Study of IBI308 With Advanced/Metastatic Esophageal Squamous Cell Carcinoma After Failure of First-line Treatment
Condition: Esophageal Squamous Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma
Intervention: IBI308; paclitaxel/ irinotecan
Intervention description: IBI308 200mg Intravenous drip every three weeks；; paclitaxel 175mg/㎡ Intravenous drip every three weeks or irinotecan 180mg/㎡ Intravenous drip every two weeks
Intervention MeSH terms: Paclitaxel; Irinotecan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 190.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      Efficacy and safety evaluation of IBI308 versus paclitaxel/irinotecan in patients with
      advanced/metastatic esophageal squamous cell carcinoma after failure of first-line treatment:
      a randomized, open-label, multicenter, phase 2 study
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologically or cytologically confirmed locally advanced unresectable or metastatic
             esophageal squamous cell carcinoma (excluding mixed adenosquamous carcinoma and other
             pathological types).

          2. Imaging evidence (e.g. CT scan) or clinical evidence (e.g. cytological report of new
             ascites or pleural effusion) of disease progression during or after first-line
             chemotherapy; Subjects have to receive at least one dose of first-line treatment,
             permitting discontinuation or dose reduction of one drug or exchange of fluorouracil
             drugs used during first-line treatment, and patients discontinuing first-line
             treatment due to intolerable toxicity are allowed to be enrolled; Neoadjuvant or
             adjuvant therapy (chemotherapy or chemo-radiotherapy) should be regarded as first-line
             treatment if there is disease progression during treatment or within 6 months after
             treatment discontinuation.

          3. At least one measurable lesion according to RECIST v1.1.

          4. ECOG PS score of 0 or 1.

          5. Subjects who have signed the written informed consent form and are able to follow the
             visit schedule and relevant procedures as specified in the study protocol.

          6. Age ≥ 18 and ≤ 75 years.

          7. Life expectancy ≥ 12 weeks.

          8. Female subjects of childbearing potential or male subjects with sexual partners of
             childbearing potential should use effective contraception throughout and within 6
             months after treatment.

          9. Adequate organ and bone marrow functions, defined as follows:

               -  Hematology: absolute neutrophil count (ANC) ≥ 1.5×10^9/L; Platelet (PLT) count ≥
                  100×10^9/L; Hemoglobin (HGB) ≥ 9.0 g/dL.

               -  Liver function: serum total bilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN);
                  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN;
                  Serum albumin ≥ 28 g/L.

               -  Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance (Ccr)
                  ≥ 40 mL/min (calculated using the standard Cockcroft -Gault formula):

                    -  Females: CrCl = (140-age) x body weight (kg) x 0.85/(72 x serum creatinine
                       (mg/dL))

                    -  Males: CrCl = (140-age) x body weight (kg) x 1.00/(72 x serum creatinine
                       (mg/dL))

        Exclusion Criteria:

          1. Prior exposure to any anti-PD-1 or anti-PD-L1 antibody.

          2. Concurrent participation in another interventional clinical study, except for
             observational (non-interventional) clinical studies or in the follow-up phase of an
             interventional study.

          3. Receipt of any investigational products within 4 weeks prior to the first dose of
             study treatment.

          4. Receipt of the last dose of anti-tumor therapy (chemotherapy, targeted therapy, tumor
             immunotherapy, tumor embolization) within 3 weeks prior to the first dose of study
             treatment.

          5. Radiotherapy within 4 weeks prior to the first dose of study treatment.

          6. Receipt of immunosuppressive agents within 4 weeks prior to the first dose of study
             treatment, excluding topical glucocorticoids for intranasal, inhalation or other
             routes of administration, or physiological doses of systemic glucocorticoids (i.e., no
             more than 10 mg/day prednisone or equivalent doses of other glucocorticoids).

          7. Receipt of a live attenuated vaccine within 4 weeks prior to the first dose of study
             treatment or planned receipt of a live attenuated vaccine during the study.

          8. Subjects who have undergone major surgical procedures (craniotomy, thoracotomy or
             laparotomy) within 4 weeks prior to the first dose of study treatment or have unhealed
             wound, ulcers or bone fracture.

          9. Presence of toxicities induced by previous anti-tumor therapy that have not recovered
             to Grade 0 or 1 as assessed per NCI CTCAE 4.03 (National Cancer Institute Common
             Terminology Criteria for Adverse Events version 4.03) prior to the first dose of study
             treatment, excluding alopecia, and non-clinically significant and asymptomatic
             laboratory abnormalities.

         10. Known symptomatic metastases to central nervous system (CNS) and/or carcinomatous
             meningitis. Subjects previously treated for brain metastasis are eligible for the
             study provided the brain metastasis has remained stable for at least 4 weeks before
             first dose of study treatment; Neurological symptoms must be recovered to grade 0 or 1
             as per NCI CTCAE version 4.03.

         11. Active, known or suspected autoimmune diseases (refer to Appendix 6) or a history of
             such disease in the past 2 years (patients with vitiligo, psoriasis, alopecia or
             Grave's disease requiring no systemic treatment in the past 2 years, patients with
             hypothyroidism requiring only thyroid hormone replacement therapy and patients with
             type I diabetes requiring only insulin replacement therapy can be enrolled).

         12. Known history of primary immunodeficiency.

         13. Known active tuberculosis (TB).

         14. Known history of allotransplantation and allogeneic hematopoietic stem cell
             transplantation.

         15. Known hypersensitivity to any component of the monoclonal antibody, paclitaxel or
             irinotecan formulation.

         16. Uncontrolled concurrent diseases, including but not limited to:

               -  HIV infection (HIV antibody positive).

               -  Active or clinically uncontrolled severe infections.

               -  Symptomatic congestive heart failure (New York Heart Association Class II-IV) or
                  symptomatic or poorly controlled arrhythmia.

               -  Uncontrolled arterial hypertension (systolic blood pressure ≥ 160 mmHg or
                  diastolic blood pressure ≥ 100 mmHg) despite standard treatment.

               -  Any arterial thromboembolism events within 6 months prior to inclusion for
                  treatment, including myocardial infarction, unstable angina, cerebrovascular
                  accident or transient ischemic attacks.

               -  Significant malnutrition, if intravenous nutrient solution supplement is
                  required; Except for malnutrition corrected for more than 4 weeks before first
                  dose of study treatment.

               -  Tumor invasion into surrounding vital organs (e.g., aorta and trachea) or a risk
                  for esophagotracheal fistula or esophagopleural fistula.

               -  Post esophageal or intratracheal stenting.

               -  History of deep vein thrombosis (DVT), pulmonary embolism, or any other serious
                  thromboembolism within 3 months prior to enrollment (implanted venous access port
                  or catheter-related thrombosis, or superficial venous thrombosis is not
                  considered as "serious"thromboembolism).

               -  Uncontrolled metabolic disorders or other non-malignant organic or systemic
                  diseases or reactions secondary to cancer, which can result in high medical risks
                  and/or uncertainty in survival evaluations.

               -  Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh class B or even more
                  severe cirrhosis.

               -  History of intestinal obstruction or the following diseases: inflammatory bowel
                  disease or extensive bowel resection (partial colectomy or extensive resection of
                  the small intestine, concurrent chronic diarrhea), Crohn's disease, ulcerative
                  colitis, or chronic diarrhea.

               -  Other acute or chronic diseases, mental disorders or abnormal laboratory findings
                  that may lead to the following results: increase risks associated with study
                  participation in the study or use of the study drug, or interfere with the
                  interpretation of study results, and render the patient ineligible for the study
                  at the investigator's discretion.

         17. Known acute or chronic active hepatitis B (HBsAg positive and HBV DNA ≥200 IU/mL or ≥
             10^3 copies/mL) or acute or chronic active hepatitis C (HCV antibody positive and
             positive for HCV RNA test).

         18. History of gastrointestinal perforation and/or fistula within 6 months prior to study
             inclusion.

         19. Presence of interstitial lung disease.

         20. Clinically uncontrollable effusion of the third space, such as pleural effusion and
             ascites that can not be controlled by drainage or other methods before enrollment.

         21. History of other primary malignancies, excluding:

               -  A malignancy with complete remission for at least 2 years before enrollment and
                  requiring no other treatment during the study;

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of relapse;

               -  Adequately treated carcinoma in situ without evidence of relapse.

         22. Pregnant or breastfeeding women.