The Record... (cont'd)

The last part of the record to view is the text part. Pharmaprojects includes a brief abstract, as well as marketing, clinical, and preclinical information. For this drug there is even additional clinical data.

I'll go ahead and send this to Sharon since it definitely gives background information on the drug.

Review the record below and then go on to the Exercises to practice what you have learned about this database.

TEXT: Vatalanib (ZK-222584; PTK-787) is an oral VEGF KDR receptor tyrosine kinase inhibitor, under co-development by Novartis and Bayer Schering Pharma (Bayer) (Schering AG before the acquisition) as an angiogenesis inhibitor for the treatment of solid tumours and age-related macular degeneration (AMD) (Ann Reps, Novartis, 2001 & 2005). It is a competitive inhibitor of the ATP binding site of the VEGF receptor (7th Meet Soc Neuro-Oncol (San Diego), 2002). It also inhibits all other VEGF receptors, the PDGF receptor and c-Kit, whose overexpression may stimulate the growth of some tumour types.

        Marketing

Registration filings for colorectal cancer and AMD are expected in 2007 and 2010, respectively (Ann Rep, Novartis, 2006). EU and US registration filing plans are under review following CONFIRM-1 and - 2 trial results (Company presentation, Novartis, 20 Sep 2005). Novartis will lead Asian and N American promotion and Schering AG will lead promotion in Africa, Australia, Europe and Latin America, with both companies co-promoting in Japan, for all oncology indications. Novartis has exclusive rights for ophthalmic indications (Press release, Novartis, 25 Jan 2005).

        Clinical

Phase III In the multinational CONFIRM-1 trial in 1168 previously-untreated metastatic colorectal cancer patients given vatalanib + oxaliplatin (qv), 5-FU and leucovorin (FOLFOX-4), patients on vatalanib + FOLFOX had a 17% reduction in risk of disease progression cf FOLFOX alone, when assessed by patients' physicians. However, central review assessment showed a 12% reduction in risk of disease progression, which was not significant. The trial has been extended, and overall survival endpoint analysis was expected in the 2nd half of 2006 (Scrip Daily Online, 4 Apr 2003, S00795906; Press release, Novartis, 13 May 2005). Preliminary results from the Phase III CONFIRM-2 trial, assessing the 2nd-line use of vatalanib + FOLFOX-4 in 830 metastatic colorectal cancer patients with disease progression following 1st-line treatment with irinotecan hydrochloride (qv) showed that vatalanib only increased progression- free survival to 7.7mth, cf 7.6mth with placebo. There was a greater effect in patients with high lactate dehydrogenase levels. Final overall survival data was expected in 2006 (Scrip Daily Online, 4 Apr 2003, S00795906 & 28 Jul 2005, S00890590; Press release, Novartis, 28 Jul 2005).

        Phase II

It is in a Phase II trial for AMD (Company presentation, Novartis, 19 Jan 2006; Ann Rep, Novartis, 2006). In a Phase II trial (GOAL) in France and Germany as a 2nd-line monotherapy, 54 patients with stage IIIb/IV nsclc were given vatalanib 1250mg po once-daily. The dose was generally well tolerated. The most frequent adverse events (AE) were vomiting, nausea and dizziness, with the most frequent grade 3 AEs being dyspnoea, hypertension and thrombosis. After 12wk, there was 1PR, 17SDs, 9 unknown and 27PDs. 29SDs were recorded at wk 4. 19 patients had SD >12wk, and 5 patients had SD >28wk. A further cohort of 55 patients is being enrolled for trials with vatalanib po bid (42nd ASCO (Atlanta), 2006, Abs 7195). Broad Phase I/II trials are ongoing to identify further indications for development, including breast, haematological, ovarian, pancreatic and prostate cancers, and glioblastoma (Press release, Novartis, 20 Jan 2005). In Phase I/II trials in 360 advanced cancer patients, PRs and SDs were obtained in colorectal cancer, renal cell carcinoma (RCC) and glioblastoma multiforme patients over 15mth. The optimal dose was 1250mg once-daily (Company Web Pages, Novartis, 31 Oct 2001 & 21 Nov 2002).

        Phase I

It is in Phase I trials for the treatment of solid tumours (Company presentation, Novartis, 20 Sep 2005). In an open-label Phase I trial in 49 patients with metastatic RCC, vatalanib 300-1500mg once- daily was well tolerated. 19% of patients had PR and a further 60% had SD. Median time to progression and median overall survival were 5.3 and 21mth, respectively. Vatalanib 1200mg/day caused a significant change in tumour blood flow in an additional 30 patients, which correlated with disease progression (3rd Targ Anticancer Ther (Amsterdam), 2005, Abs 0.302). In a dose-escalation Phase I study of 23 heavily-pretreated cancer patients, the MTD was 750mg bid. Adverse events were dose-related. Promising tumour regression was observed in heavily-pretreated patients with liver metastases from colorectal cancer (14th EORTC-NCI-AACR Symp Molec Targ Cancer Ther (Frankfurt), 2002, Abs 244). It is in a Phase I trial in patients with recurrent glioblastoma multiforme, in combination with temozolomide (qv), to determine the MTD, DLTs and antitumour efficacy. In a preliminary analysis of 11 patients, vatalanib + temozolomide 500 or 1000mg was well tolerated, and there was 0 and 1 (transient grade 3 transaminase elevation) DLTs, respectively. There was a decrease in tumour permeability after administration (7th Meet Soc Neuro-Oncol (San Diego), 2002). In a Phase 1b open-label dose-escalation trial, evaluating MTD and DLT, 42 patients with epithelial ovarian cancer were given vatalanib 250- 1250mg on days 3 to 21 of each chemotherapy cycle, paclitaxel (qv) 175mg/m2 iv over 3hr followed by carboplatin (qv) on day 1. Initial results showed 62% of patients achieved CR/PR, 14% had SD, 7% had PD and 17% unknown. No DLTs were reported. The most frequent grade 3/4 toxicities were neutropenia, leukopenia and hypertension. Vatalanib did not aggravate chemotherapy-related side effects, had no impact on carboplatin exposure and decreased paclitaxel exposure by an average of 18% in the 2nd cycle cf the 1st cycle. Further combination trials are under consideration (42nd ASCO (Atlanta), 2006, Abs 5075).

Preclinical

A back-up compound (AAL-993; qv) is under evaluation (BIO 2004 (San Francisco)). In rats, vatalanib po inhibited tumour vascularization and growth, particularly in prostate carcinomas. In mice, 50mg/kg po once-daily significantly inhibited tumour growth, and 3/7 mice had no macroscopically visible tumours at sacrifice (Scrip Daily Online, 21 Jun 2000, S00669492; 91st AACR (San Francisco), 2000, Abs 299). In nude mice with human squamous cell carcinoma, 50mg/kg po reduced tumour growth rate (11th Eur Cancer Conf (Lisbon), 2001, Abs 528). In a mouse growth factor model, vatalanib 12.5-50mg/kg/ day po dose-dependently inhibited VEGF- and PDGF-induced angiogenesis, and in nude mice transfected with human epithelial carcinoma A431 it inhibited cancer cell growth (89th AACR (New Orleans), 1998, Abs 655). Updated by JB on 19/1/2006.


Revised:      20070406

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