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

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 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.
• 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