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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hospices Civils De Lyon

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Sep 2025 → ongoing

Decision date (initial)

2025-06-02

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

IMMUNORARE received a financial support from Gilead.

External identifiers

EU CT number

2024-517254-99-00

ClinicalTrials.gov

NCT06790706

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The primary objective is to assess the efficacy of the combination of Domvanalimab and Zimberelimab in patients with 5 types of advanced rare cancers (peritoneal mesotheliomas, gestational trophoblastic tumors, thymic carcinomas, anaplastic thyroid carcinomas, and GEP-NET & carcinoid tumors) in progression/resistance after at least one standard line of treatment.

Secondary objectives 11

1. To assess the efficacy according to overall response rate.
2. To assess the efficacy according to progression-free survival (RECIST/mRECIST criteria).
3. To assess the efficacy according to resistance-free survival (cohort 2).
4. To assess the efficacy according to overall survival (cohorts 1 2, 3 and 5).
5. To assess the efficacy according to duration of response (cohorts 1, 3, 4 and 5).
6. To assess the tolerability of the combination of Domvanalimab and Zimberelimab given alone (cohorts 1-4), or in combination with FOLFOX-4 (cohort 5).
7. Exploratory study TROPHOGEN - Primary objective : To assess the efficacy of the combination of Domvanalimab and Zimberelimab in patients with advanced gestational trophoblastic tumors resistant to the first line standard treatment, according to the deregulations of the immune signaling pathways and to somatic molecular anomalies
8. Exploratory study TROPHOGEN - secondary objective 1 : To assess the efficacy of the combination of Domvanalimab and Zimberelimab according to resistance-free survival in patients with advanced gestational trophoblastic tumors resistant to the first line standard treatment, according to the deregulations of the immune signaling pathways and to somatic molecular anomalies
9. Exploratory study TROPHOGEN - secondary objective 2 : To assess the efficacy of the combination of Domvanalimab and Zimberelimab according to overall survival, in patients with advanced gestational trophoblastic tumors resistant to the first line standard treatment, according to the deregulations of the immune signaling pathways and to somatic molecular anomalies
10. Exploratory study TROPHOGEN - secondary objective 3 : To assess the safety of the combination of Domvanalimab and Zimberelimab in patients with advanced gestational trophoblastic tumors resistant to the first line standard treatment, according to the deregulations of the immune signaling pathways and to somatic molecular anomalies
11. To assess the efficacy according to progression-free survival post-initial progression (PFS PIP) for patients who will continue the study treatment beyond initial progression upon investigator decision (RECIST/mRECIST criteria) (cohorts 1, 3, 4, 5).

Conditions and MedDRA coding

The patients enrolled in IMMUNORARE will be adult patients with 5 rare cancers: -Cohort 1: Peritoneal mesotheliomas (PM) -Cohort 2: Gestational trophoblastic tumors (GTT) -Cohort 3: B3 thymomas and thymic carcinomas (TET) -Cohort 4: Anaplastic thyroid carcinomas (ATC) -Cohort 5: GEP-NET & carcinoid tumors (GEP-NET/TCT/UP-NET) Patients will have advanced/metastatic cancers found to be progressive/resistant after at least one previous line of standard systemic treatment.

