Peritoneal MesotheliomaPhase 2IMMUNORARE5NCT06790706
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
A Phase 2 study testing DOMVANALIMAB + ZIMBERELIMAB and DOMVANALIMAB + ZIMBERELIMAB + FOLFOX-4 in people with Peritoneal Mesothelioma and Gestational Trophoblastic Tumor, run by Hospices Civils de Lyon at 15 sites in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Peritoneal Mesothelioma, Gestational Trophoblastic Tumor, Anaplastic Thyroid Carcinomas
- What is being tested?
- DOMVANALIMAB + ZIMBERELIMAB and DOMVANALIMAB + ZIMBERELIMAB + FOLFOX-4
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 15 sitesFrance
- Study dates
- 1 Oct 2025to Jun 2031
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- General exclusion criteria for all cohorts:
- 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 with prednisone > 10 mg daily (or equivalent), 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.
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- 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.)
- Time window of less than 4 weeks between the last cycle of systemic treatments or the last day of radiotherapy and the first dose of study treatment (or less than 5 half-lives of the previous agents, if shorter than 4 weeks).
- An exception applies for palliative radiotherapy administered locally to control local symptoms likely to compromise the patient functional status (e.g., pain, compression, hemorrhage), as such treatment is not expected to interfere with the assessment of the efficacy or safety of the investigational systemic therapy given concurrently.
- For patients with rapidly progressive malignancies that may fast compromise their vital status, a minimum interval of two weeks between the last cycle of platinum-based chemotherapy (with or without concurrent radiotherapy) or the last day of radiotherapy, and the start of study treatment, is acceptable, upon approval by one of the two coordinators of the cohort.
- Patients receiving bisphosphonates for bone metastases may remain on a stable dose regimen, provided that treatment was initiated at least 4 weeks before the first administration of the 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).
- Ongoing participation in any other clinical trial who may interfere with the present study in the judgment of the investigator
- Patients under tutorship or guardianship.
- Specific exclusion criteria by cohort:
- Cohort 1 (Peritoneal mesothelioma)
- Planned cytoreductive surgery or PIPAC within 6 months of study treatment in order to be able to assess the primary endpoint
- Cohort 3 (B3 thymomas and thymic carcinomas)
- Neuroendocrine tumors
- Any mixed histology with A/AB/B2/B3 component
- Any paraneoplastic syndrome
- Positivity to anti RACh antibodies
- Cohort 5 (GEP-NET and carcinoid tumors)
- Poorly differentiated neuroendocrine carcinomas
- Mixed tumors
- Contraindication to FOLFOX-4 (DPD deficiency, i.e. uracilemia levels ≥ 16 ng/mL)
- Previous administration of oxaliplatin
Trial locations and contacts
15 sites in 1 country.
15 sites in 1 country
France15 sites
Institut de Cancerologie de l'Ouest , medical oncology department
Angers, 49055
Institut Bergonié, medical oncology department
Bordeaux, 33076
Hospices Civils de Lyon, Thoracic Oncology Department, Louis Pradel Hospital
Bron, 69500
Centre Hospitalier Universitaire de Lille, medical oncology department
Lille, 59037
Hospices Civils de Lyon, Medical Oncology Department, Edouard Herriot Hospital
Lyon, 69003
AP-HM, TIMONE Hospital, medical oncology department
Marseille, 13009
Institut Paoli-Calmettes Marseille, medical oncology department
Marseille, 13009
Institut Régional du Cancer de Montpellier, medical oncology department
Montpellier, 34298
Institut Curie, thoracic oncology department
Paris, 75005
AP-HP, Tenon Hospital, medical oncology department
Paris, 75020
Hospices Civils de Lyon, Medical Oncology Department, Lyon SUD Hospital
Pierre-Bénite, 69310
Centre Eugène Marquis, medical oncology department
Rennes, 35042
Insitut de Cancérologie Strasbourg Europe, medical oncology department
Strasbourg, 67200
ONCOPOLE Claudius Regaud, IUCT-Oncopole, medical oncology department
Toulouse, 31059
Institut Gustave Roussy, medical oncology department
Villejuif, 94805
About this study
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.
Read more
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
- Conditions
- Peritoneal Mesothelioma, Gestational Trophoblastic Tumor, Anaplastic Thyroid Carcinomas, Gastroenteropancreatic Neuroendocrine Tumor, Carcinoid Tumor, Thymic Carcinoma
- Being tested
- DOMVANALIMAB + ZIMBERELIMAB, DOMVANALIMAB + ZIMBERELIMAB + FOLFOX-4
- Keywords
- Rare cancers, Immunotherapy, Peritoneal mesothelioma, Gestational Trophoblastic Tumors, Thymic Carcinomas, Anaplastic Thyroid Carcinomas, Gastroenteropancreatic neuroendocrine tumors (GEP-NET), Carcinoid tumors
- Medical subject headings
- Gestational Trophoblastic Disease, Thyroid Carcinoma, Anaplastic, Gastro-enteropancreatic neuroendocrine tumor, Carcinoid Tumor, Thymoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DOMVANALIMAB + ZIMBERELIMABDrug
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).
DOMVANALIMAB + ZIMBERELIMAB + FOLFOX-4Drug
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).
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1: Peritoneal mesotheliomas | Experimental | Patients will receive a combination of Domvanalimab and Zimberelimab. Receives: Drug: DOMVANALIMAB + ZIMBERELIMAB |
| Cohort 2: Gestational trophoblastic tumors | Experimental | Patients will receive a combination of Domvanalimab and Zimberelimab. Receives: Drug: DOMVANALIMAB + ZIMBERELIMAB |
| Cohort 3: Thymic carcinomas | Experimental | Patients will receive a combination of Domvanalimab and Zimberelimab. Receives: Drug: DOMVANALIMAB + ZIMBERELIMAB |
| Cohort 4: Anaplastic thyroid carcinomas | Experimental | Patients will receive a combination of Domvanalimab and Zimberelimab. Receives: 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. Receives: Drug: DOMVANALIMAB + ZIMBERELIMAB + FOLFOX-4 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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 .
Measured: At 24 weeks after the start of study treatments
Survival rate (cohort 4)
Proportion of patients alive at 24 weeks (percent).
Measured: At 24 weeks after the start of study treatments
Secondary outcomes (6)
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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: From patient inclusion, until 5 months after the end of treatment (i.e. an average of 17 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jan 2025
- Study start1 Oct 2025
- Primary completionNov 2028 (estimated)
- Study completionJun 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Peritoneal MesotheliomaStudies of the same condition, open and under way.
- More trials run by Hospices Civils de LyonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 27 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hospices Civils de Lyon
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06790706
- Sponsor's protocol ID
- 69HCL24_0656
- Acronym
- IMMUNORARE5
- Status last verified
- Jun 2026
- First submitted
- 16 Jan 2025
- Last updated
- 25 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided