Vatalanib and Pemetrexed Disodium in Treating Patients With Advanced Solid Tumors
RATIONALE: Vatalanib and pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vatalanib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving vatalanib together with pemetrexed disodium may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of vatalanib when given together with pemetrexed disodium in treating patients with advanced solid tumors.
Unspecified Adult Solid Tumor, Protocol Specific
Drug: pemetrexed disodium
|Study Design:||Primary Purpose: Treatment|
|Official Title:||Phase I Study of PTK/ZK in Combination With Pemetrexed Disodium (ALIMTA®)|
- Dose-limiting toxicity and maximum tolerated dose (MTD) of vatalanib when administered with pemetrexed disodium as measured by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
- Overall toxicity incidence as well as toxicity profiles as measured by dose level, patient, and primary disease site as measured by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
- Pharmacokinetics of treatment, including AUC, C-max, half-life, and clearance obtained at different time points on day 1 of each course, in patients treated at the MTD [ Designated as safety issue: Yes ]
- Expression of functionally relevant polymorphisms in genes that encode proteins involved in the transport and activation of pemetrexed disodium in patients treated at the MTD [ Designated as safety issue: Yes ]
- Correlation of expression of these polymorphisms with clinical outcomes (toxicity, response, or progression status) in patients treated at the MTD [ Designated as safety issue: Yes ]
- Relation of gene expression and polymorphisms to the intracellular content of pemetrexed disodium [ Designated as safety issue: No ]
- Response (complete and partial response, stable and progressive disease) in patients with measurable disease [ Designated as safety issue: No ]
- Response profile as measured by dose level and by primary disease site [ Designated as safety issue: No ]
|Study Start Date:||May 2007|
|Estimated Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
- Determine the dose-limiting toxicity and maximum tolerated dose (MTD) of vatalanib when administered with pemetrexed disodium in patients with advanced solid tumors.
- Determine the toxicities of this regimen in these patients.
- Assess the pharmacokinetic interaction of this regimen when administered at the MTD.
- Assess the intracellular content of pemetrexed disodium polyglutamates as a measure of activity of pemetrexed disodium transport and activation enzymes in the MTD expansion group.
- Assess polymorphisms and gene expression of pemetrexed disodium target genes and genes encoding enzymes involved in the transport, activation, and inactivation of pemetrexed disodium.
- Correlate haplotype-tagged single nucleotide polymorphisms (SNPs) or gene expression levels with intracellular levels of pemetrexed disodium polyglutamates, toxicity, and/or efficacy of pemetrexed disodium in the MTD expansion group.
OUTLINE: This is a dose-escalation study of vatalanib. Patients are assigned to 1 of 2 treatment groups.
- Group I (dose escalation): Patients receive pemetrexed disodium IV over 10 minutes on day 1 and oral vatalanib twice daily on days 1-21.
Cohorts of 3-6 patients receive escalating doses of vatalanib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT) during the first 3 weeks of treatment.
- 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. Patients who experience unacceptable toxicity without progressive disease may be retreated at a lower dose.
Patients treated at the MTD (group II) undergo blood collection periodically for pharmacokinetic and pharmacogenetic analysis, including polyglutamation, gene expression, and polymorphism studies using mass spectrometry and high-performance liquid chromatography (HPLC). Genes of interest include reduced folate carrier (RFC-1), MRP, folate receptor, BCRP, FPGS, methylenetetrahydrofolate reductase (MTHFR), methionine synthase, methylthioadenosine phosphorylase, TS, DHFR, and GARFT.
PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|Study Chair:||Julian Molina, MD, PhD||Mayo Clinic|