Background: Conventional serum tumor markers for malignant germ cell tumors (MGCTs) have limited performance characteristics, especially in non-secreting histologies such as embryonal carcinoma or seminoma. Growing evidence has shown circulating microRNAs (miRNA), particularly miR-371a-3p, to be a more sensitive biomarker, elevated across all MGCT subtypes except teratoma. However, studies to date have been retrospective or non-randomized. If confirmed in prospective clinical trials, circulating miRNA may have the potential to become a universal MGCT biomarker, aiding in diagnosis, prognostication, relapse detection, and prediction of viable disease after chemotherapy. One of the key objectives of AGCT1531 is to test the performance characteristics of circulating miRNA in children, adolescents, and young adults (AYAs) with low-risk and standard-risk MGCTs. AGCT1531 is unique among MGCT trials for including patients across all ages, genders, sites, histologies, and treatments. Methods: AGCT1531 is a prospective clinical trial sponsored by the Children’s Oncology Group (COG), co-designed with United Kingdom, Japan, and India, and supported by all NCTN groups. It has three strata for low-risk tumors, defined as stage I tumors treated with surgery followed by active surveillance: non-seminomatous tumors of any site; testis seminomas; and ovarian immature teratomas. Patients of any age are eligible. Target accruals are 432, 277, and 212 patients, respectively. Key endpoints include overall and event-free survival and longitudinal measurements of circulating miRNA. Serum is collected at intervals aligned with NCCN follow-up guidelines to minimize testing burden. For patients over 11 years old with stage I non-seminomatous tumors, serum is collected at enrollment, months 4, 8, 12, 18, and 24; and (if applicable) at relapse. The trial also has two strata for standard-risk MGCTs: SR1 for children under age 11 years and SR2 for AYAs age 11-25 years. Target accruals are 518 and 595 patients, respectively. Both strata are randomized trials of cisplatin-based versus carboplatin-based regimens, with carboplatin used at doses higher than those previously tested in adult MGCTs. Serum collection is recommended at enrollment, months 6, 12, 18, 24, and (if applicable) at relapse. AGCT1531 was activated in August 2017. The low-risk seminoma stratum was added on November 2021. The trial is currently open at 466 sites across seven countries. For adults with testicular GCTs, data from AGCT1531 can contribute to joint analyses of parallel trials evaluating circulating miR-371a-3p in this population: SWOG1823, ANZUP1906 (CLIMATE), and ANZUP P3BEP. Together, this suite of trials will help validate the utility of circulating miRNA and set the stage for future investigations where miRNA is used to influence real-time management decisions for patients with MGCTs. Clinical trial information: NCT03067181.