Sample record Adis R&D Insight (File 107/907)
5/9/1 DIALOG(R)File 107: Adis R&D Insight (c) 2007 Adis Data Information BV. All rights reserved. 00240128 012103 Drug Name: Vatalanib Record Revision Date: 20061229 Synonyms: CGP 79787; PTK 787; PTK/ZK; PTK787; ZK 222584 Chemical Name: 1-(p-chloroanilino)-4-(4-pyridylmethyl)phthalazine Molecular Formula: C20H15ClN4 CAS Registry Number: 212141-54-3 WHO ATC Code: L01 - Antineoplastic Agents; S01X - Other Ophthalmologicals EPHMRA ATC Code: L1 - Antineoplastics; S1X - Other OphthalmologicalsMechanism of Action: Tyrosine kinase inhibitors; Protein kinase inhibitors; Protein kinase modulators; Phosphotransferase (Alcohol Group Acceptor) inhibitors; Phosphotransferase (Alcohol Group Acceptor) modulators; Kinase inhibitors; Kinase modulators; Transferase inhibitors; Transferase modulators; Enzyme inhibitors; Enzyme modulators; Vascular endothelial growth factor antagonists; Angiogenic protein inhibitors; Protein inhibitors; Peptide antagonists; Growth factor antagonists; Intercellular signalling peptide and protein inhibitors; Protein modulators
Originator Company: Bayer Schering Pharma (Germany); Novartis (Switzerland); M. D. Anderson Cancer Center (USA); Novartis (USA)
Parent Company: Bayer; M. D. Anderson Cancer Center; Novartis Licensee: Bayer Schering Pharma; Novartis Highest Phase: Phase III Development Status: Phase III, Switzerland, Colorectal cancer Phase III, USA, Colorectal cancer Phase II, Switzerland, Age-related macular degeneration Phase II, Italy, Glioblastoma Phase II, Netherlands, Glioblastoma Phase II, France, Non-small cell lung cancer Phase II, Germany, Non-small cell lung cancer Phase II, Switzerland, Solid tumours Phase II, USA , Solid tumours Phase I, Germany, Colorectal cancer Phase I, Germany, Glioblastoma Phase I, Germany, Ovarian cancer Phase I, Germany, Renal cancer Phase I, Switzerland, Renal cancer Preclinical, USA, Multiple myeloma Text: Introduction:Vatalanib is an oral small molecule inhibitor of most known drivers of angiogenesis, including vascular endothelial growth factor receptors (VEGFRs) and kinase insert domain receptor (KDR) tyrosine kinases. Vatalanib is undergoing development with Novartis Pharma in Switzerland, Bayer Schering Pharma AG (formerly Schering AG) in Germany, and the University of Texas M.D. Anderson Cancer Center in the US as a potential anticancer agent. It is also possible that the agent will have potential in the treatment of other diseases whose pathology also relies on angiogenesis.
Company agreements
In June 2006, Schering AG was acquired by Bayer and was subsequently renamed as Bayer Schering Pharma AG/1/ /2/.
Novartis and Schering AG (now Bayer Schering Pharma AG) have been jointly researching and co-developing vatalanib since 1995. A commercialisation agreement was finalised in January 2005 in which Novartis will lead North American co-promotion activities and Schering will lead European co-promotion activities with both companies sharing co-promotion activities equally in Japan. Novartis will exclusively promote vatalanib in Asia (excluding Japan) and Middle East. Schering will exclusively promote vatalanib in Latin America, Africa and Australia/3/. In January 2005, in a separate agreement with Schering, Novartis obtained exclusive rights to develop vatalanib for the treatment of wet age-related macular degeneration (AMD). Under the agreement, Novartis will obtain full global and exclusive developmental and commercialisation rights to vatalanib in ophthalmics. Novartis will pay an upfront fee, milestone payments and royalties on ophthalmics sales/3/.
Key development milestones
Colorectal cancer: Novartis and Schering AG (now Bayer Schering Pharma AG) have conducted two phase III clinical trials, the CONFIRM 1 and CONFIRM 2 trials, in patients with metastatic colorectal cancer in combination with first- and second-line chemotherapy/4/. Together, these trials enrolled approximately 2000 patients at over 200 centres worldwide.
Data from an interim analysis of the CONFIRM 1 trial revealed that vatalanib did not achieve statistical significance on progression-free survival. However, trial data is being reevaluated to determine if significant efficacy was achieved in subpopulations within the trial, and results from this are expected in the second half of 2006/5/.
The CONFIRM 1 trial (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in First-line) studied the potential progression-free and overall survival benefit of once daily oral treatment with vatalanib in combination with oxaliplatin/5- fluorouracil/leucovorin (FOLFOX4) compared to FOLFOX4 + placebo in chemotherapy naive patients (n = 1090)/6/.
The CONFIRM 2 trial (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in Second-line) is investigating the survival benefit of the same regimen as in CONFIRM 1 among patients (n = 830) with metastatic colorectal cancer who have progressed after irinotecan-based first-line chemotherapy/7/. In July 2005, Schering and Novartis disclosed that a planned interim analysis of the CONFIRM 2 trial indicated a low probability of demonstrating an overall survival benefit, following a review by an independent Data Safety Monitoring Board (DSMB). Investigators will be informed of the DSMB findings to allow for a discussion and decision regarding continuation of treatment/8/. This does not impact the CONFIRM 1 trial.
Novartis and Schering will delay filing for approval with the FDA and the EMEA until early 2007.
Glioblastoma: a phase I/II trial is underway in Italy and the Netherlands to evalute vatalanib when administered in combination with temozolomide and radiation therapy to patients with newly diagnosed glioblastoma multiforme. The European Organization for Research and Treatment of Cancer (EORTC) is conducting this trial.
Non-small cell lung cancer: in February 2005, Schering initiated a phase II trial of vatalanib in patients with non-small cell lung cancer at sites in France and Germany. The trial known as the GOAL Study for Growth Arrest with Oral Anti-Angiogenesis in Lung Cancer, will include patients with stage IIIB/IV NSCLC who have relapsed or are refractory to first-line therapy/9/.
Ovarian cancer: Novartis presented results from a phase Ib trial in patients with ovarian cancer in December 2005/10/.
Solid tumours: a broad phase I/II programme is underway to identify additional indications for further development, including prostate, non-small cell lung, breast, pancreatic and ovarian cancers, as well as glioblastoma and haematological malignancies.
Schering AG, Novartis and the Tumour Clinic at Freiburg, Germany have conducted phase I/II trials in patients with solid tumours including patients with colorectal cancer, renal cell carcinoma and glioblastoma multiforme. Novartis announced at the JP Morgan H&Q 21st Annual Healthcare conference held in January 2003 that partial responses and stable disease had been observed in some patients. Vatalanib was also found to be well tolerated at the chosen dose of 1250mg once daily.
Age-related macular degeneration: vatalanib is in phase II clinical trials for age-related macular degeneration.
Commercial Summary: Colorectal cancer (solid tumours) / Tyrosine kinase
inhibitor (VEGF)
----------------------------------------------------------------------
Company Region Launch Date Peak Sales Patent Expiry
----------------------------------------------------------------------
Bayer ex-US 2008 $300m
Novartis US 2010 $400m 2018
Novartis ex-US 2008 $300m 0
----------------------------------------------------------------------
Copyright (C) Lehman Brothers International. All rights reserved.
ADIS Evaluation:
Solid tumours 76 (PO).
