E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare overall survival (OS) between the ONO-4538 group and control group (docetaxel or paclitaxel) in patients with esophageal cancer refractory or intolerant to combination therapy with fluoropyrimidine and platinum-based drugs. |
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E.2.2 | Secondary objectives of the trial |
• To compare progression-free survival (PFS) between the ONO-4538 group and control group (docetaxel or paclitaxel) in patients with esophageal cancer refractory or intolerant to combination therapy with fluoropyrimidine and platinum-based drugs. • To compare objective response rates between the ONO-4538 group and control group (docetaxel or paclitaxel) in patients with esophageal cancer refractory or intolerant to combination therapy with fluoropyrimidine and platinum-based drugs.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Sex: Male or female 2. Age (at the time of informed consent): 20 years and older 3. Patients with esophageal cancer and whose major lesion in the esophagus (if already resected, the major lesion in the esophagus prior to resection) satisfies the following criteria. For patients with multiple lesions, the deepest invasion by clinical diagnosis should be considered the major lesion. Lesions other than the major lesion should be considered as secondary lesions. Esophageal cancer in this study is defined as a cancer that has primarily developed from the esophagus. • Patients with a major lesion located in the cervical esophagus or thoracic esophagus (upper, middle, or lower thoracic region; including the esophagogastric junction) • Patients whose histological type of major lesion was pathologically proven squamous cell carcinoma or adenosquamous cell carcinoma (pathological diagnosis of secondary lesions in the esophagus is not mandatory) 4. Patients who are refractory or intolerant to combination therapy with fluoropyrimidine and platinum-based drugs for esophageal cancer, have previously received 1 treatment regimen, and are not indicated for a radical resection. The definition of refractory should be defined as follows; and a therapy applicable to the following should be counted as 1 regimen. • Patients whose PD or recurrence was confirmed by imaging during their initial chemotherapy (including chemoradiation) or within 8 weeks after the last dose of chemotherapy will be assessed as “refractory.” • Patients who underwent a radical resection (R0 resection confirmed) in conjunction with chemotherapy including neo-adjuvant/adjuvant therapy and chemoradiation (including patients who underwent chemoradiation followed by salvage surgery) whose recurrence was confirmed by imaging within 24 weeks after the last dose of chemotherapy will be determined as “refractory.” • If a CR (≥2 consecutive CRs confirmed by imaging after an interval of ≥4 weeks) was assessed as a result of the initial chemotherapy (including chemoradiation), patients whose recurrence was confirmed by imaging during the initial chemotherapy (including chemoradiation) or within 24 weeks after the last dose of chemotherapy will be determined as “refractory.” 5. Patients who have at least 1 measurable or non-measurable lesion per the RECIST Guideline Ver. 1.1 as confirmed by imaging within 28 days before randomization. The following requirements should also be satisfied: • The primary esophageal cancer should be deemed to be non-measurable lesion. • If patients only have lesions that were previously treated with radiation, the lesion should be limited to one with confirmed aggravation by imaging after radiation. • If patients have pericardial or pleural effusion or ascites only, the lesion should be limited to one with cytologically confirmed malignancy. 6. ECOG Performance Status Score 0 or 1 7. Patients with a life expectancy of at least 3 months 8. Patients must provide tumor tissue (stored tissue or tissue from the last biopsy) for analysis of PD-L1 expression. For patients who are unable to undergo another biopsy, stored tissue can be used for analysis. Tissue specimens must contain at least 100 evaluable tumor cells and must be available at the time of informed consent. 9. Patients whose latest laboratory data meet the below criteria within 7 days before randomization. If the date of the laboratory tests at the time of randomization is not within 7 days before the first dose of the investigational product, testing must be repeated within 7 days before the first dose of the investigational product, and these latest laboratory tests must meet the following criteria. Of note, laboratory data will not be valid if the patient has received a granulocyte colony-stimulating factor (G-CSF) or blood transfusion within 14 days before testing. • White blood cells ≥2,000/mm3 and neutrophils ≥1,500/mm3 • Platelets ≥100,000/mm3 • Hemoglobin ≥9.0 g/dL • AST (GOT) and ALT (GPT) ≤3.0-fold the upper limit of normal (ULN) of the study site (or ≤5.0-fold the ULN of the study site in patients with liver metastases) • Total bilirubin ≤1.5-fold the ULN of the study site • Creatinine ≤1.5-fold the ULN of the study site or creatinine clearance (either the measured or estimated value using the Cockcroft-Gault equation) >45 mL/min 10. Women of childbearing potential (including women with chemical menopause or no menstruation for other medical reasons)#1 must agree to use contraception#2 from the time of informed consent until 320 days or more after the last dose of the investigational product. Also, women must agree not to breastfeed from the time of informed consent until 320 days or more after the last dose of the investigational product. 11. Men must agree to use contraception#2 from the start of study treatment until 320 days or more after the last dose of the investigational product.
