Combination of Spartalizumab, mDCF and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma

Inclusion Criteria:

1. Male or female, aged ≥18 years,
2. Performance status Eastern Cooperative Oncology Group World Health Organization (ECOG-WHO) ≤1,
3. Histologically proven metastatic or locally advanced recurrent squamous cell carcinomaof anus (SCCA)
4. Presence of a evaluable lesion on CT-scan/MRI assessed by RECIST v1.1 criteria,
5. Patient eligible to the mDCF regimen
6. CT scan performed within 30 days prior inclusion,
7. PET scan performed within 30 days prior inclusion
8. Life expectancy ≥12 months,
9. Adequate organ and marrow function, based upon meeting all of the following laboratorycriteria within 14 days before first dose of study treatment:

• Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocytecolony-stimulating factor support.
• White blood cell count ≥ 2500/mm3 (≥ 2.5 GI/L).
• Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without transfusion.
• Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 3 x upperlimit of normal (ULN), or ≤ 5 x ULN with documented liver metastases.
• Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN).
• Serum albumin ≥ 2.8 g/dl.
• Calculated creatinine clearance ≥ 60 mL/min (using the MDRD formula):
• Urine protein/creatinine ratio (UPCR) ≤ 1 g/g

10. Signed and dated informed consent, to participate indicating that the subject hasunderstood the purpose and the procedures required by the study and that he agrees toparticipate in the study and to comply with the requirements and restrictions inherentin this study
11. Patient affiliated to or beneficiary of French social security system
12. Ability to comply with the study protocol, in the Investigator's judgment

Exclusion Criteria:

1. HIV positive patient , CD4 count < 400 cells/mm3 (HIV test mandatory before inclusion)
2. Diagnosis of additional malignancy within 2 years prior to the inclusion with theexception for superficial skin cancers, or localized, low grade tumors deemed curedand not treated with systemic therapy,
3. Any medical or psychiatric condition or disease, which would make the patientinappropriate for entry into this study,
4. Current participation in a study of an investigational agent or in the period ofexclusion,
5. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment,
6. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before the first dose of study treatment. Subjects withclinically relevant ongoing complications from prior radiation therapy are noteligible,
7. Pregnancy, breast-feeding or absence/refusal of adequate contraception for fertilepatients during the period of treatment and for 6 months from the last treatmentadministration,
8. Patient under guardianship, curatorship or under the protection of justice.
9. Inability to perform radiotherapy
10. Untreated or symptomatic central nervous system (CNS) lesion. However, patients areeligible if: a) all known CNS lesions have been treated with radiotherapy or surgeryand b) patient remained without evidence of CNS disease progression ≥ 4 weeks aftertreatment and c) patients must be off corticosteroid therapy for ≥ 2 weeks
11. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, M-CSF),thrombopoietin mimetics or erythroid stimulating agents ≤ 2 weeks prior start of studytreatment. If erythroid stimulating agents were initiated more than 2 weeks prior tothe first dose of study treatment and the patient is on a stable dose, they can bemaintained.
12. Use of any live vaccines against infectious diseases within 4 weeks of initiation ofstudy treatment
13. Elevated Cardiac troponin T (cTnT) or cardiac troponin I (cTnI) elevation > 2x ULN
14. Systemic chronic steroid therapy (> 10mg/day prednisone or equivalent) or anyimmunosuppressive therapy 7 days prior to planned date of first dose of studytreatment. Note: Topical, inhaled, nasal and ophthalmic steroids are allowed. For patients withadrenal insufficiency, replacement dose of prednisone > 10 mg/ day or equivalent arepermitted
15. Active, known or suspected autoimmune disease or a documented history of autoimmunedisease Note: Patients with vitiligo, controlled type I diabetes mellitus on stableinsulin dose, residual autoimmune-related hypothyroidism only requiring hormonereplacement or psoriasis not requiring systemic treatment are permitted.
16. Allogenic bone marrow or solid organ transplant
17. History of severe hypersensitivity reactions to other monoclonal antibodies, which inthe opinion of the investigator may pose an increased risk of serious infusionreaction
18. Pre-existing neuropathy, hearing problem, or cardiorespiratory pathology, whichprevent the administration of cisplatin.
19. clinically significant active heart disease or myocardial infarction within 6 months
20. recent or concomitant treatment with brivudine
21. persistent toxicities related to prior treatment of grade greater than 1
22. History or current interstitial lung disease or non-infectious pneumonitis
23. History of major surgery within 28 days before treatment
24. Active infection
25. Active Hepatitis B infection (HBsAg positive)
26. Active hepatitis C (HCV RNA positive)
27. Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory testwithin 72 hours prior to initiating study treatment. Note: Low levels of hCG may also be considered a tumor marker, therefore if low hCGlevels are detected, another blood sample at least 4 days later must be taken toassess the kinetics of the increase and transvaginal ultrasound must be performed torule out pregnancy.
28. Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using highly effective methods of contraceptionduring dosing and for 7.5 months after stopping treatment with Spartalizumab.
29. Complete or partial deficit in dihydropyrimidine dehydrogenase (DPD) activity
30. Active inflammatory bowel disease Note: In case of a history of inflammatory boweldisease, it is advisable to take the advice of the referring gastroenterologist of thepatient to ensure the absence of the evolution of inflammatory bowel disease (inflammatory thrust in progress) before the initiation of docetaxel treatment