Pharmacology Overview:
Antimicrobial activity:
Pharmacodynamics:
Inhibits VEGF-dependent tumour growth in xenograft models; reduces blood
flow into tumour; reduces number of primary renal cell xenografts;
reduces vascular permeability in patients with glioblastoma; inhibts
the growth of multiple myeloma cells in culture; enhances the
anti-growth effect of dexamethasone in multiple myeloma cells
Immunogenicity:
Mechanism of action:
Tyrosine kinase inhibitors
Protein kinase inhibitors
Protein kinase modulators
Phosphotransferase (Alcohol Group Acceptor) inhibitors
Phosphotransferase (Alcohol Group Acceptor) modulators
Kinase inhibitors
Kinase modulators
Transferase inhibitors
Transferase modulators
Enzyme inhibitors
Enzyme modulators
Vascular endothelial growth factor antagonists
Angiogenic protein inhibitors
Protein inhibitors
Peptide antagonists
Growth factor antagonists
Intercellular signalling peptide and protein inhibitors
Protein modulators
------------------------------------
tmax (h) (oral) 1.1 - 2 (Adult)
t (1/2) beta (h) 4.5 - 4.7 (Adult)
------------------------------------
Activity versus parent drug: unspecified parent
Clinical Overview:
Route(s) of Administration: PO
Administration Freq.(per day): , od
Adverse events:
occasional: Aphasia, Ataxia, Confusion, Deep vein thrombosis, Dizziness,
Fatigue, Headache, Nausea, Vomiting.
Drug Interactions:
Unknown.
Adverse Events:
Clinical studies: In a phase I trial, IV and oral formulations
of vatalanib were generally well tolerated. The most
frequent adverse events (AEs) were nausea and fatigue;
two patients experienced grade 3 treatment-related
AEs and five patients discontinued the study due to
AEs/11/.In a phase Ib trial, 19 patients with stage IC-IV ovarian cancer received paclitaxel, carboplatin, and vatalanib; vatalanib was dosed at 250-1250 mg/day on days 3-21 of each 21-day cycle. The most common adverse event (AE) was grade 1-2 hypertension. Only one patient discontinued treatment due to an AE; no patients experienced dose- limiting toxicity or serious AEs/10/.
In an ongoing phase I trial, oral vatalanib (150-750 mg/day) was administered od for 28 days to 12 patients with solid tumours (3 patients/dose level). No hepatic, haematological or dose-limiting toxicity was observed and dose escalation is continuing/12/.
Vatalanib had acceptable tolerability at dosages of 500-2000 mg/day in patients with recurrent glioblastoma. Adverse events included confusion, aphasia, gait abnormalities, headache, fatigue, nausea, and deep vein thrombosis/13/.
Nausea and vomiting are the dose-limiting toxicities of vatalanib in patients with acute myeloid leukaemia and myelodysplastic syndromes. The maximum tolerated dose of vatalanib is 1500 mg/day in patients with acute myeloid leukaemia and myelodysplastic syndromes/14/.
A phase I, open-label, dose-escalation and dose-expansion study in 45 patients with metastatic renal cell carcinoma determined the tolerability, safety and clinical efficacy of vatalanib at five dose levels of 300 to 1500 mg/day. Dose-limiting toxicity (DLT) occurred in 2 patients (1 with grade 3 headache and 1 with grade 3 hypertension). The most frequently reported adverse events included nausea (59%), fatigue (41%), vomiting (35%), dizziness (29%) and headache (24%)/15/.
Results from a phase I trial involving 27 patients with liver metastases from solid tumours showed vatalanib was well tolerated at doses up to 1200 mg/day; the principal dose-limiting toxicity appeared to be ataxia/16/.
Vatalanib was well tolerated in combination with oxaliplatin/5- fluorouracil/leucovorin (FOLFOX4) or irinotecan/5-fluorouracil/ leucovorin (FOLFIRI) at dose levels up to 1250 mg/day among patients with metastatic colorectal cancer in a phase I/II trial. The principal dose-limiting toxicities of vatalanib were neuropathy and fatigue/17/.
