Gut Microbiome in Patients With Lung and Melanoma Cancer and Intestinal Microbiota in Gynecologic Cancers

• sample collection (Biological): Clinical and radiological assessment will be performed at the enrollment and every 3 +/- 1 months. Clinical information and biological samples will be collected also at 2 years from surgery or start of therapy. We plan collection of a maximum of 13 faecal and blood samples per patient (1 baseline + a maximum of 11 during treatment ± 1 disease progression, ± 10%). In addition, we expect to collect fresh stools and tissue biopsies from at least 3-5 patients per group every year, which will be dedicated to our translational studies.

Primary outcomes

• Primary Endopoint [1 year]: Correlation between Bacterial Antigens Mimicking-Tumor associated antigens (BAM-Ts) and clinical response to Immune Checkpoint Blockade (ICB).

Secondary outcomes

• Secondary Endpoints [2 year]: A. Correlation between circulating immunological factors during ICB and clinical response: Relapse-Free Survival (RFS) or Progression Free Survival (PFS), Overall Response Rate (ORR), Overall Survival (OS);

Other outcomes

• Exploratory Endpoints [5 year]: Correlation between, HLA allotypes and microbiota in correlation with clinical response RFS or PFS and OS;

Sex: All, ages: 18 Years to any

4.1 INCLUSION CRITERIA:

* Histologically or cytologically confirmed disease (see 3.1)
* (i) patients with local advanced or metastatic NSCLC candidate to first-line ICB monotherapy or chemo-ICB combination OR (ii) patients with cutaneous melanoma candidate to first-line or adjuvant ICB (iii) patients with primary advanced or first recurrence endometrial or cervical cancer candidate to chemo-ICB combination
* Signed Written Informed Consent
* Males and Females, ages ≥18 years of age
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Have evaluable disease based on i-RECIST 1.1
* Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and all protocol procedures.
* Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion, whenever possible.
* Known mutation/molecular status as determined by local institutional standard (NSCLC: available comprehensive molecular analysis, melanoma: PD-L1 TPS score, BRAF V600, EC: p53, POLE, MMR status, CC: PD-L1 CPS score. Both wild type and mutation positive are eligible. Regarding gynecologic cancers, EC patients will be eligible for the study regardless of the MMR status (MMRd or MMRp), while only CC patients with a PD-L1 combined positive score (CPS) ≥1 will be eligible.
* Patients who have been previously treated in the adjuvant setting for melanoma will be eligible for treatment after a 28-day washout period.
* Patients must be medically fit enough to undergo surgery as determined by the treating medical and surgical oncology team.
* Demonstrate adequate organ function as defined below: Hematologic Absolute neutrophil count (ANC) >/= 1.5 X 10\^9/L; Hemoglobin >/= 9.5 g/dL Platelets >/= 100 X 10\^9/L PT/INR and PTT </= 1.5 X ULN. Hepatic Total bilirubin </= 1.5 X ULN (isolated bilirubin >1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) AST and ALT Albumin </= 2.5 X ULN 1 >/=2.5 g/dL Renal Creatinine OR Calculated creatinine clearance OR 24-hour urine creatinine clearance </=1.5 X ULN 2 >/= 50 mL/min >/= 50 mL/min.
* The individual methods of contraception and duration should be determined in consultation with the investigator.
* Women must not be breastfeeding.

Exclusion Criteria:

* Previous chemotherapy (< 28 days washout), radiation therapy, immunotherapy, or biologic therapy
* Any major surgery within the last 3 weeks
* Pregnant or lactating female
* Unwillingness or inability to follow the procedures
* Grade 3 and 4 adverse event conditioning ICB interruption
* Known oncogene-addicted NSCLC, with the exception of KRAS G12C and BRAF V600E mutant NSCLC Any serious or uncontrolled medical disorder
* Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast with local control measures (surgery, radiation).
* Patients with active, known or suspected autoimmune disease such as Inflammatory Bowel Disease, Lupus, etc. or other conditions requiring systemic corticosteroids or other systemic immunosuppressive medications.
* Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.
* Prior treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody.
* Antibiotic or antimycotic medications within 45 days from the beginning of ICB
* Positive test result for hepatitis B or C virus
* Human immunodeficiency virus or known acquired immunodeficiency syndrome
* Concomitant Medications/Vaccinations: medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the ongoing study. If there is a clinical indication for one of these or other medications or vaccinations specifically prohibited during the study that the investigator considers necessary for a subject's welfare, it will be administered at the discretion of the investigator in keeping with the community standards of medical care. All concomitant medication (within 28 days before the first dose) will be recorded on the case report form (CRF).
* Patients are prohibited from receiving the following therapies during the Screening and Treatment Phase (including retreatment for post-complete response relapse) of this study:
* Immunotherapy not specified in this protocol
* Chemotherapy not specified in this protocol
* other Investigational agents
* Radiation therapy
* Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.
* Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic aetiology. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
* Patients who, in the assessment by the investigator, require the use of any of the aforementioned treatments for clinical management should be removed from the study. Patients may receive other medications that the investigator deems to be medically necessary. The Exclusion Criteria describes other medications which are prohibited in this study.

• Luigi Nezi, PhD, Principal investigator, Istituto Europeo di Oncologia
• Monica Casiraghi, MD PhD, Principal investigator, Istituto Europeo di Oncologia