EAU 2017: APACHE: An open label, randomized, phase 2 study of the anti-Programmed Death-Ligand 1 (PD-L1) Durvalumab (D, MEDI4736), alone or in combination with Tremelimumab (T), in patients (pts) with advanced germ cell tumors (GCT)

London, England (UroToday.com) The prognosis of advanced germ cell tumor (GCT) patients who have failed multiple chemotherapy regimens is quite dismal. PD-L1 is frequently expressed by immunohistochemistry (IHC) in GCT. Durvalumab is a monoclonal antibody that inhibits the binding of PD-L1. Tremelimumab, an anti-CTLA4 monoclonal antibody, is an immunomodulatory therapy. Combination immunotherapy has been shown to improve activity compared to monotherapy. We aimed to investigate the activity of Durvalumab, alone or in combination with Tremelimumab, in chemorefractory GCT.

This trial is an open-label, randomized, 3-stage, phase 2 study. Patients who have failed ≥2 prior chemotherapy regimens (including high-dose chemotherapy) will be randomized to receive one of the following: Durvalumab, 1.5 g via IV infusion every 4 weeks, for up to a total of 12 months (13 doses/cycles) alone or with Tremelimumab, 75 mg IV every 4 weeks, starting on week 0, for up to 4 months (4 doses/cycles).

Serum tumor markers, computed tomography and FDG-PET scans will be repeated every 8 weeks. The primary endpoint is the objective response-rate (ORR= complete response or partial response with normal markers). The null hypothesis is: ORR rate ≤10%, while H1: ORR ≥25%, with type I and II error defined at 10%.

In stage 1, 11 patients will be allocated in each arm. According to Gehan’s rule, the trial will be terminated whenever no response will be observed. In stage 2 - 29 additional patients will be added to each arm fulfilling stage 1 criteria. ORR in ≥7 pts will be required. In stage 3, patients from stage 1-2 of both arms will be retrospectively evaluated for PDL 1 IHC. In case of negative findings at the end of stage 2, if the target benefit is likely to occur only in PD-L1+ pts, further study prosecution in accordance with an enrichment strategy will be undertaken.

In particular, predictive power (PP) will be calculated assuming expansion of PD-L1+ cohorts up to a maximum of 60 pts. Each arm will be categorized as not promising (PP<30%) or promising (PP ≥30%). The promising one will enter the stage 3. Should both arms be judged promising, the one yielding ≥20% PP advantage will be selected; monotherapy will be preferred otherwise.

The trial has started recruiting patients on February 2017 and is expected to recruit the last patient in February 2020.

Presented by: Necchi A., Mariani L., Anichini A., Giannatempo P., Raggi D., Togliardi E, Calareso G., Nicolai N., Crippa F., Salvioni R.

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto
Twitter: @GoldbergHanan

at the #EAU17 -March 24-28, 2017- London, England