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 36

1. Histologically proven advanced solid tumors that progressed/resisted after minimum one line of standard systemic treatment, or resisted during the first-line of treatment
2. Life expectancy ≥ 16 weeks
3. Highly effective contraception for men and childbearing age women. Effective contraceptive methods and guidelines can be found in the Annex 1 of this protocol (Breastfeeding is prohibited during the participation in IMMUNORARE trial)
4. Signed informed consent prior to participating in any study related procedures.
5. Patients affiliated to the French social security system
6. Patient able to comply with the protocol, including follow-up visits and examinations
7. Specific inclusion criteria for Cohort 1 : Histologically-confirmed malignant peritoneal mesotheliomas (epithelioid, sarcomatoid, or biphasic)
8. Specific inclusion criteria for Cohort 1 : 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)
9. Specific inclusion criteria for Cohort 2 : 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)
10. Specific inclusion criteria for Cohort 2 : Evidence of resistance or relapse after at least one line of polychemotherapy (e.g. EP low dose, BEP regimen, EMA-CO regimen …)
11. Specific inclusion criteria for Cohort 3 : Thymic carcinoma, histologically confirmed by a referent pathologist of the RYTHMIC network
12. 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)
13. Specific inclusion criteria for Cohort 3 : Evidence of progression or relapse after at least one line of platinum-based chemotherapy
14. Specific inclusion criteria for Cohort 4 : Anaplastic thyroid carcinoma with non-mutated or mutated B-RAF, histologically or cytologically-confirmed by a referent pathologist of the Tuthyref network
15. Specific inclusion criteria for Cohort 4 : 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
16. Specific inclusion criteria for Cohort 4 : In B-RAF mutated anaplastic thyroid carcinoma: evidence of progression after a standard B-RAF inhibitor
17. Specific inclusion criteria for Cohort 5 : 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
18. Specific inclusion criteria for Cohort 5 : Indication of oxaliplatin-based regimen treatment
19. Specific inclusion criteria for Cohort 5 :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.
20. Specific inclusion criteria for Exploratory study TROPHOGEN : Cohort A = Patients who gave their informed consent to participate to the IMMUNORARE5 clinical trial
21. Specific inclusion criteria for Exploratory study TROPHOGEN : Cohort A = Patients with gestational trophoblastic tumors (including placenta site trophoblastic tumors and epithelioid carcinomas), histologically-confirmed by a referent pathologist the French National Center for Trophoblastic Diseases
22. Specific inclusion criteria for Exploratory study TROPHOGEN : Cohort A = Patients who are eligible to participate to the IMMUNORARE5 trial and to receive domvanalimab and Zimberelimab treatments (i.e. patients who successfully completed the screening procedures)
23. 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)
24. Specific inclusion criteria for Exploratory study TROPHOGEN : Cohort A = Signed informed consent prior to participating in this study related procedures.
25. Specific inclusion criteria for Exploratory study TROPHOGEN : Cohort B = Male partner of a patient enrolled in the IMMUNORARE5 trial who meets the inclusions criteria for cohort A
26. Specific inclusion criteria for Exploratory study TROPHOGEN : Cohort B = Male partner who fathered the pregnancy that gave rise to the gestational trophoblastic tumor
27. Specific inclusion criteria for Exploratory study TROPHOGEN : Cohort B = Subjects older than 18 years
28. Specific inclusion criteria for Exploratory study TROPHOGEN : Cohort B = Signed informed consent prior to participating in this study related procedures.
29. Specific inclusion criteria for Exploratory study TROPHOGEN : Cohort B = Subjects affiliated to the French social security system or beneficiaries of a similar scheme
30. Patients older than 18 years
31. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
32. 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 coordinator of the cohort)
33. Patients with adequate bone marrow function measured within 28 days prior to administration of study treatment: •Absolute Neutrophil count > 1.5x 10^9/L; •Platelets count ≥ 100 X 10^9/L; •Hemoglobin ≥ 9 g/dL
34. Patients with adequate renal function: Calculated creatinine clearance ≥ 30 ml/min according to the local institutional standard method (MDRD preferred)
35. Serum bilirubin ≤ 1.5 x UNL (≤ 3 x ULN for patients with known Gilbert’s syndrome), AST/ALT ≤ 2.5 X UNL (≤ 5 X UNL for patients with liver metastases)
36. 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

