexed as second-line treatment in 510patients with locally advanced or metastatic NSCLC who have failed first-line anti-cancer therapy.
- ZEPHYR (Zactima Efficacy Study for NSCLC Patients with History of EGFR-TKI and Chemo-Resistance), which evaluates vandetanib plus best supportive care (BSC) versus BSC alone, is currently recruiting patients.
Vandetanib also is being evaluated as a treatment option in medullary thyroid cancer and has been awarded Food and Drug Administration (FDA) orphan drug status and fast track designation for this tumor type.
Vandetanib targets cancer through two important mechanisms: inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2), which blocks the development of tumor blood supply; and inhibiting the epidermal growth factor receptor (EGFR), which may lead to direct inhibition of cancer cell growth and survival.1,2 Vandetanib also inhibits RET kinase activity which may be important to the growth and development of certain tumors.3
Once-daily oral cediranib moves to Phase III for advanced CRC Cediranib is a once-daily oral investigational anti-cancer drug that is being evaluated as a first-line treatment in patients with advanced CRC. In February 2008 AstraZeneca announced that its HORIZON III Phase II/III head-to-head study of cediranib with chemotherapy versus bevacizumab with chemotherapy in patients with first-line metastatic CRC will be progressing directly into Phase III at 20 mg. Patients will also continue to be recruited at 20 mg into the first line CRC HORIZON II study of cediranib with chemotherapy versus chemotherapy alone.
- The HORIZON Independent Data Monitoring Committee (IDMC) conducted a planned end of Phase II (EOP II) review of efficacy and tolerability data from HORIZON I, HORIZON II and HORIZON III. Data from HORIZON I, in second-line colorectal cancer, would not by itself have contributed to a positive EOP II decision. However, when combined with a review of data from HORIZON II and III by the IDMC, the IDMC confirmed the HORIZON program in first-line CRC could continue and HORIZON II and III had met pre-defined EOP II criteria.
- HORIZON III is a randomized, double-blind study to evaluate cediranib in combination with the standard chemotherapy regimen FOLFOX (fluorouracil, leucovorin and oxaliplatin) compared with bevacizumab in combination with FOLFOX for the first-line treatment of advanced CRC.
- HORIZON II is a randomized, double-blind study to evaluate cediranib in combination with standard chemotherapy versus standard chemotherapy alone for the first-line treatment of patients with advanced CRC.
- AstraZeneca also announced that the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) has informed AstraZeneca that the BR24 Phase II/III study of cediranib at 30 mg in first-line NSCLC will not continue into Phase III following the planned end of Phase II efficacy and tolerability analysis by the study's Data Safety Monitoring Committee. Although evidence of clinical activity was seen, there appeared to be an imbalance in toxicity and therefore the study was considered not to have met the pre-defined criteria for automatic continuation into Phase III. AstraZeneca is working in close collaboration with the NCIC-CTG to understand the BR24 data further.
In addition to colorectal cancer, the cediranib development program includes trials in recurrent glioblastoma and a number of signal search studies in other tumors.
Cediranib is a highly potent and selective VEGF signaling inhibitor that inhibits all three VEGF receptors.4 VEGF signaling is a key driver of angiogenesis " the formation of new blood vessels that tumors need to grow and spread. Cediranib inhibits this signal by binding to the intracellular domain of all three VEGF receptors, and in particular VEGFR-2, the predominant receptor through which VEGF exerts its effects on angiogenesis.4 This can effectively "starve" the tumor of the oxygen and nutrients it needs to grow.
About AstraZenecaAstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with healthcare sales of $29.55 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. In the United States, AstraZeneca is a $13.35 billion dollar healthcare business with 12,200 employees committed to improving people's lives. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.
For more information visit http://www.astrazeneca-us.com.
ZACTIMA is a registered trademark of the AstraZeneca group of companies.RECENTIN is a trademark of the AstraZeneca group of companies.
1 Wedge, SR et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002;62(16):4645-55.2 Holden SN, Eckhardt SG, Basser R et al. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol 2005; 16(8):1391-1397.3 Tada, H, Vasselli, J, Langmuir, P. Clinical Potential of Vandetanib, an Oral Inhibitor of Key Tumor Signaling Pathways. Proceedings of the 10th International Symposium on Anti-Angiogenesis Agents. Feb. 7-9, 2008.4 Wedge SR et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005 65(10):4389-4400.03/08 261109
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