Results of a phase I/II trial of vatalanib plus FOLFIRI in patients with metastatic colorectal cancer showed that the combination was safe and well tolerated. The most commonly reported grade 1 and 2 adverse events were nausea, vomiting, fatigue, dizziness, epistaxis and diarrhoea. Grade 3 events were reported in two patients receiving 500 and 1000 mg/day and were fatigue and hypertension, respectively. Both resolved within 2 weeks of treatment discontinuation. In the trial 19 patients received single daily oral doses of vatalanib 500, 1000, 1250 or 1500 mg/day. FOLFIRI was administered as irinotecan (180 mg/m sup(2), day 1) plus leucovorin (200 mg/m sup(2), 2-hour infusion) and 5-fluorouracil (400 mg/m sup(2) bolus followed by a 22-hour infusion of 600 mg/m sup(2)) on days 1 and 2/18/.
Animal toxicology: daily administration of vatalanib 50 mg/kg to mice bearing murine renal cell carcinoma produced no significant changes in body weight or general well being of the animals. In contrast, animals treated with AGM 1470 30 mg/kg every 2 days had to be withdrawn from treatment because of excessive weight loss and ataxia/19/.
Drug Interactions:
Pharmacokinetics:
Clinical studies: In a phase I trial, the pharmacokinetics of IV and oral formulations of vatalanib were investigated. In this two-part study, patients received single doses of IV vatalanib 22.5mg, 45mg or 90mg (part 1), and IV vatalanib 90mg on day 1, oral vatalanib 1250 mg/day on days 8-22 and a second dose of IV vatalanib 90mg on day 23 (part 2). The mean absolute bioavailability of vatalanib was 0.58 after single dosing and 0.37 after multiple dosing, a statistically significant difference; this was due to an increase in oral clearance after multiple oral dosing/11/.
In a phase Ib trial, 19 patients with stage IC-IV ovarian cancer received a 3-hour infusion of paclitaxel 175 mg/m sup(2) and an IV infusion of carboplatin AUC 5 mg x min/mL on day 1, plus vatalanib 250-1250 mg/day on days 3-21, each 21-day cycle. Steady-state plasma concentrations of vatalanib were observed between cycles one and two. Vatalanib had no effect on systemic exposure of free platinum, and paclitaxel exposure was not impacted by vatalanib at a dosage of 1250 mg/day/10/.
In a phase I trial, oral vatalanib (150-750 mg/day) was administered once daily for 28 days to 12 patients with solid tumours (3 patients/dose level). The T sub(max) was 1.1-2.0h and the mean t sub(1/2) was 4.5h. Vatalanib was rapidly absorbed, with no evidence of accumulation. There was a slight decrease in mean AUC from days 1-15 for all dose levels. The mean AUC sub(0-infinity) was proportional to the dose administered for all dose levels/12/.
Oral vatalanib was well tolerated in animals bearing human tumours and did not impair wound healing. It had no significant effects on circulating blood cells or bone marrow leukocytes when used as a single agent, nor did it impair haematopoietic recovery after concomitant chemotherapy challenge/20/.
Results from a phase I trial involving 27 patients with liver metastases from solid tumours showed vatalanib was rapidly absorbed (t sub(max) of 1.7h) with a mid-range terminal half-life (t sub(1/2) of 4.7h) and no accumulation during once-daily dosing/16/.
Preliminary results from a phase I study of eight patients with advanced cancers who received vatalanib 1000 mg/day for 14 days showed that at 22 days post administration (when it was determined that four patients had completed radiolabeled drug excretion), excretion of the drug and its metabolites was mainly biliary (23% in urine) and faecal (60%)/21/.
Coadministration of vatalanib had no clinically significant effect on the pharmacokinetic profiles of oxaliplatin or irinotecan among 51 patients with metastatic colorectal cancer in a phase I/II trial/17/.