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E.4 | Principal exclusion criteria |
1. significant malnutrition. Patients will be excluded if they are receiving intravenous hyperalimentation, or require continuous infusion therapy with hospitalization. Patients whose nutrition has been well controlled for ≥28 days prior to randomization may be enrolled. 2. apparent tumor invasion on organs located adjacent to the esophageal disease (e.g., the aorta or respiratory tract). Patients will be excluded if they are receiving stent therapy in esophagus or respiratory tract. 3. multiple primary cancers 4. residual adverse effects of prior therapy or effects of surgery that would affect the safety evaluation of the investigational product in the opinion of the investigator or subinvestigator 5. current or past history of severe hypersensitivity to any other antibody products 6. concurrent autoimmune disease or history of chronic or recurrent autoimmune disease 7. current or past history of interstitial lung disease or pulmonary fibrosis diagnosed based on imaging or clinical findings. Patients with radiation pneumonitis may be randomized if the radiation pneumonitis has been confirmed as stable (beyond acute phase) without any concerns about recurrence. 8. concurrent diverticulitis or symptomatic gastrointestinal ulcerative disease 9. any metastasis in the brain or meninx that is symptomatic or requires treatment. Patients may be randomized if the metastasis is asymptomatic and requires no treatment. 10. pericardial fluid, pleural effusion, or ascites requiring treatment 11. uncontrollable, tumor-related pain 12. transient ischemic attack, cerebrovascular accident, thrombosis, or thromboembolism (pulmonary arterial embolism or deep vein thrombosis) within 180 days before randomization 13. history of uncontrollable or significant cardiovascular disease meeting any of the following criteria: ・ Myocardial infarction within 180 days before randomization ・ Uncontrollable angina pectoris within 180 days before randomization ・ New York Heart Association (NYHA) Class III or IV congestive heart failure ・ Uncontrollable hypertension despite appropriate treatment (e.g., systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg lasting 24 hours or more) ・ Arrhythmia requiring treatment 14. anticoagulant therapy for a disease. Patients receiving antiplatelet therapy including low-dose aspirin may be enrolled. 15. uncontrollable diabetes mellitus 16. systemic infections requiring treatment 17. ≥ Grade 2 peripheral neuropathy 18. systemic corticosteroids (except for temporary use, e.g., for examination or prophylaxis of allergic reactions) or immunosuppressants within 28 days before randomization 19. antineoplastic drugs (e.g., chemotherapy agents, molecular-targeted therapy agents, or immunotherapy agents) within 28 days before randomization 20. surgical adhesion of the pleura or pericardium within 28 days before randomization 21. surgery under general anesthesia within 28 days before randomization 22. surgery involving local or topical anesthesia within 14 days before randomization 23. radiotherapy within 28 days before randomization, or radiotherapy to bone metastases within 14 days before randomization 24. any radiopharmaceuticals (except for examination or diagnostic use of radiopharmaceuticals) within 56 days before randomization 25. positive test result for any of the following: HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, or HCV antibody 26. Patients with a negative HBs antigen test but a positive test result for either HBs antibody or HBc antibody with a detectable level of HBV-DNA 27. Women who are pregnant or breastfeeding, or possibly pregnant 28. Patients who have received any other unapproved drug (e.g., investigational use of drugs, unapproved combined formulations, or unapproved dosage forms) within 28 days before randomization 29. Patients who have previously received taxane agents to treat esophageal cancer. Patients who were not proven refractory (see the definition of refractory in inclusion criteria 4) or intolerant to taxane-based combination therapy and subsequently received fluoropyrimidine and platinum-based combination therapy, and then proven refractory or intolerant may be randomized. 30. Patients who are contraindicated to docetaxel or paclitaxel 31. Patients who have previously received ONO-4538 (MDX-1106 or BMS-936558), anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody or other therapeutic antibodies or pharmacotherapies for regulation of T-cells 32. Patients judged to be incapable of providing consent for reasons such as concurrent dementia 33. Other patients judged by the investigator or subinvestigator to be inappropriate as subjects of this study
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The time from randomization until death from any cause. |
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E.5.2 | Secondary end point(s) |
1. Objective response rate (ORR) 2. Disease control rate (DCR) 3. Progression free survival (PFS) 4. Duration of response 5. Time to response 6. Best overall response (BOR) 7. Maximum percent change from baseline in the sum of diameters of the target lesion
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
These endpoints were set to assess the efficacy of ONO-4538 and docetaxel or paclitaxel from various perspectives in patients with esophageal cancer. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Denmark |
Germany |
Italy |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |