Clinical trial NCT02844387: Supplementation of L-arginine in Patients With Non-resectable Brain Metastases
Official title: Oral L-arginine Supplementation in Patients With Non-resectable Brain Metastases Treated With Radiation Therapy With Palliative Intent
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Unresectable Multiple Brain Metastases
Keywords: cancer
brain
arginine
radiation
Lead sponsor: Instituto de Oncología Ángel H. Roffo
Sponsor class: OTHER
First posted: 2016-07-26
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: This study evaluates the nutritional supplement arginine as supportive measure for patients with unresectable metastatic brain tumors that receive radiation therapy with palliative intent

Detailed description: Brain metastasis, the most common intracranial tumor, is associated with neurological disability and short survival time. For selected patients this outcome can be improved by achieving greater local control. Virtually all cancer patients with brain metastases receive radiotherapy; a majority as part of their primary treatment while others in connection with surgery or palliation. Agents that increase the sensitivity of cancer cells to radiation may improve the control of the disease. Previous data indicates that arginine supplementation can modify the metabolism of cancer and immune cells making tumors more susceptible to standard treatments liked radiation. In this phase 1/2 comparative study the investigators will investigate whether 10 mg of arginine oral supplementation (compared to placebo administration) administered twice a day prior to the radiation therapy can modify tumor metabolism, immune response and effect of radiation. The primary end-points are safety and toxicity of arginine, quality-of-life and clinical response. The secondary end-points are imaging response and neurological progression-free survival. Additional exploratory end-points include intensity of radiation administered, effects on tumor metabolism by magnetic resonance spectroscopy, immune response by cytokine pattern in serum, body composition and nutritional parameters , overall survival and progression free survival

Eligibility criteria: Patients with pathology-confirmed diagnostic of solid cancer and measurable brain metastases by CT scan and/or MRI

Inclusion Criteria:

* Unresectable criteria by neurosurgeon
* Recursive partitioning analysis (RPA) -Radiation Therapy Oncology Group (RTOG) class II (Karnofsky's performance score ≥ 70 and extracranial metastases and/or non-controlled primary tumor)
* Measurable brain lesion/s by contrast-enhanced CT or MRI
* Absolute granulocyte count more or equal than 2000/mm3
* Hemoglobin more or equal than 9 g/L (patients with lower levels were transfused before the randomization)
* Normal renal laboratory (serum creatinine \<1.5 mg/dL and 24-h creatinine clearance \>60 mL/min)
* Normal hepatic function (aspartate aminotransferase and alanine aminotransferase \<2.5 times the upper limit of normal)
* Stable body weight and composition for at least one month prior enrollment

Exclusion Criteria:

* Prior treatment for brain metastases and/or brain tumor.
* Primary brain tumor
* Hematologic malignancies
* Solid tumors of germinal origin
* Contraindication for external radiation therapy.
* Allergy to L-arginine.

Primary outcomes:
measure: Change from baseline of the scoring form NCI CTCAE v3 for detecting and quantifying potential adverse events
timeFrame: Baseline and thereafter every 7 days starting from day 1 of L-arginine or placebo administration and through study completion, an average of 1 year
measure: Change from baseline of quality of life questionnaire
timeFrame: Baseline and thereafter every 7 days starting from day 1 of L-arginine or placebo administration and through study completion, an average of 1 year
measure: Change from baseline in signs and symptoms of neurological disease
timeFrame: Baseline and at 4 weeks counted from the last day of treatment
Secondary outcomes:
measure: Imaging response
timeFrame: One month after the last day of radiation and one month after the first response assessment
measure: Neurological progression-free survival
timeFrame: Time with no radiological or symptomatic progression counted from the first of radiation therapy until the day of first documented neurological progression or date of death from any cause, whichever came first, assessed up to 50 months
Other outcomes:
measure: Intensity of radiation administered
timeFrame: From the first of radiation therapy through study completion, an average of 1 year
measure: effects on tumor metabolism by magnetic resonance spectroscopy
timeFrame: Before and one hour after the first dose of L-arginine (or placebo) administration without radiation therapy
measure: Change from baseline in cytokine pattern in serum
timeFrame: Before treatment (baseline), at 4 weeks after the last of treatment and at 8 weeks after the last of treatment
measure: Change from baseline in body weight
timeFrame: Baseline and thereafter every 7 days starting from day 1 of L-arginine or placebo administration and through study completion, an average of 1 year
measure: Progression free survival
timeFrame: Time with no radiological or symptomatic progression in any site of disease counted from the first of radiation therapy until the day of first documented disease progression or date of death from any cause, whichever came first, assessed up to 50 months
measure: Overall survival
timeFrame: Survival time counted from the first of radiation therapy until the date of death from any cause or lost of follow-up, assessed up to 50 months
Locations:
Study officials:
affiliation: Instituto de Oncología Ángel H. Roffo
name: Alfredo H Navigante, MD, Phd
role: PRINCIPAL_INVESTIGATOR
References:
citation: Castillo L, Beaumier L, Ajami AM, Young VR. Whole body nitric oxide synthesis in healthy men determined from [15N] arginine-to-[15N]citrulline labeling. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11460-5. doi: 10.1073/pnas.93.21.11460.
citation: Cho-Chung YS, Clair T, Bodwin JS, Berghoffer B. Growth arrest and morphological change of human breast cancer cells by dibutyryl cyclic AMP and L-arginine. Science. 1981 Oct 2;214(4516):77-9. doi: 10.1126/science.6269181.
citation: Bode-Boger SM, Boger RH, Galland A, Tsikas D, Frolich JC. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol. 1998 Nov;46(5):489-97. doi: 10.1046/j.1365-2125.1998.00803.x.
citation: Kang K, Shu XL, Zhong JX, Yu TT. Effect of L-arginine on immune function: a meta-analysis. Asia Pac J Clin Nutr. 2014;23(3):351-9. doi: 10.6133/apjcn.2014.23.3.09.
citation: Cerchietti LC, Bonomi MR, Navigante AH, Castro MA, Cabalar ME, Roth BM. Phase I/II study of selective cyclooxygenase-2 inhibitor celecoxib as a radiation sensitizer in patients with unresectable brain metastases. J Neurooncol. 2005 Jan;71(1):73-81. doi: 10.1007/s11060-004-9179-x.