In a phase I/II trial of a combination of vatalanib and infusional 5- fluorouracil/leucovorin/irinotecan (FOLFIRI) in patients with metastatic colorectal cancer pharmacokinetics of vatalanib were unaffected by FOLFIRI. Coadministration of vatalanib 1250 mg/day with FOLFIRI had very little effect on irinotecan exposure. However, the AUC of SN38 in serum was lowered by ~40%. In the trial 19 patients received single daily oral doses of vatalanib 500, 1000, 1250 or 1500 mg/day. FOLFIRI was administered as irinotecan (180 mg/m sup(2), day 1) plus leucovorin (200 mg/m sup(2), 2-hour infusion) and 5- fluorouracil (400 mg/m sup(2) bolus followed by a 22-hour infusion of 600 mg/m sup(2)) on days 1 and 2/18/.
Animal studies: oral administration of vatalanib (50 mg/kg) to mice resulted in plasma concentrations of > 1 micromol/L maintained for > 8h/20/.
Pharmacodynamics (Cancer):
Preclinical studies: treatment with vatalanib (50 mg/kg/day) 7 days after injection with SKOV3 i.p.1 human ovarian cancer cells increased the median survival time of nude mice to 70 days, compared with 39 days for untreated controls. The mean tumour weights in the treatment and control groups were 1.2 and 3g, respectively. The volume of tumour ascites in mice treated with vatalanib was 1.5ml, vs 5ml for the control group. Vatalanib had no effect against vascular endothelial growth factor- (VEGF) independent HEY-A8 ovarian cancer xenografts/22/.
Once daily administration of vatalanib (25-100 mg/kg) induced dose- dependent growth inhibition of vascular endothelial cell growth factor- and platelet derived growth factor- induced angiogenesis in epithelial carcinoma implanted in nude mice. The same dose range also inhibited the growth of a number of different human carcinomas implanted SC in nude mice. In addition, vatalanib inhibited murine renal cell carcinoma and its metastases in a syngenic orthotopic model/20/.
Daily administration of vatalanib 50 mg/kg to mice bearing murine renal cell carcinoma resulted in a significant 61 and 67% reduction in the number of primary tumours after 14 and 21 days of treatment, respectively. In addition, the incidence of lung metastases was significantly reduced by 98 and 78% at 14 and 21 days, respectively. Blood vessel density was also significantly reduced as was the flow of blood to the tumour. Blood flow correlated with the changes in vessel density and not with tumour volume/19/.
A combined dosing regimen consisting of vatalanib + gemcitabine, in nude mice bearing human pancreatic L3.6pl cancer cells, significantly decreased the incidence of lymph node and liver metastases. These events correlated with a significantly improved survival duration. Furthermore, microvessel density was significantly reduced in tumours treated with either vatalanib alone or in combination with gemcitabine. Microvessel density correlated with tumour cell proliferation and inversely correlated with apoptosis of tumour cells associated with endothelial cells/23/ .
In multiple myeloma cells, vatalanib inhibited proliferation by as much as 50% at doses ranging from 1-5 micromol/L. Vatalanib also increased interleukin-6 and vascular endothelial growth factor secretion in cultures of multiple myeloma cells adherent to bone marrow stem cells. The agent enhanced the inhibitory effect of dexamethasone on the growth of multiple myeloma cells and overcame the protective effect of interleukin-6 against dexamethasone-induced apoptosis/24/.
Clinical studies: vatalanib reduced tumour vascular permeability and cerebral blood volume at days 2 and 30 in patients with recurrent glioblastoma multiforme; the decreases observed at day 30 appeared to be dose-dependent/13/ /25/.
Therapeutic Trials:
Cancer:
Colorectal cancer: addition of vatalanib to oxaliplatin/5- fluorouracil/leucovorin (FOLFOX4) or irinotecan/5-fluorouracil/ leucovorin (FOLFIRI) appeared to have promising activity in the first- line treatment of patients with metastatic colorectal cancer in a phase I/II trial (n = 51). Objective responses were observed in 15/35 and 4/16 patients, respectively. Median times to progression of 11.0 and 6.7 months, respectively/17/.
Antitumour activity was observed in a phase I/II trial of a combination of vatalanib and FOLFIRI in patients with metastatic colorectal cancer. Partial responses were achieved by 41% of patients while the other 59% had stable disease. Median progression-free survival was 7.1 months for 17 patients; median overall survival was 24.3 months for 19 intent-to-treat patients. In the trial 19 patients received single daily oral doses of vatalanib 500, 1000, 1250 or 1500 mg/day. FOLFIRI was administered as irinotecan (180 mg/m sup(2), day 1) plus leucovorin (200 mg/m sup(2), 2-hour infusion) and 5- fluorouracil (400 mg/m sup(2) bolus followed by a 22-hour infusion of 600 mg/m sup(2)) on days 1 and 2/18/.
Glioblastoma multiforme: in a phase I study, at a dose of 1200 or 1500 mg/day in patients with recurrent glioblastoma multiforme vatalanib showed preliminary evidence of antitumour activity in 31 patients. There was one partial response (3%) and 20 cases of stable disease (65%). Seven patients had stable disease for >120 days/25/.
In a phase I study, partial response was obtained in 2/21 and 1/12 patients with recurrent glioblastoma multiforme who were treated with vatalanib + temozolomide and vatalanib + lomustine, respectively. Median time to progression was 15.0 and 15.6 weeks, respectively/26/.
Leukaemia: vatalanib showed no activity in 17 patients with relapsed/ refractory acute myeloid leukaemia in a phase I study. 2/12 patients with myelodysplastic syndromes had ongoing stable disease for 4 and 8 months per case, respectively/14/.
Renal cancer: a phase I, open-label, dose-escalation and dose- expansion study in 45 patients with metastatic renal cell carcinoma determined the tolerability, safety and clinical efficacy of vatalanib at five dose levels of 300 to 1500 mg/day. Although, the maximum tolerated dose (MTD) was not reached at 1500 mg/day, the dose of 1200 mg/day was selected for the dose-expansion phase based on the pharmacokinetic, pharmacodynamic and safety data. Among 37 evaluable patients receiving vatalanib >= 1000 mg/day, 7 (19%) had measurable response with a median time to progression (TTP) of 5.5 months. 17 (46%) patients achieved stable disease, 5 (14%) had progressive disease and 8 (22) patients discontinued therapy because of either adverse events or administrative reasons. Only 28% patients experienced rapid disease progression compared with the expected rate of 49.7 (based on cytokine treatment in a similar patient group). One- year overall survival rate was 63.7%/15/.
Liver metastases: results from a phase I trial involving 27 patients with liver metastases showed stable disease in 52% of patients with metastases from colorectal, breast or other solid tumours. The median duration of stable disease was 4.3 months and the median survival duration was 11.6 months/16/.
Solid tumours: results from three phase I studies in 65 patients with advanced colorectal cancer and glioblastoma have shown that plasma vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) may be useful as soluble biomarkers for detecting the biological activity of vatalanib and its associated tumour response. VEGF and bFGF are pro-angiogenic factors that were assessed to provide markers of biological activity for vatalanib. The results support previous dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data, which showed a reduction in tumour vascular permeability and vascularisation within 36 hours after the first dose of vatalanib administered. In addition, a dose dependent rise in both biomarkers was observed within the first 28 days of vatalanib treatment/27/.
Drug Update Information:
07-Aug-2001: Phase-II clinical trials for Solid tumours in Switzerland (PO)
07-Aug-2001: Phase-II clinical trials for Solid tumours in USA (PO)
25-Oct-2000: A preclinical study has been added to the Cancer pharmacodynamics and adverse events sections (843972)
25-Oct-2000: Preclinical development for Renal cancer in Germany (PO)
25-Oct-2000: Preclinical development for Renal cancer in Switzerland (PO)
23-Aug-2000: A preclinical study has been added to the pharmacodynamics, pharmacokinetics and adverse events sections (825908)
09-Nov-1999: A clinical study has been added to the pharmacokinetics and adverse events sections (771670)
09-Nov-1999: Phase-I clinical trials for Solid tumours in Switzerland (PO)
09-Nov-1999: Phase-I clinical trials for Solid tumours in USA (PO)
03-Jun-1999: New profile
03-Jun-1999: Preclinical development for Cancer in Switzerland (Unknown route)
03-Jun-1999: Preclinical development for Cancer in USA (Unknown route)
References:
1. Bayer AG. Takeover Offer Completed; Bayer Controls 92.4 Percent of Outstanding Schering Shares. Media Release. : 12 Jul 2006. Available from: URL: http://www.bayer.com. (English).
