Anaplastic Thyroid Carcinomas, Carcinoid Tumor, Gastroenteropancreatic Neuroendocrine Tumor, Gestational Trophoblastic Tumor, Peritoneal Mesothelioma, Thymic Carcinoma
Conditions
Keywords
Rare cancers, Immunotherapy, Peritoneal mesothelioma, Gestational Trophoblastic Tumors, Thymic Carcinomas, Anaplastic Thyroid Carcinomas, Gastroenteropancreatic neuroendocrine tumors (GEP-NET), Carcinoid tumors
Brief summary
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: Thymic Carcinomas (TC) * 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
Interventions
DRUGDOMVANALIMAB + ZIMBERELIMAB
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).
DRUGDOMVANALIMAB + ZIMBERELIMAB + FOLFOX-4
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).
Sponsors
Hospices Civils de Lyon
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
General inclusion criteria for all cohorts * Histologically proven advanced solid tumors that progressed/resisted after minimum one line of standard systemic treatment, or resisted during the first-line of treatment * Participation in IMMUNORARE5 trial testing DOMVANALIMAB and ZIMBERELIMAB, validated by a multidisciplinary tumor board recognized by the national reference center, or validated by at least one national coordinator of the cohort * No indication of curative surgery for this disease at inclusion (For cohort 1 only (peritoneal mesothelioma), debulking surgery could be considered after minimum 6 months of study treatment in the case of important tumor response) * Evaluable lesions (target or non-target lesions) for radiological response according to RECIST 1.1 (cohorts 3, 4, 5), or mRECIST (cohort 1), or assessable for biological response with serum hCG (cohort 2) * Patients older than 18 years * Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 * Patients must be willing to provide an archival tumor tissue block or slides, or undergo procedure to obtain a new biopsy in absence of medical contraindication (If either a fresh biopsy or archival material is not available, patient inclusion has to be discussed and validated with the coordinators of the cohort) * Patients with adequate bone marrow function measured within 28 days prior to administration of study treatment: * Absolute Neutrophil count \> 1.5 x 109/L * Platelets count ≥ 100 X 109/L * Hemoglobin ≥ 9.0 g/dL * Patients with adequate renal function: Calculated creatinine clearance ≥ 30 ml/min according to the local institutional standard method (MDRD preferred) * Serum bilirubin ≤ 1.5 x UNL (Upper Normal Limit) (\< 3 x UNL for patients with known Gilbert's syndrome), AST/ALT ≤ 2.5 X UNL (≤ 5 X UNL for patients with liver metastases) * Life expectancy ≥ 16 weeks * Highly effective contraception for men and childbearing age women. Breastfeeding is prohibited during the participation in IMMUNORARE trial * Signed informed consent prior to participating in any study related procedures. * Patients affiliated to the French social security system or equivalent * Patient able to comply with the protocol, including follow-up visits and examinations Specific inclusion criteria for each cohort: * Cohort 1 (Peritoneal mesothelioma) * Histologically-confirmed malignant peritoneal mesotheliomas (epithelioid, sarcomatoid, or biphasic) * Evidence of progression or recurrence after at least one line of platinum based-chemotherapy regimen (Previous treatment with pressurized intra-peritoneal aerosol chemotherapy (PIPAC) is authorized) * Cohort 2 (Gestational trophoblastic tumors) * Gestational trophoblastic tumors (including placenta site trophoblastic tumors and epithelioid carcinomas) histologically or cytologically-confirmed by a referent pathologist of the French National Center for Gestational Trophoblastic Diseases (In exceptional cases, the patients with typical clinical presentation of gestational trophoblastic tumors with elevated hCG, and experiencing resistance to polychemotherapy, can be included even if the gestational trophoblastic tumor was not histologically or cytologically-confirmed, provided that the French gestational trophoblastic center has validated the case and the inclusion of the patient) * Evidence of resistance or relapse after at least one line of polychemotherapy (e.g. EP low dose, BEP regimen, EMA-CO regimen …) * Cohort 3 (Thymic carcinomas) * Thymic carcinoma, histologically confirmed by a referent pathologist of the RYTHMIC network * Evidence of progression or relapse after at least one line of platinum-based chemotherapy * Cohort 4 (Anaplastic thyroid carcinomas) * Anaplastic thyroid carcinoma with non-mutated or mutated B-RAF, histologically or cytologically-confirmed by a referent pathologist of the Tuthyref network * In B-RAF non-mutated anaplastic thyroid carcinomas: Persistent disease at the first evaluation after chemoradiation or disease progression/relapse after the end of chemoradiation * In B-RAF mutated anaplastic thyroid carcinoma: evidence of progression after a standard B-RAF inhibitor * Cohort 5 (GEP-NET and carcinoid tumors) * Histologically or cytologically-confirmed well-differentiated neuroendocrine tumor (WHO classification as NET G1, G2 or G3), or typical/atypical carcinoid tumor (according to WHO classification for thoracic NETs), from gastroenteropancreatic, thoracic (thymus or lung) or unknown primary origin * Indication of oxaliplatin-based regimen treatment * Evidence of progression or relapse after at least 1 line of systemic treatment, such as somatostatine analog, or targeted agents such as everolimus or sunitinib, or chemotherapy without oxaliplatin, or peptide receptor radionuclide therapy.
Exclusion criteria
General
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival rate (cohort 1, 3 and 5) | At 24 weeks after the start of study treatments | 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 |
| Successful hCG normalization rate (cohort 2) | At 24 weeks after the start of study treatments | 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 . |
| Survival rate (cohort 4) | At 24 weeks after the start of study treatments | Proportion of patients alive at 24 weeks (percent). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (cohorts 1, 3, 4 and 5) | Through treatment period, an average of 1 year | 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. |
| Progression-free survival (cohorts 1, 3, 4 and 5) | Through study completion (maximum 6 years and 11 month) | 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 |
| Resistance-free survival (cohort 2). | Through study completion (maximum 6 years and 11 month) | 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. |
| Overall survival (cohorts 1, 2, 3 and 5) | Through study completion (maximum 6 years and 11 month) | 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. |
| Duration of response (cohorts 1, 3, 4 and 5) | Through study completion (maximum 6 years and 11 month) | Duration of response defined as the delay (in days) between overall response and progression or death whichever occurs first. |
| Tolerability : Adverse events | From patient inclusion, until 5 months after the end of treatment (i.e. an average of 17 months) | 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. |
Countries
France
Outcome results
None listed