| Eligibility |
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 and unresectable locally advanced recurrent or metastatic
squamous cell anal carcinoma,
4. Presence of a target lesion on CT-scan assessed by RECIST v1.1 criteria,
5. Patient eligible to the mDCF regimen,
6. CT scan performed within 28 days prior inclusion,
7. PET scan performed within 28 days prior inclusion,
8. Signed and dated informed consent,
9. Patient affiliated to or beneficiary of French social security system,
10. Ability to comply with the study protocol, in the Investigator's judgment,
11. Life expectancy = 6 months,
12. Adequate hematologic and end-organ function.
13. Previous concomitant chemoradiotherapy is permitted if completed before 28 days of
starting treatment.
Exclusion Criteria:
Non-eligibility to clinical trials if one of the following parameter is reported:
1. Previously received chemotherapy for metastatic disease,
2. Previously received cisplatin except for concomitant chemoradiotherapy,
3. Previously received taxanes (paclitaxel or docetaxel) or another spindle poison
(navelbine) in the treatment of SCCA,
4. Previously received anti-tumor immunotherapy (HPV vaccination is allowed),
5. Previous radiotherapy within 28 days of randomization (14 days if radiotherapy of bone
metastases)
6. Diagnosis of additional malignancy within 3 years prior to the randomization with the
exception for curatively treated basal cell carcinoma of the skin and/or curatively
resected in situ cervical or breast cancer,
7. Any medical or psychiatric condition or disease, which would make the patient
inappropriate for entry into this study,
8. Current participation in a study of an investigational agent or in the period of
exclusion,
9. Pregnancy, breast-feeding or absence/refusal of adequate contraception for fertile
patients during the period of treatment and for 6 months from the last treatment
administration, men must refrain from donating sperm during this same period.
10. Patient under guardianship, curatorship or under the protection of justice.
Non-eligible to chemotherapy:
11. Inadequate organ functions: uncontrolled cardiac condition, known cardiac failure,
unstable coronaropathy, respiratory failure, and Chronic Obstructive Pulmonary Disease
(COPD),
12. Diabetes with vascular or neurovascular complications,
13. Preexistent peripheral neuropathy or impaired audition,
14. HIV positive with CD4 count under 400 cells/mm3 (VIH test is mandatory before
inclusion),
15. Active hepatitis B or C virus (HBV or HCV) infection (chronic or acute), (Defined as
having a positive HBV surface antigen (HBsAg) test at screening. Patients with a past
or resolved HBV infection, defined as having a negative HBsAg test and a positive
total HBV core antibody (HBcAb) test at screening, are eligible for the study. HCV
infection, defined as having a positive HCV antibody test followed by a positive HCV
RNA test at screening. The HCV RNA test will be performed only for patients who have a
positive HCV antibody test),
16. Active tuberculosis,
17. Concomitant treatment with CYP3A4 inhibitor like ritonavir, indinavir, or
ketoconazole, etc. Replacement by another drug before randomization, whenever is
possible, is allowed,
18. Known hypersensitivity or contraindication to any of the study chemotherapy drugs
(taxanes, cisplatin, 5FU), according with the SmPC of each drug
19. Uncontrolled infection or another life-risk condition,
20. Known hearing impairment that contraindicates cisplatin administration,
21. Administration of a live (attenuated) vaccine within 28 days of planned start of study
therapy of known need for this vaccine during treatment,
22. Administration of prophylactic phenytoin,
23. Inadequate laboratory values: creatinine clearance (CrCl by Modification of Diet in
Renal Disease [MDRD] formula) <60 ml/min, neutrophil count <1500 /mm3, platelets
<100000/mm3, bilirubin 2.5 x upper limit of normal (ULN), aspartate transaminase
(AST)/alanine transaminase (ALT) 2.5 x ULN or 5 x ULN with liver metastasis.
24. Patient with known dihydropyridine dehydrogenase (DPD) deficiency or history of severe
and unexpected reactions to a fluoropyrimidine-containing regimen, or in case of
clinically significant active heart disease or myocardial infarction within 6 months
or if patient treated with sorivudine or its clinically related analogues, such as
brivudine
Non-eligible to immunotherapy:
25. Any immunosuppressive therapy (i.e. corticosteroids >10mg of hydrocortisone or
equivalent dose) within 14 days before the planned start of study therapy,
26. Active autoimmune disease that has required a systemic treatment in past 2 years (i.e.
corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine,
insulin) is allowed.
Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,
or multiple sclerosis, (see Annex 7 for a more comprehensive list of autoimmune
diseases and immune deficiencies) with the following exceptions:
27. Patients with a history of autoimmune-related hypothyroidism who are on thyroid
replacement hormone are eligible for the study,
28. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are
eligible for the study,
29. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are met:
- Rash must cover < 10% of body surface area,
- Disease is well controlled at baseline and requires only low-potency topical
corticosteroids,
- No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents,
oral calcineurin inhibitors, or high potency or oral corticosteroids within the
previous 12 months,
30. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
31. Known active central nervous system metastases and/or carcinomatous meningitis.
Subject with previously treated brain metastases and with radiological and clinical
stability are allowed,
32. Previously received an anti-PD1, anti-PDL1, or anti-CTLA4 agent,
33. Known hypersensitivity or allergy to Chinese hamster ovary cell products or any
component of atezolizumab formulation,
34. History of colorectal inflammatory disease,
35. History of idiopathic or secondary pulmonary fibrosis (history of radiation
pneumonitis in the radiation field fibrosis is permitted), or evidence of active
pneumonitis requiring a systemic treatment with 28 days before the planned start of
study therapy,
36. Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
of study treatment, or anticipation of need for a major surgical procedure during the
course of the study,
37. Severe infection within 4 weeks prior to initiation of study treatment, including, but
not limited to, hospitalization for complications of infection, bacteremia, or severe
pneumonia,
38. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a
urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
eligible for the study.
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