There are several studies that are enrolling currently, including AGCT 1531 and SWOG 1823. AGCT 1531 is a phase III study of active surveillance for adult and pediatric patients with germ cell tumors, with inclusion criteria of stage IA/IB seminoma/NSGCT, TanyN0M0S0. Patients will get standard surveillance imaging, labs, and follow-up per NCCN guidelines, as well as miR-371a-3p levels. This is an international trial with sites across North America, Australia, Europe, and Southeast Asia. The target accrual is 432 patients, with a current accrual of 198 and ahead of schedule.
Similarly, SWOG 1823 is a prospective observational cohort study to assess miRNA 371 for outcome prediction in patients with newly diagnosed germ cell tumors. Inclusion for this trial includes stage I-IIA seminoma/NSGCT, and patients are followed with standard surveillance imaging, as well as miR-371a-3p assays. Primary endpoints for S1823 are to establish the PPV of miR371 in predicting active germ cell tumors and to establish lead time (if any) of miRNA 371 expression versus conventional serum tumor markers/imaging to detect recurrence. The target accrual is ~1000 patients (powered to detect 100 NSGCT relapses) with a planned interim analysis at 50 recurrences to evaluate for efficacy. Currently, the trial has accrued ~30 patients. As Dr. Bagrodia notes, for both AGCT 1531 and SWOG 1823, these are complimentary trials with the main study objective to assess characteristics of miR-371a-3p for early-stage germ cell tumors. The plan is for cross-validation in the future and investigators can co-register for both trials.
A developing trial is the microRNA 371-driving trial in stage I NSGCT developing by the ECOG/ACRIN GCT working group. miRNAs in low stage disease decrease in circulation following orchiectomy and the presence of miR-371a-3p after orchiectomy is associated with 83% sensitivity and 96% specificity for identifying relapses.1 Nappi et al.2 looked at 25 patients with stage I GCT and found that the circulating miR-371a-3p test correctly identified all patients that ultimately recurred (1/25) and those that did not (24/25). As such, the trial design will be as follows:
The primary endpoint for this trial will be concordance of viable GCT in miRNA-371 positive patients, and secondary endpoints will be RFS in miR-371 patients, as well as RFS in all patients. Patients that are negative for miR-371 and in the surveillance arm will be observed per AUA guidelines. Two sample size assumptions are that there will be a 30% node-positive rate based on historical controls and a 70% node-positive rate in positive miRNA 371. A sample size of 18 patients with miRNA 371 positivity achieves 90% power to detect a difference of 40% using a two-sided exact binomial test with a significance level of 0.05. The trialists expect to screen 60 patients to obtain 18 patients with positive miRNA-371 status since it is expected that 30% of patients are miRNA positive. Recruitment is set to be targeted at 72 patients, considering a 20% dropout rate.
Additional trials include:
- PATRIOTISM: A phase II comparison of standard treatment approaches inoperable stage II seminoma incorporating serum miRNA
- PANTHER: Phase III Randomized trial of adaptive dose intense treatment for high-risk germ cell tumors
- Oral etoposide following HDCT for NSGCT: patients will be randomized to receive oral etoposide versus observation with the primary endpoint of PFS. Exploratory objectives will be to evaluate miR-371a-3p expression at the time of screening and to correlate miR-371a-3p with progression/relapse.
- miRNAs are poised to change the way patients are diagnosed, treated, and surveyed
- Ongoing and upcoming clinical trials address pressing questions regarding miRNAs in GCT patients
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC
References:
- Dieckmann KP, Radtke A, Geczi L, et al. Serum levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study. J Clin Oncol. 2019 Jun 1;37(16):1412-1423.
- Nappi L, Thi M, Lum A, et al. Developing a highly specific biomarker for germ cell malignancies: Plasma miR371 expression across the germ cell malignancy spectrum. J Clin Oncol. 2019 Nov 20;37(33):3090-3098.