A Phase I Trial of NG-Nitro-L-Arginine (L-NNA), a Nitric Oxide Synthase Inhibitor, Given as a Single Intravenous Infusion Over 10 Minutes in Patients With Advanced Solid Tumors
A Phase I Trial of NG-Nitro-L-Arginine (L-NNA), a Nitric Oxide Synthase Inhibitor, Given as a Single Intravenous Infusion Over 10 Minutes in Patients With Advanced Solid Tumors
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
Secondary
Tertiary
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.
DISEASE CHARACTERISTICS:
Histologically or cytologically confirmed advanced solid tumor
Disease assessable by DCE-CT
Disease assessable by DCE-MRI (patients enrolled in the expanded cohort study only)
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:
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
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
At least 14 days since prior and no concurrent medicines known to prolong QTc, including domperidone