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

NCT01324115 | Terminated Phase 1

• 3 other identifiers: CDR0000697500CRUK-CR0709-11EUDRACT-2009-013621-42
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Keywords

unspecified adult solid tumor, protocol specific

Outcome Measures

Primary Outcomes (3)

• 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

Secondary Outcomes (6)

• 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)

Interventions

NG-nitro-L-arginine DRUG

laboratory biomarker analysis OTHER

pharmacological study OTHER

computed tomography PROCEDURE

dynamic contrast-enhanced magnetic resonance imaging PROCEDURE

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed advanced solid tumor * Refractory to conventional treatment or for which no conventional therapy exists or therapy is declined by the patient * Disease assessable by DCE-CT * Must be a minimum size of 2 cm measured on the longest axis * Disease assessable by DCE-MRI (patients enrolled in the expanded cohort study only) * Must be in sites that do not move with respiration or vascular pulsation unless this can be compensated for * No squamous cell carcinomas PATIENT CHARACTERISTICS: * WHO performance status 0-1 * Life expectancy ≥ 12 weeks * Hemoglobin ≥ 10.0 g/dL * Absolute neutrophil count ≥ 1.5 x 10\^9/L * Platelet count ≥ 100 x 10\^9/L * Serum bilirubin ≤ 1.5 times upper limit of normal (ULN) * ALT/AST ≤ 2.5 times ULN (≤ 5 times ULN if due to tumor) * Glomerular filtration rate ≥ 50 mL/min (uncorrected) assessed by \^51Cr-EDTA * INR ≤ 1.4 sec * Serum potassium normal * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use 2 forms of highly effective contraception (1 for men) 4 weeks prior to, during, and for 6 months after completion of study therapy * No post-radiation bowel symptoms of any grade following radiotherapy within the abdomen or pelvis * No high medical risk due to non-malignant systemic disease, including active uncontrolled infection * No known serologically positive hepatitis B or C or HIV * No previous or suspected allergy to imaging contrast medium * No heart disease, including any of the following: * History of angina (including Prinzmetal angina) or myocardial infarction (including pathological Q waves on 12-lead ECG ) * History of heart failure * History of hemodynamically significant arrhythmia (not including atrial fibrillation with well-controlled ventricular rate) * Cardiomyopathy (including hypertrophic cardiomyopathy, dilated cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy) * Hemodynamically significant valvular abnormalities (including aortic valve stenosis) * Congenital heart disease * LVEF ≥ 50% by ECHO or MUGA scan * No QT prolongation (QTc ≥ 470 msec for women and ≥ 450 for men) or any other clinically significant ECG abnormality * No peripheral arterial disease (including all diseases caused by obstruction of large arteries in arms and legs, abdominal aortic aneurism, previous aortic dissection, or connective tissue disease resulting in thoracic aortic dilation, such as Marfan syndrome) * No current hypertension, defined as BP consistently greater than 140/90 mm Hg or the requirement for anti-hypertensive drug treatment * No history of thromboembolic disease or platelet/clotting disorders * No history of cerebrovascular disease (e.g., transient ischemic attack or stroke) * No clinically significant history of renal or hepatic impairment * No diabetes mellitus * Able to tolerate and comply with imaging protocol (patients with high levels of pain, urinary incontinence, or claustrophobia should be excluded) * 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

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Cancer Research UK: lead

Study Sites (1)

Mount Vernon Cancer Centre at Mount Vernon Hospital

Northwood, England, HA6 2RN, United Kingdom

Location

MeSH Terms

Interventions

Nitroarginine

Intervention Hierarchy (Ancestors)

Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino

Study Officials

• Peter J. Hoskin, MD

  Mount Vernon Cancer Centre at Mount Vernon Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Purpose: TREATMENT
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 25, 2011
• First Posted: March 28, 2011
• Study Start: April 1, 2011
• Primary Completion: September 1, 2012
• Study Completion: September 1, 2012
• Last Updated: March 5, 2015

Record last verified: 2015-03

Locations

GB (1)