loss of accrual

Background:

The prognosis of pts who have failed multiple chemotherapy (CT) regimens is quite dismal. PD-L1 is frequently expressed by immunohistochemistry (IHC) in germ cell tumors (GCT). D is a monoclonal antibody (mAb) that inhibits the binding of PD-L1. T, an anti-CTLA4 mAb, is an immunomodulatory therapy. Combination immunotherapy has shown improved activity compared to monotherapy. The investigators aimed to investigate the activity of D, alone or in combination with T, in chemorefractory GCT.

Trial Design:

This is an open-label, randomized, 3-stage, phase 2 study. Pts who have failed ≥2 prior CT regimens (including high-dose CT) will be randomized to receive one of the following: D, 1.5 g via IV infusion q4w, for up to a total of 12 months (13 doses/cycles) alone or with T, 75 mg IV q4w, starting on week 0, for up to 4 months (4 doses/cycles). Serum tumor markers, computed tomography and fluorodeoxyglucose positron emission tomography (FDG-PET) scans will be repeated q8 weeks. The primary endpoint is the objective response-rate (ORR=complete response or partial response with normal markers). H0: ORR rate ≤10%, H1: ORR ≥25%, type I and II error rates at 10%.

In stage 1, 11 pts will be allocated in each arm. According to Gehan's rule, the trial will be terminated whenever no response will be observed. 29 additional pts will be added to each arm fulfilling stage 1 criteria. ORR in ≥7 pts will be required. In stage 3, pts from stage 1-2 of both arms will be retrospectively evaluated for Programmed cell Death Ligand-1(PD-L1) IHC. The Ventana PD-L1 IHC assay will be used. 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. Details on the algorithm to be used for PD-L1 IHC in this study will be finalized (EudraCT number 2016-001688-35).

This is an open-label, randomized, 3-stage, phase 2 study. Pts who have failed ≥2 prior CT regimens (including high-dose CT) will be randomized to receive one of the following: D, 1.5 g via IV infusion q4w, for up to a total of 12 months (13 doses/cycles) alone or with T, 75 mg IV q4w, starting on week 0, for up to 4 months (4 doses/cycles).

Inclusion Criteria:

• Age ≥ 18 years
• Male of female gender.
• Histological or clinical diagnosis of GCT.
• Availability of archival tumor samples for local assessment (by immunohistochemistry) of PD-L1 expression.
• Either gonadal or extragonadal tumor primary.
• Failure of ≥2 prior chemotherapy regimens for metastatic disease (1-2 cycles of cisplatin, etoposide and bleomycin (PEB) or 1 cycle carboplatin area under the curve (AUC) 7 given in the adjuvant setting for clinical stage I disease will not be counted as prior lines).
• Failure of high-dose chemotherapy will be allowed.
• Brain metastases: patients who present with brain metastases as the sole site of disease relapse/progression are not allowed to enter the study. Otherwise, patients with metastatic disease including brain metastases will be allowed provided that they have been irradiated, are stable from at least 4 weeks, and a wash-out period from steroids has occurred (28 days).
• Subjects must provide written informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Adequate end-organ system function tests.
• See the study full protocol for durvalumab-specific and tremelimumab requirements.

Exclusion Criteria:

• Prior exposure to immune-mediated therapy, including but not limited to, other anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines.
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Patients with Grade <2 neuropathy will be evaluated on a case-by-case basis after consultation with the Principal Investigator.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included after consultation with the Principal Investigator.
• Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment.
• History of allogenic organ transplantation that requires use of immunosuppressive agents.
• Active or prior documented autoimmune or inflammatory disorders.
• Active infection including active tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
• Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy.