Phase II Study Evaluating Safety and Efficacy of Tislelizumab for Elderly Patients Unfit for Chemotherapy, With Advanced Esophageal Squamous-cell Carcinoma

This is a multicenter open-label single arm phase II study to evaluate Tislelizumab in monotherapy in frontline metastatic or locally advanced ESCC.

Patient aged ≥70 years will be selected for inclusion after a diagnosis of metastatic or locally advanced ESCC, and if they are not eligible for a platinum-based chemotherapy regimen.

Tislelizumab (200 mg flat dose every 3 weeks) will be received by intravenous perfusion until progression or unacceptable toxicity, for a maximum of 2 years.

The patients will be included regardless of PD-L1 status; A comparison for all study population will be carried out centrally as part of the ancillary enquiries.

Inclusion criteria

• Histologically proven esophageal squamous cell carcinoma (ESCC)
• Metastatic or locally advanced cancer
• Absence of previous treatment (immunotherapy, chemotherapy or radiotherapy) in first line setting
• Ineligibility for a platinum-based chemotherapy assessed by oncologist and geriatrician
• At least one evaluable and/or measurable lesion as defined by RECIST v1.1 criteria
• Patients ≥ 70 years
• Subjects with WHO performance status ≤ 2
• Estimated life expectancy >3 months
• Adjuvant therapy finished >6 months
• Adequate marrow and organ functions defined as:

• Absolute neutrophil count (ANC) ≥ 1 × 109/L,
• Platelet count ≥ 75 × 109/L,
• Hemoglobin ≥ 90 g/L,
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 × ULN, or AST and ALT ≤5 ×ULN for patients with liver metastases
• ALP ≤ 5 x ULN unless liver metastases are present, in which case it must be ≤ 10x ULN
• Measured creatinine clearance (CL) > 40 mL/min (MDRD method)
• Male patients must use a condom during treatment and for 6 months after the last dose when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential during treatment and for 6 months after the last dose.
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits and examinations including follow up.
• Signed written informed consent obtained prior to any study specific procedures
• Patient affiliated to a social security scheme

Exclusion criteria

• History of another primary malignancy. May be included, patients with:

• Malignancy treated with curative intent and with no known active disease ≥ 2 years before the first dose of treatment
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
• Locally advanced esophageal carcinoma that is resectable or potentially curable with radiation therapy per local investigator
• Participation in another clinical study with an investigational product during the last 2 months.
• Concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• History of allogenic organ, bone marrow, or double umbilical cord blood transplantation
• Active documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). May be included:

• 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 with celiac disease controlled by diet alone
• Previous immune checkpoint inhibitor therapy within the 2 years before inclusion
• Uncontrolled intercurrent illness; uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention (recurrence ≤ 14 days after intervention). Patients with the following diseases are not excluded and may proceed to further screening:

• Controlled Type I diabetes
• Hypothyroidism (provided it is managed with hormone replacement therapy only)
• Controlled celiac disease
• Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia)
• Any other disease that is not expected to recur in the absence of external triggering factors
• Patients with evidence of fistula (either oesophageal/bronchial or oesophageal/aorta)
• Patients considered at poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial infarction, pulmonary embolism/deep vein thrombosis, cerebrovascular accident, and heart failure, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, interstitial bilateral lung disease on high Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs or might impair compliance with study conduct. A history of severe hypersensitivity reactions to other monoclonal antibodies. Has received any chemotherapy, immunotherapy (eg, interleukin, interferon, thymosin, etc) or any investigational therapies within 14 days or 5 half-lives (whichever is shorter) of the first study drug administration.
• Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
• Patient with symptomatic central nervous system (CNS) metastases.
• History of active primary immunodeficiency.
• Known non-controlled serologically positive human immunodeficiency virus (HIV) patients with CD4 < 400 / mm3.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), active untreated hepatitis B (known positive HBV surface antigen (HBsAg) result), active untreated hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of -immunotherapy. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• Receipt of live attenuated vaccine within 30 days prior to the first dose of ICI
• Follow-up impossible, according to investigator's decision
• Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol or follow-up schedule
• Persons i) deprived of liberty by judicial or administrative decision, persons subject to psychiatric care under Articles L. 3212-1 and L. 3213-1 who do not fall under the provisions of Article L. 1121-8 and persons admitted to a health or social care facility for purposes other than research, and (ii) adults subject to a legal protection measure or unable to express their consent (Article L1121-8)