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