RATIONALE: NG-nitro-L-arginine may stop the growth of tumor cells by disrupting blood flow to the tumor. PURPOSE: This phase I trial is studying the side effects and best dose of NG-nitro-L-arginine in treating patients with advanced solid tumors.
OBJECTIVES: Primary * To determine if there is a differential effect of NG-nitro-L-arginine (L-NNA) on tumor and normal tissue vasculature (blood flow/volume) in patients with advanced solid tumors in order to propose a safe recommended dose range for further evaluation. Secondary * To determine the correlation between plasma concentration of L-NNA and toxicity and vascular effects. * To further determine the effects of nitric oxide synthase (NOS) inhibition on tumor tissue vasculature. * To determine the pharmacokinetics of L-NNA. * To determine the safety profile of L-NNA. Tertiary * To evaluate the potential pharmacodynamic effect of NOS inhibition on angiogenesis. * To evaluate the effect of L-NNA on circulating NOS levels. * To evaluate the correlation between expression levels of iNOS and eNOS and vasoconstrictive effects of L-NNA in tumor tissue (where available). OUTLINE: This is a dose-escalation study. Patients receive a single dose of NG-nitro-L-arginine (L-NNA) IV over 10 minutes on day 1. All patients undergo up to 6 dynamic contrast-enhanced computed tomography (DCE-CT). Patients enrolled in the expanded cohort study undergo 4 additional scans of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as well as DCE-CT scans. Blood samples are collected periodically for pharmacokinetic and biomarker studies. Samples are analyzed for L-NNA levels via a reverse-phase high performance liquid chromatography, NOS inhibition via cGMP analysis, and VEGF-A and osteopontin levels. Previously collected biopsy samples are analyzed for iNOS and eNOS expression. After completion of study treatment and one week assessments, patients are followed up once a week for 28 days and then monthly thereafter (if required). Peer Reviewed and Funded or Endorsed by Cancer Research UK.
Study Type
INTERVENTIONAL
Purpose
TREATMENT
Enrollment
6
Mount Vernon Cancer Centre at Mount Vernon Hospital
Northwood, England, United Kingdom
Dose-limiting toxicities (DLT) and/or subsequent maximum dose
Dose at which there is no additional differential effect of L-NNA on the tumor vasculature as measured by dynamic contrast-enhanced computed tomography (DCE-CT)
Pharmacokinetic (predominantly AUC-dependent specific vascular effects) dependent effects (duration and magnitude of effect on blood flow/volume) in the tumor tissue compared to renal tissue using data from volumetric assessments via DCE-CT
Effect on tumor blood perfusion using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with additional blood oxygen level-dependent (BOLD) imaging and diffusion-weighted imaging (DWI) sequences
Causality of each adverse event to L-NNA and severity grade according to NCI CTCAE Version 4.02
Tertiary Outcome(s) - Measurement of L-NNA concentrations in plasma samples
Measurement of serum biomarker concentrations, osteopontin, and vascular endothelial growth factor (VEGF-A)
Measurement of NOS concentrations in circulating blood (cyclic guanine monophosphate analysis)
Measurement of iNOS and eNOS expression levels in pre-treatment tumor biopsy samples (where available)
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