Exclusion criteria 29

1. Previous treatment with immune checkpoint inhibitors (including anti-TIGIT, anti-PD1, anti-PD-L1, anti-CTLA4,), or other types of immunotherapy
2. Specific exclusion criteria for Cohort 3 : Any paraneoplastic syndrome
3. Specific exclusion criteria for Cohort 3 : Positivity to anti RACh antibodies
4. Active or prior documented autoimmune disorders. (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 coordinator of the cohort)
5. 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)
6. 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.
7. 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.
8. All subjects with meningeal involvement.
9. 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
10. 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.
11. Treatment with other investigational agents prone to interact with outcomes of the trial upon to investigator opinion.
12. Bowel occlusive syndrome, inflammatory bowel disease, immune colitis, or other gastro-intestinal disorders that do not allow oral medication such as malabsorption.
13. Specific exclusion criteria for Cohort 5 : Poorly differentiated neuroendocrine carcinomas
14. Specific exclusion criteria for Cohort 5 : Mixed tumors
15. Specific exclusion criteria for Cohort 5 : Contra-indication to FOLFOX-4 (DPD deficiency, i.e. uracilemia levels ≥ 16 ng/mL)
16. Active HIV, HBV or HCV infection.
17. Prior organ transplantation, including allogeneic stem cell transplantation (excluding autologous bone marrow transplant).
18. Ongoing participation in any other clinical trial who may interfere with the present study in the judgment of the investigator
19. Patients under tutorship or guardianship.
20. Specific exclusion criteria for Cohort 1 : Planned cytoreductive surgery or PIPAC within 6 months of study treatment in order to be able to assess the primary endpoint
21. Specific exclusion criteria for Cohort 3 : Neuroendocrine tumors
22. Specific exclusion criteria for Cohort 3 : Any mixed histology with A/AB/B2/B3 component
23. Specific exclusion criteria for Cohort 5 : Previous administration of oxaliplatin
24. Specific exclusion criteria for Exploratory study TROPHOGEN : Cohort A = Absence of archival tumor tissue and impossibility to obtain a new biopsy
25. Specific exclusion criteria for Exploratory study TROPHOGEN : Cohort A = Impossibility to realize a blood drawn
26. Specific exclusion criteria for Exploratory study TROPHOGEN : Cohort B = Persons under tutorship or guardianship
27. Specific exclusion criteria for Exploratory study TROPHOGEN : Cohort B = Persons deprived of their liberty by a judicial or administrative decision
28. Specific exclusion criteria for Exploratory study TROPHOGEN : Cohort B = Persons under psychiatric care
29. Specific exclusion criteria for Exploratory study TROPHOGEN : Cohort B = Impossibility to realize a blood drawn

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint will be assessed 24 weeks after the start of study treatment. It will be different across the different cohorts to take into account their prognosis specificities: Cohort 1 = Progression free survival rate at 24 weeks; Cohort 2 = Successful hCG normalization rate at 24 weeks ; Cohort 3 = Progression free survival rate at 24 weeks; Cohort 4 = Survival rate at 24 weeks; Cohort 5 = Progression free survival rate at 24 weeks

Secondary endpoints 11

1. 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.
2. 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.
3. 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.
4. Overall survival (cohorts 1-3 and 5) 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.
5. Duration of response (cohorts 1, 3-5): delay between overall response and progression or death whichever occurs first
6. Adverse events and grades according to NCI-CTCAE v 5 criteria.
7. Exploratory study TROPHOGEN - Primary endpoint : Proportion of patients experiencing a successful hCG-normalization within 24 weeks while on study treatment (%), according to deregulations of the immune signaling pathways and to somatic molecular anomalies
8. Exploratory study TROPHOGEN - secondary endpoint 1 : 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, according to the deregulations of the immune signaling pathways and to somatic molecular anomalies
9. Exploratory study TROPHOGEN - secondary endpoint 2 : Overall survival defined as the time elapsed between inclusion and patient’s death regardless of the cause, according to the deregulations of the immune signaling pathways and to somatic molecular anomalies. Patients alive will be censored at the last date of last news. Patients without resistance will be censored at the date of last news.
10. Exploratory study TROPHOGEN - secondary endpoint 3 : Adverse events and grades according to NCI-CTCAE v 5 criteria
11. PFS-post initial progression (PFS-PIP), defined as the time elapsed between inclusion and the 2nd progression or death (whichever occurs first) following an initial disease progression, according to RECIST criteria (cohorts 3-5) or according to mRECIST criteria (cohort 1), for patients who continued the treatment after an initial disease progression upon investigator discretion. Patients alive without this 2nd progression will be censored at the last date of imaging assessment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hospices Civils De Lyon

Sponsor organisation

Hospices Civils De Lyon

Address

3 Quai Des Celestins, Bp 2251 Bp 2251

City

Lyon Cedex 02

Postcode

69229

Country

France

Scientific contact point

Organisation

Hospices Civils De Lyon

Contact name

Pr Benoit YOU

Public contact point

Organisation

Hospices Civils De Lyon

Contact name

Pr Benoit YOU

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Urgent safety measures 1 · Art. 54 CTR

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications