Abstract | IMPORTANCE: OBJECTIVE: DESIGN, SETTING, AND PARTICIPANTS: INTERVENTIONS: Randomization 2:1 to arginine deprivation ( ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti-ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography. RESULTS: Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, -1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. CONCLUSIONS AND RELEVANCE: TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01279967.
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Authors | Peter W Szlosarek, Jeremy P Steele, Luke Nolan, David Gilligan, Paul Taylor, James Spicer, Michael Lind, Sankhasuvra Mitra, Jonathan Shamash, Melissa M Phillips, Phuong Luong, Sarah Payne, Paul Hillman, Stephen Ellis, Teresa Szyszko, Gairin Dancey, Lee Butcher, Stephan Beck, Norbert E Avril, Jim Thomson, Amanda Johnston, Marianne Tomsa, Cheryl Lawrence, Peter Schmid, Timothy Crook, Bor-Wen Wu, John S Bomalaski, Nicholas Lemoine, Michael T Sheaff, Robin M Rudd, Dean Fennell, Allan Hackshaw |
Journal | JAMA oncology
(JAMA Oncol)
Vol. 3
Issue 1
Pg. 58-66
(Jan 01 2017)
ISSN: 2374-2445 [Electronic] United States |
PMID | 27584578
(Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)
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Chemical References |
- Biomarkers, Tumor
- Polyethylene Glycols
- Arginine
- Hydrolases
- ADI PEG20
- Argininosuccinate Synthase
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Topics |
- Aged
- Aged, 80 and over
- Arginine
(metabolism)
- Argininosuccinate Synthase
(blood)
- Biomarkers, Tumor
(blood, genetics)
- Citrullinemia
(blood, drug therapy, genetics, pathology)
- DNA Methylation
(genetics)
- Disease-Free Survival
- Endpoint Determination
- Female
- Humans
- Hydrolases
(administration & dosage)
- Lung Neoplasms
(blood, drug therapy, genetics, pathology)
- Male
- Mesothelioma
(blood, drug therapy, genetics, pathology)
- Mesothelioma, Malignant
- Middle Aged
- Polyethylene Glycols
(administration & dosage)
- Treatment Outcome
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