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

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 (ORIENT-2)

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.

All randomized participants

Through the Analysis data cutoff date of 2-October-2019 (up to approximately 26 months). The cutoff date for the primary efficacy analysis was 02 August 2019 when 150 OS events were actually observed. Upon the observation, the study follow-up was extended for another 2 months. The safety data was cut off as of 2-October-2019. AEs were collected till 90 days after the last dose.

All-Cause Mortality assessed for all the participants who Started the study and Serious and Other (Not Including Serious) Adverse Events were assessed in all participants who received ≥1 dose of study treatment. 181 treated (94 sintilimab, 87chemotherapy).