NG-Nitro-L-Arginine in Treating Patients With Advanced Solid Tumors

NCT ID: NCT01324115

Last Updated: 2015-03-05

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-04-30
• Study Completion Date: 2012-09-30

Brief Summary

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.

Detailed Description

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.

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Study Design

• Primary Study Purpose: TREATMENT

Interventions

NG-nitro-L-arginine

Intervention Type: DRUG

laboratory biomarker analysis

Intervention Type: OTHER

pharmacological study

Intervention Type: OTHER

computed tomography

Intervention Type: PROCEDURE

dynamic contrast-enhanced magnetic resonance imaging

Intervention Type: PROCEDURE

Eligibility Criteria

Exclusion Criteria

• No other condition which, in the investigator's opinion, would not make the patient a good candidate for the clinical trial
• No pacemakers or implantable cardioverter defibrillators (for patients enrolled in the expanded cohort study only)
• No metal fragments in the eyes, shrapnel, or bullet injuries (for patients enrolled in the expanded cohort study only)

PRIOR CONCURRENT THERAPY:

• Recovered from all previous toxicities (except for alopecia or certain Grade 1 toxicities that, in the opinion of the investigator and the Drug Development Office, should not exclude the patient)
• At least 6 weeks since prior endocrine therapy

• Stable therapy allowed if there has been no changes to the therapy within six weeks prior to treatment with L-NNA
• At least 6 weeks since prior major surgery (for patients enrolled in the expanded cohort study only)
• At least 4 weeks since prior radiotherapy (except for control of bone pain outside of the investigation site for CT evaluation), immunotherapy, or chemotherapy (6 weeks for nitrosoureas and mitomycin C)
• No prior heart or brain surgery (for patients enrolled in the expanded cohort study only)
• No major thoracic or abdominal surgery from which the patient has not yet recovered
• No concurrent drugs known to affect vascular tone (e.g., angiotensin-converting enzyme inhibitors or nitrates)
• No concurrent anticoagulants (1 mg warfarin for central line maintenance is acceptable during the trial) or anti-hypertensives
• At least 72 hours since prior non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase 2 (COX2) inhibitors
• No concurrent participation or plan to participate in another interventional clinical trial

• Participation in an observational trial is acceptable
• At least 14 days since prior and no concurrent medicines known to prolong QTc, including domperidone

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cancer Research UK

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter J. Hoskin, MD

Role: PRINCIPAL_INVESTIGATOR

Mount Vernon Cancer Centre at Mount Vernon Hospital

Locations

Mount Vernon Cancer Centre at Mount Vernon Hospital

Northwood, England, United Kingdom

Countries

United Kingdom

Other Identifiers

CRUK-CR0709-11

Identifier Type: -

Identifier Source: secondary_id

EUDRACT-2009-013621-42

Identifier Type: -

Identifier Source: secondary_id

CDR0000697500

Identifier Type: -

Identifier Source: org_study_id