Durvalumab Alone or With Tremelimumab in Refractory Germ Cell Tumors

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Brief Title

Durvalumab Alone or With Tremelimumab in Refractory Germ Cell Tumors

Official Title

An Open Label, Randomized, Phase 2 Study of the Anti-Programmed Death-Ligand 1 (PD-L1) Durvalumab, Alone or in Combination With Tremelimumab, in Patients With Advanced and Relapsed Germ Cell Tumors

Brief Summary

      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).
    

Detailed Description

      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).
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Objective response-rate

Secondary Outcome

 Overall survival

Condition

Germ Cell Tumor

Intervention

Durvalumab

Study Arms / Comparison Groups

 Durvalumab
Description:  Durvalumab, 1500 mg IV, q4 weeks, until disease progression or onset of unacceptable toxicity

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

36

Start Date

February 1, 2017

Completion Date

December 6, 2019

Primary Completion Date

December 6, 2019

Eligibility Criteria

        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.
      

Gender

Male

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

andrea necchi, MD, , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT03081923

Organization ID

INT123-16


Responsible Party

Sponsor

Study Sponsor

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Collaborators

 AstraZeneca

Study Sponsor

andrea necchi, MD, Principal Investigator, Fondazione IRCCS Istituto Nazionale tumori - Milano


Verification Date

May 2021