2. Bayer. Renaming of Schering entered in the commercial register: Bayer Schering Pharma AG officially launched. Media Release. : 29 Dec 2006. Available from: URL: http://www.bayer.com. (English).
3. Novartis Pharma AG. Ad hoc: Novartis and Schering AG finalize commercialization agreement. Media Release. : 25 Jan 2005. Available from: URL: http://www.novartis.com. (English).
4. Spectrum Health Cancer Center. Spectrum Health Seeks Patients With Metastatic Colorectal Cancer For Study Of New Drug. Media Release. : 29 Sep 2003. Available from: URL: http://www.spectrum-health.org. Summary in 2 parts (Part A). (English). 809026001
5. Schering AG, Novartis Pharma AG. PTK/ZK CONFIRM 1 Phase III Study Shows Positive Drug Effects in Metastatic Colorectal Cancer - Filing Now Anticipated for Early 2007. Media Release. : 21 Mar 2005. Available from: URL: http://www.schering.de. (English). 809046771
6. Novartis. Novartis/Schering AG Oral Angiogenesis Inhibitor PTK/ZK Completes Enrollment for Key Phase III Metastatic Colorectal Cancer Trial. Media Release. : 3 Jun 2004. Available from: URL: http:// www.novartis.com. (English). 809035481
7. Schering AG. Oral Angiogenesis Inhibitor Enters Phase III Trials for Treatment of Patients With Metastatic Colorectal Cancer. Media Release. : 2 Apr 2003. Available from: URL: http://www.schering.de. (English).
8. Schering AG, Novartis Pharma AG. Planned Interim Analysis of CONFIRM 2 Trial of PTK/ZK Indicates Low Probability of Demonstrating Overall Survival Benefit in Second-Line Therapy of Metastatic Colorectal Cancer. Media Release. : 28 Jul 2005. Available from: URL: http://www.schering.de. (English).
9. Schering AG. New Phase II Clinical Study of PTK/ZK in Lung Cancer. Media Release. : 2 Mar 2005. Available from: URL: http:// www.schering.de. (English). 809045949
10. Schroeder W, Abadie S, et al. Antiangiogenesis as new treatment modality in ovarian cancer: a phase Ib, open label, safety and pharmacokinetics study of escalating doses of PTK787/ZK222584 in combination with paclitaxel and carboplatin in patients with stage IC to IV epithelial ovarian cancer. EJC Supplements. 3: 273 (plus poster) abstr. 949, No. 2, Oct 2005. (English).
11. Pavel M, Schuppan D, et al. A phase I, open-label study with escalating doses of intravenous PTK787/ZK 222584, a multi-VEGF receptor inhibitor, followed by multiple oral daily dosing to assess the absolute bioavailability of PTK787/ZK 222584 after single and multiple doses in advanced cancer patients. EJC Supplements. 3: 427 (plus poster) abstr. 1474, No. 2, Oct 2005. (English).
