Immunotherapy Master Trial for Advanced Cancers

Inclusion Criteria:

1. Age ≥12 years with at least 40kg body weight or otherwise as per specified in sub-protocol.
2. Prior to the inclusion in the METAREM master protocol, patients must have signed a written informed consent to baseline PORTRAIT evaluation and on-treatment PORTRAIT evaluation.

   Note:
   1. When the patient is physically unable to give his/her written consent, an impartial witness a trusted person of his/her choice, independent from the investigators or the sponsor, can confirm in signing the patient's consent.
   2. For patients aged between \> 12 and \< 18, specific consent from legal tutors should be obtained on top of the minor consent and prior procedures.
3. Patients with advanced cancer, as defined as unresectable locally advanced malignancies or metastatic cancers (including leukemias and lymphomas).
4. Having measurable disease (i.e one measurable lesion according to RECIST v1.1 for solid tumors or one consensus method of blast quantification / minimal residual disease assessment for leukemias).
5. Eastern cooperative oncology group (ECOG) performance status between 0 and 2.
6. Patients amenable to undergo a blood draw procedure and a tumor biopsy procedure. For patients with more than 10% malignant cells in their bone marrow or blood, a bone marrow aspirate or blood draw could replace the tumor biopsy.
7. Adequate organ function as defined by the following criteria:

   * Total bilirubin ≤1.5 ULN, or ≤3.0 ULN in participants with Hepato-Cellular Carcinoma (HCC) or known Gilbert's syndrome if the increase is predominantly due to unconjugated bilirubin.
   * ALT ≤ 3 x ULN; if liver metastases ALT ≤ 5 x ULN
   * Absolute Neutrophils count (ANC) ≥ 1000 cells/mm³ in the absence of G-CSF or GM-CSF within ≤2 weeks before the first dose of study treatment.
   * Platelets ≥100 000 cells/mm³
   * Hemoglobin ≥ 9.0 g/dL
   * Albumin ≥ 30 g/L
   * Calculated creatinine clearance ≥50 mL/min/1.73 m2
8. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment.
9. Both sexually active WOCBP and males (and their WOCBP partners) patients must agree to use two methods of effective contraception, one of them being a physical barrier method, or to abstain from sexual activity during the study and for the period indicated in specific sub-protocol after the last study drug administration.
10. Patient affiliated to the French social security regimen.
11. Patients with mental and legal ability to fully consent for undergoing the exploratory procedures (blood draws and biopsies) prior (at baseline PORTRAIT) and upon treatment and (on-treatment PORTRAIT).
12. Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.

Exclusion Criteria:

1. Any life-threatening allergy to one of the experimental products tested in the sub-protocol where the patient is eligible. In case of allergy to contrast media, patient monitoring should be performed with alternate methods (both CT-scan or MRI).
2. History of life threatening autoimmune/immune mediated inflammatory disease, including but not limited to severe colitis, pneumonitis, Guillain-Barré syndrome, anti-phospholipid syndromes and myocarditis. Patients with a history of auto-immune endocrinopathy (hypo/hyper thyroiditis, type 1 diabetes mellitus, …) and who are stable on hormone replacement therapy are eligible for the study. Patients with a history of vitiligo, alopecia areata, cutaneous psoriasis and grade 1-2 Sjogren syndrome are eligible.
3. Treatment with systemic long-term immunosuppressive medications unless otherwise specified in the specific therapeutic sub-protocols. Those immunosuppressive drugs must have been stopped at least 4 weeks prior to enrollment. Hormone replacement therapy with physiological doses of hydrocortisone is acceptable.
4. Chemotherapy, hormonotherapy, radiotherapy or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks or 5 half-life times (whatever the shortest) prior to treatment with the trial drugs.
5. Administration of a live, attenuated vaccine within 4 weeks before registration.
6. Radiotherapy to the chosen RECIST target lesion(s) (unless a progression after radiotherapy has been documented).
7. Persistence of a clinically relevant treatment-related toxicity from previous chemotherapy, targeted therapy and/or radiotherapy which could hamper the safety or efficacy assessment of the therapy tested (for previous disease).
8. Patients with symptomatic brain metastases or leptomeningeal disease are excluded unless otherwise specified by a specific therapeutic sub-protocol. Clinically asymptomatic brain metastases and clinically asymptomatic leptomeningeal disease are allowed (treatment with steroids prior to initiation of the trial is not allowed).
9. Patients with evolving tumors next to cavitary or major blood vessels at high risk of massive bleeding and/or perforation.
10. History of clinically significant hemoptysis within the past 3 months.
11. Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial.
12. Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned major surgery during the on-treatment study period.
13. History of clinically significant hemorrhagic or thromboembolic event in the past 3 months.
14. History of significant cardiovascular diseases (i.e., supraventricular tachycardia, uncontrolled hypertension, unstable angina, history of infarction within the past 12 months prior to start of study treatment, congestive heart failure \> NYHA II, serious cardiac arrhythmia, pericardial effusion).
15. Ongoing uncontrolled endocrinopathy. Ancient endocrinopathy currently stable with substitutive therapy should not be excluded from the trial.
16. Other malignancies within the past 5 years other than superficial malignancies (e.g localized squamous or basal cell skin cancer) or carcinoma in situ (e.g cervix, breast, prostate, bladder) which have undergone curative therapies. A history of more than 3 years without subsequent relapse of local prostate cancer treated by surgery and without PSA elevation since surgery, or local breast carcinoma treated by surgery without relapse or resected non-muscle invasive bladder cancers are eligible.
17. Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy. A wash out of more than 3 weeks is required after last systemic antibiotics to allow reconstitution of the microbiome. Patients infected by HIV but having efficient anti-retroviral therapy and CD4+ T-cell counts \>500/mm³ are eligible. Patients with a history of HBV or HCV that are cured and have eligible liver function criteria are also eligible.
18. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug in case an oral drug is tested in the sub-protocol for which the patient is screened.
19. Pregnancy or breast feeding.
20. Intake of Ganoderma Lucidum mushroom (also called "Reishi") and/or herbal remedies and/or traditional medicines within the past weeks prior to start of study treatment or concomitantly with the trial because of their potential to increase treatment related adverse events.
21. Any psychological, familial, sociological, geographical factors, lifestyle, behavior, clinical or biological parameters or elements in the past medical history of the patients that, according to the investigator, could preclude the ability of the trial to directly reach its objectives, or indirectly via treatment observance or study follow up. Patients with active alcoholism and/or drug abuse are excluded.
22. Person deprived of their liberty or under protective custody or guardianship.