Immune checkpoint inhibitors (ICI) have revolutionized the management of advanced cancers. However, most rare cancers have been excluded from this progress due to the lack of clinical trials involving these diseases. After the standard first-line treatment, there are no other validated treatments for most of them. The management of these patients in ≥ 2nd line treatment relies on historic poorly effective regimens. This creates an inequity between patients with frequent cancers beneficiating from medical progresses and approvals of innovative drugs, and patients with rare cancers are still treated with old and toxic drugs. Few available data on case reports and early phase studies indicate a beneficial role of the immunotherapy in rare cancers. The investigators assume that the combination of Domvanalimab and Zimberelimab is more effective than historical standard treatments in patients with 5 types of advanced rare cancers, after failure of at least one line of standard treatment in the advanced setting: * Cohort 1: Peritoneal Mesotheliomas (PM) * Cohort 2: Gestational Trophoblastic Tumors (GTT) * Cohort 3: B3 Thymomas and Thymic Carcinomas (TET) * Cohort 4: Refractory Thyroid Carcinomas (ATC) * Cohort 5: GEP-NET and carcinoid tumors (GEP-NET (Gastroenteropancreatic neuroendocrine tumors)/TCT (Thoracic carcinoid tumor)/UP-NET (Neuroendocrine tumor of unknown primary)) The primary objective is to assess the efficacy of the combination of Domvanalimab and Zimberelimab in terms of progression-free survival rate at 24 weeks (for cohorts 1,3,5), successful hCG (Human Chorionic Gonadotropin) normalisation rate at 24 weeks for cohort 2 and survival rate for cohort 4. The secondary objectives are to assess the efficacy of the combination of anti-TIGIT (T cell Immunoreceptor with Ig and ITIM domains) and anti-PD-1 (Programmed Death-1) immunotherapies in terms of overall response rate, progression-free survival (cohort 1-3 and 5), resistance-free survival (cohort 2), overall survival (cohorts 1-3 and 5), duration of the response (cohorts 1-3 and 5); and to assess the tolerability of the doublet of immunotherapy in terms of adverse events. Patients will be treated until disease progression or alternatively 2 years in case of complete response (upon discussion with the coordinator of the study, the coordinator of the cohort and the investigator), unacceptable toxicity, or death. At the end of treatment, patients will be followed up for at least 1 year. IMMUNORARE5 is composed of five independent open-label national multicenter single-arm phase II trials, sponsored by Lyon University Hospital, led in collaboration with the corresponding French national reference centers, with a centralized coordination by a dedicated team. Each phase II trial is designed as a two-stage Simon design, with early termination for futility. For each cohort, a null hypothesis (H0) and an alternative hypotheses (H1) regarding the percentages of patients with success has been defined, with 5% one-sided alpha level and 80% power. The trial will be conducted in 15 French Centers with an inclusion period of 36 months
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
154
Patients will be treated with intravenous Domvanalimab at flat dose of 1200 mg + intravenous Zimberelimab at flat dose of 360 mg, administered every 3 weeks (Q3W, one cycle = 3 weeks).
Patients will be treated with intravenous Domvanalimab at flat doses of 1600 mg + intravenous Zimberelimab at flat dose of 480 mg, administered every 4 weeks (Q4W), together with an induction treatment of intravenous FOLFOX-4 (Oxaliplatin 85 mg/m2 IV, L-folinic acid 200 mg/m2 IV, and fluorouracil 400 mg/m2 IV bolus on Day 1, fluorouracil 2400 mg/m2 IV continuous infusion over 46-48 hours starting on Day 1) given every 2 weeks, for 4 months (one cycle = 4 weeks).
Institut de Cancerologie de l'Ouest , medical oncology department
Angers, France
NOT_YET_RECRUITINGInstitut Bergonié, medical oncology department
Bordeaux, France
NOT_YET_RECRUITINGHospices Civils de Lyon, Thoracic Oncology Department, Louis Pradel Hospital
Bron, France
RECRUITINGCentre Hospitalier Universitaire de Lille, medical oncology department
Lille, France
NOT_YET_RECRUITINGHospices Civils de Lyon, Medical Oncology Department, Edouard Herriot Hospital
Lyon, France
RECRUITINGAP-HM, TIMONE Hospital, medical oncology department
Marseille, France
NOT_YET_RECRUITINGInstitut Paoli-Calmettes Marseille, medical oncology department
Marseille, France
NOT_YET_RECRUITINGInstitut Régional du Cancer de Montpellier, medical oncology department
Montpellier, France
NOT_YET_RECRUITINGInstitut Curie, thoracic oncology department
Paris, France
NOT_YET_RECRUITINGAP-HP, Tenon Hospital, medical oncology department
Paris, France
NOT_YET_RECRUITING...and 5 more locations
Progression-free survival rate (cohort 1, 3 and 5)
Proportion of patients alive without disease progression at 24 weeks (in %). Progression is defined as followed: * Cohort 1: clinical progression OR radiological progression based on modified RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria * Cohort 3 and 5: radiological progression based on RECIST 1.1 criteria
Time frame: At 24 weeks after the start of study treatments
Successful hCG normalization rate (cohort 2)
Proportion of patients experiencing a successful hCG-normalization within 24 weeks while on study treatment (in percent). The hCG normalization is defined as a hCG value that reach the institutional normal threshold .
Time frame: At 24 weeks after the start of study treatments
Survival rate (cohort 4)
Proportion of patients alive at 24 weeks (percent).
Time frame: At 24 weeks after the start of study treatments
Overall response rate (cohorts 1, 3, 4 and 5)
Overall response rate defined as the proportion of patients experiencing complete or partial radiological response as the best radiological tumor response on the study period according to RECIST 1.1 for cohorts 3-5 and mRECIST for cohort 1.
Time frame: Through treatment period, an average of 1 year
Progression-free survival (cohorts 1, 3, 4 and 5)
Progression-free survival (PFS) defined as the time elapsed between inclusion and disease progression/death whichever occurs first, according to RECIST criteria (cohorts 3-5) or according to mRECIST criteria (cohort 1). Patients alive without progression will be censored at the last date of imaging assessment
Time frame: Through study completion (maximum 6 years and 11 month)
Resistance-free survival (cohort 2).
Resistance-free survival (RFS) calculated as the time elapsed between inclusion and disease resistance defined as the date of subsequent treatment start for lack of efficacy of study treatment (cohort 2). Patients without resistance will be censored at the date of last news. Disease resistance is defined as a rise (i.e ≥ 20% rise between 2 assays twice in three consecutive weekly assays) or a plateau (i.e. one or more of a ≤ 10% decrease between two assays three time in four consecutive weekly assays) in the hCG level.
Time frame: Through study completion (maximum 6 years and 11 month)
Overall survival (cohorts 1, 2, 3 and 5)
Overall survival defined as the time elapsed between inclusion and patients death regardless of the cause. Patients alive will be censored at the last date of last news.
Time frame: Through study completion (maximum 6 years and 11 month)
Duration of response (cohorts 1, 3, 4 and 5)
Duration of response defined as the delay (in days) between overall response and progression or death whichever occurs first.
Time frame: Through study completion (maximum 6 years and 11 month)
Tolerability : Adverse events
Tolerability of the combination of Domvanalimab and Zimberelimab will be assessed by a description of the adverse events (SAE, AE related to study treatment, AE of special interest) according to CI-CTCAE v5 criteria.
Time frame: From patient inclusion, until 5 months after the end of treatment (i.e. an average of 17 months)
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