Phase I Study of PTK/ZK in Combination With Pemetrexed Disodium (ALIMTA)

OBJECTIVES: I. To determine the dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of PTK/ZK and pemetrexed disodium when given in combination. II. To describe the toxicities associated with the combination of PTK/ZK with pemetrexed disodium. III. To evaluate the pharmacokinetic interaction of combination of PTK/ZK with pemetrexed disodium at the MTD (Group II). IV. To evaluate the intracellular content of pemetrexed disodium polyglutamates as a measure of activity of pemetrexed disodium transport and activation enzymes in the MTD expansion cohort (Group II). V. To evaluate polymorphisms and gene expression of pemetrexed disodium target genes, and genes encoding enzymes involved in the transport, activation, and inactivation of pemetrexed disodium, and correlate haplotype-tagged SNPs or gene expression levels with intracellular levels of pemetrexed disodium polyglutamates, toxicity and/or efficacy or pemetrexed disodium in Group II. VI. To evaluate pharmacogenetic, metabolic and clinical markers that may predict for hypertension induced by anti-VEGF therapy. OUTLINE: This is a dose-escalation study of vatalanib. Patients are assigned to 1 of 2 treatment groups. GROUP I (dose escalation, closed to accrual 12/18/2007): Patients receive pemetrexed disodium IV over 10 minutes on day 1 and oral vatalanib twice daily on days 1-21. GROUP II (MTD expansion group): Patients receive pemetrexed disodium IV on day 1, as in group I. Patients also receive oral vatalanib at the MTD twice daily on days 8-21 during course 1 and on days 1-21 during all subsequent courses. In both groups, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.