Abstract
[Background] Vatalanib (PTK787/ZK 222584) is an orally active and selective inhibitor of the vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. A phase I/II study examined the safety and response profile of vatalanib in combination with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). [Patients and Methods] Patients with previously untreated, inoperable, measurable, advanced-stage CRC were administered escalating doses of vatalanib (500-2000 mg/day p.o.) in 42-day cycles. The FOLFOX4 regimen was coadministered with vatalanib, and treatment was continued until disease progression or unacceptable toxicity occurred. Tumor response was assessed every 12 weeks. [Results] Vatalanib was well tolerated, and the majority of adverse events were grade 1 or 2. Grade 3/4 adverse events included dizziness, diarrhea, fatigue, nausea, vomiting, and sensory neuropathy. The pharmacokinetics and toxicity profiles of both vatalanib and FOLFOX4 were unaffected by coadministration. One patient achieved a complete response, and
16 patients achieved a partial response. Disease progression on therapy was seen in only 1 patient. Median progression-free survival was 11.2 months (95% CI, 8.7-13.6 months). [Conclusion] The oral VEGFR inhibitor vatalanib can be safely combined with FOLFOX4 in metastatic CRC. Dizziness and neurologic toxicities were seen at higher doses of vatalanib. Ongoing trials are evaluating the efficacy and safety of vatalanib in combination with FOLFOX4 in patients with newly diagnosed or relapsed advanced-stage CRC.
Generic Name: Vatalanib succinate (recommended INNM; USAN)
Chemical Name: N-(4-Chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine succinate
Formula: C24H21CLN4O4
CAS Registry No.:
212142-18-2 (Succinate)
212141-51-0 (diHCl)
212141-52-1 (hydrochloride)
212141-54-3 (free base)
212141-89-4 (fumarate)
212141-90-7 (methanesulfonate)
212142-19-3 (oxalate salt)
Vatalanib (PTK787/ZK 222584), a potent orally active and selective inhibitor of the vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, targets VEGFR-1 (Flt-1) and VEGFR-2 (KDR).1-3 Vatalanib has been shown to inhibit growth and reduce microvasculature of human tumor xenografts.3,4 Early pharmacokinetic studies in patients with various tumor types revealed that the serum half-life of vatalanib was relatively short at 3-6 hours, necessitating daily administration.5 Vatalanib doses as high as 2000 mg/day were well tolerated and had biologic activity, as evidenced by
reductions in tumor blood flow by dynamic contrast-enhanced
magnetic resonance imaging.
Vatalanib has been safely combined with the oxaliplatin-containing chemotherapy regimen of 5-fluorouracil (5-FU)/leucovorin (LV)/oxaliplatin (FOLFOX4) in patients with previously untreated metastatic colorectal cancer (CRC).6 The safety profile of vatalanib/FOLFOX4 did not appear to differ from that expected with FOLFOX4 alone in those patients.
In an expanded phase I/II dose-escalation study, Dr. Steward and colleagues examined the safety and efficacy of vatalanib/FOLFOX4 as first-line therapy in patients with advanced or metastatic CRC. The results of the trial were presented at the 40th Annual Meeting of the American Society of Clinical Oncology and are summarized below.7
Study Design
Patients with metastatic CRC were enrolled in the study. Eligible patients had previously untreated, measurable, advanced-stage CRC. Selected cohorts received doses of oral vatalanib once daily at doses of 500 mg (n = 4), 1000 mg (n = 3), 1250 mg (n = 23), 1500 mg (n = 3), or 2000 mg (n = 2) in 42-day cycles.
The FOLFOX4 regimen was coadministered with vatalanib. FOLFOX4 consisted of LV 200 mg/m2 and 5-FU 400 mg/m2 bolus followed by 600 mg/m2 continuous infusion for 22 hours on days 1 and 2 plus oxaliplatin 85 mg/m2 on day 1, every 2 weeks. Treatment was continued until disease progression or unacceptable toxicity occurred, and tumor response was assessed every 12 weeks.
Results
A total of 35 patients with previously untreated metastatic CRC were enrolled in the study. Liver metastases were seen in 86% of the patients, and 54% of the patients had lung metastases.
The majority of adverse events were grade 1 or 2, and no increase in toxicity was seen with the addition of vatalanib to FOLFOX4. The incidence and severity of toxicity was consistent with the known safety profile of FOLFOX4 or vatalanib administered as monotherapy. Of the 35 patients evaluable for toxicity, 9 (26%) experienced grade 3/4 neutropenia. Other common grade 3/4 adverse events included dizziness (17%), diarrhea (14%), fatigue (11%), nausea (9%), vomiting (6%), and sensory neuropathy (6%) (Table 1).
No dose-limiting toxicities of vatalanib occurred at the 1000-mg/day dose. However, serious adverse events occurred at the 1500- and 2000-mg dose levels. Grade 3 dizziness and dysphasia occurred in 1 of the 3 patients receiving vatalanib 1500 mg/day, and grade 3 fatigue occurred in the second patient. Vatalanib administered at a dose of 2000 mg/day resulted in grade 4 dizziness and grade 3 neurotoxicity/light-headedness in 1 of the 2 patients treated at that dose level and grade 3 neurotoxicity in the second patient. Doses were reduced to 1500 mg/day for both patients. Vatalanib 1250 mg/day was recommended as the maximum tolerated dose.
The pharmacokinetics of oxaliplatin were not altered by the coadministration of vatalanib. The mean area under the concentration time curve from 0-24 hours of vatalanib remained unchanged with the coadministration of oxaliplatin.
Vatalanib/FOLFOX4 showed clinical activity in patients with metastatic CRC. Of the 32 patients evaluable for efficacy, 1 patient (3%) achieved a complete response, 16 patients (50%) achieved a partial response, and 14 patients (44%) had stable disease. Progressive disease occurred in 1 patient. Responses according to dose level are shown in (Table 2).
Median progression-free survival for the 35 intent-to-treat patients was 11.2 months (95% CI, 8.7-13.6 months), which compares favorably with historical reports in a similar poor-prognosis population. The estimated median overall survival for all 35 patients was 18.6 months (95% CI, 15.1 months-not reached) (Table 3).
Clinical Relevance
The oral VEGFR tyrosine kinase inhibitor vatalanib can be
safely combined with FOLFOX4 in patients with metastatic CRC. At the higher doses of vatalanib, dizziness and neurologic toxicities were seen. Ongoing randomized phase III trials (CONFIRM-1 and CONFIRM-2) are evaluating the efficacy and safety of vatalanib in combination with FOLFOX4 in patients with newly diagnosed or relapsed advanced-stage CRC.
References
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4. Drevs J, Hofmann I, Hugenschmidt H, 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 Res 2000; 60:4819-24.
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ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 2003; 21:3955-64.
6. Trarbach T, Thomas AL, Bartel C, et al. Preliminary phase I results of the oral, once-daily angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK) in combination with chemotherapy for the treatment of metastatic colorectal cancer. Eur J Cancer 2003; 1(suppl 5):S91 (abstract 297).
7. Steward WP, Thomas A, Morgan B, et al. Expanded phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in combination with FOLFOX-4 as first-line treatment for patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 2004; 23:259 (abstract 3556).