12. Drevs J, Mross K, et al. Phase I dose escalation, pharmacokinetic study of a novel vascular endothelial growth factor receptor inhibitor, PTK787/ZK 222584. European Journal of Cancer. 35 (Suppl. 4): 283, Sep 1999. (English). 800771670
13. Yung WA, Friedman H, et al. A phase I trial of PTK787/ZK 222584, a novel oral VEGFR TK inhibitor in recurrent glioblastoma. 38th Annual Meeting of the American Society of Clinical Oncology. 21: 79, Part 1, 18 May 2002. (English). 800883518
14. Roboz GH, List AF, et al. Phase I trial of PTK787/ZK 222584, an inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in acute myeloid leukemia and myelodysplastic syndrome. Blood. 100: 337, Part 1, 16 Nov 2002. (English). 800930484
15. George D, Michaelson D, et al. Phase I study of PTK787/ZK 222584 in metastatic renal cell carcinoma. 39th Annual Meeting of the American Society of Clinical Oncology. : 385 (plus poster) abstr. 1548, 31 May 2003. (English). 800947090
16. Drevs J, Mross K, et al. Phase I dose-escalation and pharmacokinetic study of the VEGF inhibitor PTK787/ZK 222584 in patients with liver metastases. 39th Annual Meeting of the American Society of Clinical Oncology. : 284 (plus poster) abstr. 1142, 31 May 2003. (English). 800949391
17. Trarbach T, Thomas AL, et al. Preliminary phase I results of the oral, once-daily angiogenesis inhibitor PTK787/ZK 222584 in combination with chemotherapy for the treatment of metastatic colorectal cancer. EJC Supplements. 1: 91 (plus poster) abstr. 297, No. 5, Sep 2003. (English). 800955761
18. Vanhoefer U, Trarbach T, et al. Phase I/II study of PTK787/ZK 222584, a novel, oral angiogenesis inhibitor in combination with FOLFIRI as first-line treatment for patients with metastatic colorectal cancer. Annals of Oncology. 15 (Suppl. 3): 94-95 (plus poster) asbtr.352P, 2004. (English). 800983687
19. Drevs J, Hofmann I, et al. Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Research. 60: 4819-4824, 1 Sep 2000. (English).
20. Wood JM, Bold G, et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Research. 60: 2178-2189, 15 Apr 2000. (English).
21. Knoblich J, Paldanius PM, et al. Clinical results from an ADME (absorption, distribution, metabolism, and excretion) trial of PTK787/ZK 22284: a novel, oral angiogenesis inhibitor in patients with advanced cancer. EJC Supplements. 1: 170, No. 5, Sep 2003. (English).
22. Xu L, Herrera CA, et al. Therapy of VEGF-dependent human ovarian carcinoma by oral administration of CGP 79787/ZK222584, an inhibitor of the VEGF receptor tyrosine kinase. 90th Annual Meeting of the American Association for Cancer Research. : 457, 10 Apr 1999. (English). 800743129
23. Solorzano CC, Baker CH, et al. Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Cancer Biotherapy and Radiopharmaceuticals. 16: 359-370, Oct 2001. (English).
24. Lin B, Podar K, et al. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Cancer Research. 62: 5019-5026, 1 Sep 2002. (English).
25. Yung WKA, Friedman H, et al. A phase I trial of single-agent PTK 787/ZK 222584 (PTK/ZK), an oral VEGFR tyrosine kinase inhibitor, in patients with recurrent glioblastoma multiforme. 39th Annual Meeting of the American Society of Clinical Oncology. : 99 (plus oral presentation) abstr. 395, 31 May 2003. (English). 800897867
26. Reardon D, Friedman HS, et al. A phase I trial of PTK787/ZK 222584, an oral VEGF tyrosine kinase inhibitor, in combination with either temozolomide or lomustine for patients with recurrent glioblastoma multiforme. 39th Annual Meeting of the American Society of Clinical Oncology. : 103 (plus poster) abstr. 412, 31 May 2003. (English). 800897868
27. Drevs J, Steward WP, et al. Biomarkers (VEGF, BFGF) for assessing the biolgoical activity of PTK787/ZK222584, a vascular endothelial growth factor (VEGF) receptor inhibitor, in tumours known to overexpress VEGF. European Journal of Cancer. 38 (Suppl. 7): 78, Nov 2002. (English).
References No.: 809026001; 809046771; 809035481; 809045949; 800771670; 800883518; 800930484 ; 800947090; 800949391; 800955761; 800983687; 800743129; 800897867; 800897868
File 107 Sample Record