IMMUNORARE5: A National Platform of 5 Academic Phase II Trials Coordinated by Lyon University Hospital to Assess the Safety and the Efficacy of the IMMUNOtherapy With Domvanalimab + Zimberelimab Combination in Patients With Advanced RARE Cancers

NCT06790706 | Recruiting Phase 2 DMC

• 1 other identifier: 69HCL24_0656
• Study Type: interventional
• Target: 154
• Locations: 1 country
• Sites: 15

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: 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

Conditions

Peritoneal Mesothelioma; Gestational Trophoblastic Tumor; Thymoma and Thymic Carcinoma; Anaplastic Thyroid Carcinomas; Gastroenteropancreatic Neuroendocrine Tumor; Carcinoid Tumor

Keywords

Rare cancers; Immunotherapy; Peritoneal mesothelioma; Gestational Trophoblastic Tumors; Thymomas and Thymic Carcinomas; Anaplastic Thyroid Carcinomas; Gastroenteropancreatic neuroendocrine tumors (GEP-NET); Carcinoid tumors

Outcome Measures

Primary Outcomes (3)

• 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

  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 .

  At 24 weeks after the start of study treatments

• Survival rate (cohort 4)

  Proportion of patients alive at 24 weeks (percent).

  At 24 weeks after the start of study treatments

Secondary Outcomes (6)

• Overall response rate (cohorts 1, 3, 4 and 5)

  Through treatment period, an average of 1 year

• Progression-free survival (cohorts 1, 3, 4 and 5)

  Through study completion (maximum 6 years and 11 month)

• Resistance-free survival (cohort 2).

  Through study completion (maximum 6 years and 11 month)

• Overall survival (cohorts 1, 2, 3 and 5)

  Through study completion (maximum 6 years and 11 month)

• Duration of response (cohorts 1, 3, 4 and 5)

  Through study completion (maximum 6 years and 11 month)

Study Arms (5)

Cohort 1: Peritoneal mesotheliomas

EXPERIMENTAL

Patients will receive a combination of Domvanalimab and Zimberelimab.

Drug: DOMVANALIMAB + ZIMBERELIMAB

Cohort 2: Gestational trophoblastic tumors

EXPERIMENTAL

Patients will receive a combination of Domvanalimab and Zimberelimab.

Drug: DOMVANALIMAB + ZIMBERELIMAB

Cohort 3: B3 thymomas and thymic carcinomas

EXPERIMENTAL

Patients will receive a combination of Domvanalimab and Zimberelimab.

Drug: DOMVANALIMAB + ZIMBERELIMAB

Cohort 4: Anaplastic thyroid carcinomas

EXPERIMENTAL

Patients will receive a combination of Domvanalimab and Zimberelimab.

Drug: DOMVANALIMAB + ZIMBERELIMAB

Cohort 5: GEP-NET & carcinoid tumors

EXPERIMENTAL

Patients will receive a combination of Domvanalimab and Zimberelimab together with an induction treatment of intravenous FOLFOX-4.

Drug: DOMVANALIMAB + ZIMBERELIMAB + FOLFOX-4

Interventions

DOMVANALIMAB + ZIMBERELIMAB DRUG

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).

Cohort 1: Peritoneal mesotheliomas; Cohort 2: Gestational trophoblastic tumors; Cohort 3: B3 thymomas and thymic carcinomas; Cohort 4: Anaplastic thyroid carcinomas

DOMVANALIMAB + ZIMBERELIMAB + FOLFOX-4 DRUG

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).

Cohort 5: GEP-NET & carcinoid tumors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically proven advanced solid tumors that progressed/resisted after minimum one line of standard systemic treatment, or resisted during the first-line of treatment
• 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 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.
• 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

You may not qualify if:

• Previous treatment with immune checkpoint inhibitors (including anti-TIGIT, anti-PD1, anti-PD-L1, anti-CTLA4), or other types of immunotherapy.
• Active or prior documented autoimmune or immune-related disorders (Stevens-Johnson syndrome, immune-related myocarditis, immune-related pneumonitis, immune-related colitis, immune-related hepatitis, immune mediated dermatologic adverse reactions, immune-mediated nephritis). (The following are exceptions to this criterion: Patients with vitiligo or alopecia; Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; Any chronic skin condition that does not require systemic therapy; Patients without active disease and no treatment for the last 5 years may be included but only after consultation with the coordinator of the cohort)
• Medical condition that requires chronic systemic steroid therapy, or any other forms of immunosuppressive medication. (For example, patients with autoimmune disease that requires systemic steroids or immunosuppression agents should not to be included. Replacement therapy (eg., thyroxine, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.)
• Uncontrolled intercurrent illness, including but not limited to, congestive heart failure; respiratory distress; liver failure; allergy; psychiatric illness/social situations that would limit compliance with study requirement according to the investigator, or that substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• Patients with a second primary cancer, except for: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other hematological or solid cancers curatively treated with no evidence of disease for ≥ 3 years.
• All subjects with meningeal involvement.
• Untreated or symptomatic Central nervous system (CNS) metastases. (Patients are eligible if the following criteria are met:
• CNS lesions are asymptomatic and previously treated.
• Patient does not require ongoing steroid treatment
• Imaging demonstrates stability of disease 28 days from last treatment for CNS metastases.)
• Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 6 weeks from the last dose prior to study treatment (or at least 5 half-lives depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment with study drug.
• Treatment with other investigational agents prone to interact with outcomes of the trial upon to investigator opinion.
• Bowel occlusive syndrome, inflammatory bowel disease, immune colitis, or other gastro-intestinal disorders that do not allow oral medication such as malabsorption.
• Active HIV, HBV or HCV infection.
• Prior organ transplantation, including allogeneic stem cell transplantation (excluding autologous bone marrow transplant).

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (15)

Institut de Cancerologie de l'Ouest , medical oncology department

Angers, 49055, France

NOT YET RECRUITING

Institut Bergonié, medical oncology department

Bordeaux, 33076, France

NOT YET RECRUITING

Hospices Civils de Lyon, Thoracic Oncology Department, Louis Pradel Hospital

Bron, 69500, France

RECRUITING

Centre Hospitalier Universitaire de Lille, medical oncology department

Lille, 59037, France

NOT YET RECRUITING

Hospices Civils de Lyon, Medical Oncology Department, Edouard Herriot Hospital

Lyon, 69003, France

RECRUITING

AP-HM, TIMONE Hospital, medical oncology department

Marseille, 13009, France

NOT YET RECRUITING

Institut Paoli-Calmettes Marseille, medical oncology department

Marseille, 13009, France

NOT YET RECRUITING

Institut Régional du Cancer de Montpellier, medical oncology department

Montpellier, 34298, France

NOT YET RECRUITING

Institut Curie, thoracic oncology department

Paris, 75005, France

NOT YET RECRUITING

AP-HP, Tenon Hospital, medical oncology department

Paris, 75020, France

NOT YET RECRUITING

Hospices Civils de Lyon, Medical Oncology Department, Lyon SUD Hospital

Pierre-Bénite, 69310, France

RECRUITING

Centre Eugène Marquis, medical oncology department

Rennes, 35042, France

NOT YET RECRUITING

Insitut de Cancérologie Strasbourg Europe, medical oncology department

Strasbourg, 67200, France

NOT YET RECRUITING

ONCOPOLE Claudius Regaud, IUCT-Oncopole, medical oncology department

Toulouse, 31059, France

NOT YET RECRUITING

Institut Gustave Roussy, medical oncology department

Villejuif, 94805, France

NOT YET RECRUITING

MeSH Terms

Conditions

Gestational Trophoblastic Disease; Thymoma; Thyroid Carcinoma, Anaplastic; Gastro-enteropancreatic neuroendocrine tumor; Carcinoid Tumor

Interventions

zimberelimab

Condition Hierarchy (Ancestors)

Trophoblastic Neoplasms; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Pregnancy Complications, Neoplastic; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Neoplasms, Complex and Mixed; Thymus Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lymphatic Diseases; Hemic and Lymphatic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neuroendocrine Tumors; Neuroectodermal Tumors; Adenocarcinoma; Neoplasms, Nerve Tissue

Central Study Contacts

Benoit YOU, Prof; MD/PhD

CONTACT

0478864385; benoit.you@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 16, 2025
• First Posted: January 24, 2025
• Study Start: October 1, 2025
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): June 1, 2031
• Last Updated: October 6, 2025

Record last verified: 2025-10

Locations

FR (15)