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 Ophthalmologicals
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
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)
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