Supplementation of L-arginine in Patients With Non-resectable Brain Metastases

Oral L-arginine Supplementation in Patients With Non-resectable Brain Metastases Treated With Radiation Therapy With Palliative Intent

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

Study Overview

• Status: Completed
• Conditions: Unresectable Multiple Brain Metastases
• Intervention / Treatment: Dietary supplement: L-arginine hydrochloride solution; Other: Placebo

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

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arginine; In the Arginine arm patients will receive 10 mg of L-arginine hydrochloride solution oral supplementation (in 200 ml of flavoured drinking water solution) administered twice a day prior to the radiation therapy fraction	Dietary supplement: L-arginine hydrochloride solution; Patients with unresectable brain metastases from solid tumors that are candidates from twice-daily fractionated radiation therapy will be randomized to receive either oral arginine supplementation one-hour prior to each fraction of radiation. Radiation therapy consist in whole-brain treated by two lateral fields to a total dose of 32 Gy in 20 fractions of 1.6 Gy each two times a day with a 6 hours interval between treatments (10 days), followed by a 22.4 Gy boost over the evident lesions with the same fractionation schedule (7 days). The spinal cord dose will be limited to 40 Gy; Other Names: L-arginine; Arginine; L-arginine monohydrochloride
Placebo Comparator: Placebo; In the Placebo arm patients will receive 200 ml of flavoured drinking water oral solution administered twice a day prior to the radiation therapy fraction	Other: Placebo; Patients with unresectable brain metastases from solid tumors that are candidates from twice-daily fractionated radiation therapy will be randomized to receive oral placebo one-hour prior to each fraction of radiation. Radiation therapy consist in whole-brain treated by two lateral fields to a total dose of 32 Gy in 20 fractions of 1.6 Gy each two times a day with a 6 hours interval between treatments (10 days), followed by a 22.4 Gy boost over the evident lesions with the same fractionation schedule (7 days). The spinal cord dose will be limited to 40 Gy; Other Names: flavoured drinking water solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline of the scoring form NCI CTCAE v3 for detecting and quantifying potential adverse events	NCI CTCAE v3 form will be completed baseline and every 7 days starting from day 1 of L-arginine or placebo administration thereafter. This form will detect adverse events including clinical laboratory alterations associated with the administration of of L-arginine or placebo including those that may exacerbate the adverse events expected from the radiation therapy	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
Change from baseline of quality of life questionnaire	Quality of life questionnaire with assessment of the Karnofsky's index will be completed baseline and every 7 days starting from day 1 of L-arginine or placebo administration thereafter	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
Change from baseline in signs and symptoms of neurological disease	Signs and symptoms of neurological disease will be evaluated by caregiver and investigator according to response criteria evaluation guidelines. Clinical response will be considered as the changes in signs and symptoms that occur between baseline state and 30 days counted from the last day of treatment	Baseline and at 4 weeks counted from the last day of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Imaging response	The investigators will follow the R.E.C.I.S.T. criteria for imaging and overall response evaluation	One month after the last day of radiation and one month after the first response assessment
Neurological progression-free survival	The investigators will follow the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for imaging (CT and MRI) response evaluation based on measurable disease, assessed up to 50 months	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intensity of radiation administered	Actual daily and total dose of radiation administered as fractional product of the planned (proposed) daily and total dose of radiation	From the first of radiation therapy through study completion, an average of 1 year
effects on tumor metabolism by magnetic resonance spectroscopy	Before and one hour after the first dose of L-arginine (or placebo) administration without radiation therapy	Before and one hour after the first dose of L-arginine (or placebo) administration without radiation therapy
Change from baseline in cytokine pattern in serum	The investigators will determine levels of circulating (serum) cytokines in a sub-group of patients from both arms to determine immune effects of L-arginine. Comments [5] :	Before treatment (baseline), at 4 weeks after the last of treatment and at 8 weeks after the last of treatment
Change from baseline in body weight	Body weight (kg) will be determined baseline and every 7 days starting from day 1 of L-arginine or placebo administration thereafter. The reported value will be number of patients with change of 10% or higher in any value at any time point from baseline	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
Progression free survival	The investigators will follow the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for imaging (CT and MRI) response evaluation based on measurable disease assessed up to 50 months	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
Overall survival	Survival time counted from the day 1 of radiation therapy to death or lost of follow-up, assessed up to 50 months	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

Collaborators and Investigators

• Sponsor: Instituto de Oncología Ángel H. Roffo
• Investigators: Principal Investigator: Alfredo H Navigante, MD, Phd, Instituto de Oncología Ángel H. Roffo

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2004
• Primary Completion (Actual): November 1, 2007
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: June 21, 2016
• First Submitted That Met QC Criteria: July 21, 2016
• First Posted (Estimate): July 26, 2016

Study Record Updates

• Last Update Posted (Estimate): July 28, 2016
• Last Update Submitted That Met QC Criteria: July 27, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: cancer; radiation; brain; arginine
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Pharmaceutical Solutions
• Other Study ID Numbers: LABM-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes