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.
- 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.
- To determine the correlation between plasma concentration of L-NNA and toxicity and
- To further determine the effects of nitric oxide synthase (NOS) inhibition on tumor
- To determine the pharmacokinetics of L-NNA.
- To determine the safety profile of L-NNA.
- To evaluate the potential pharmacodynamic effect of NOS inhibition on angiogenesis.
- To evaluate the effect of L-NNA on circulating NOS levels.
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).
Minimum age: 18 Years.
Maximum age: N/A.
- 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
- 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
- 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
- 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
- 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
- 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
- Participation in an observational trial is acceptable
- At least 14 days since prior and no concurrent medicines known to prolong QTc,