JCOG2311: A randomized controlled phase II trial comparing nivolumab, ipilimumab plus radiotherapy versus nivolumab plus ipilimumab for metastatic esophageal cancer

JRCT ID: jRCT1031240461

Registered date:05/11/2024

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Esophageal cancer
• Date of first enrollment: 05/11/2024
• Target sample size: 74
• Study type: Interventional

Intervention(s)

Group A: Nivolumab (360 mg/body every 3 weeks or 240 mg/body every 2 weeks) + Ipilimumab (1 mg/kg every 6 weeks) in 6-week courses, continuing until progressive disease.

Group B: Three-dimensional conformal radiation therapy (24 Gy/3 fractions or 25 Gy/5 fractions) daily excluding weekends and holidays. Starting within 7 days after the last day of radiation therapy, Nivolumab (360 mg/body every 3 weeks or 240 mg/body every 2 weeks) + Ipilimumab (1 mg/kg every 6 weeks) in 6-week courses, continuing until progressive disease.

Outcome(s)

• Primary Outcome: Progression-free survival

Secondary Outcome

Overall survival
Response rate
Duration of response
Adverse event rate

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

(1) Diagnosed histologically with squamous cell carcinoma, adenosquamous carcinoma, or basaloid squamous cell carcinoma from endoscopic biopsy of the primary esophageal lesion.
(2) PD-L1 expression test result determined by Tumor Proportion Score (TPS) is known. Cases with unknown expression are ineligible.
(3) The primary lesion of the esophageal disease (primary tumor) is located in the cervical esophagus, thoracic esophagus, or esophagogastric junction (according to UICC-TNM 8th edition).
(4) Diagnosed with unresectable or recurrent esophageal cancer based on contrast-enhanced CT of the neck, chest, and abdomen, fulfilling one of the following conditions (A) or (B):
(A) For unresectable esophageal cancer, all the following conditions (i)-(iv) must be met:
(i) The wall invasion depth of the primary esophageal lesion is cT1-4a (UICC-TNM 8th edition), without lymph node metastasis invading the aorta, vertebrae, trachea, bronchi, or pulmonary vessels.
(ii) Distant metastasis other than #102mid (deep cervical lymph nodes) and #104 (supraclavicular lymph nodes).
(iii) Dysphagia score <= 2.
(iv) At least one lesion meets (a), (b), or (c) for radiation therapy:
(a) Unirradiated primary esophageal lesion with wall invasion depth of cT2 or deeper.
(b) Unirradiated lymph node lesion with a short diameter of 1.5 cm or more.
(c) Unirradiated distant metastasis with a long diameter of 1 cm or more.
(B) For recurrent esophageal cancer, all the following conditions (i)-(vi) must be met:
(i) If there is an esophageal lesion, the wall invasion depth is cT1-4a (UICC-TNM 8th edition), without lymph node metastasis invading the aorta, vertebrae, trachea, bronchi, or pulmonary vessels.
(ii) Distant metastasis other than #102mid (deep cervical lymph nodes) and #104 (supraclavicular lymph nodes).
(iii) Dysphagia score <= 2.
(iv) Not a single local regional recurrence.
(v) Not a single pulmonary lesion.
(vi) At least one lesion meets (a), (b), or (c) for radiation therapy:
(a)Unirradiated esophageal lesion with wall invasion depth of cT2 or deeper.
(b) Unirradiated lymph node lesion with a short diameter of 1.5 cm or more.
(c) Unirradiated distant metastasis with a long diameter of 1 cm or more.
(5) Has measurable lesions other than the lesions targeted for radiation therapy in this trial.
(6) Aged 18 years or older on the day of registration.
(7) Performance status is 0 or 1 according to ECOG criteria.
(8) No symptomatic bone metastasis or symptomatic brain metastasis.
(9) In a pre-registration consultation with a radiation oncologist, it is determined that prescribed radiation therapy can be administered to measurable lesions (target lesions) used for efficacy evaluation in this trial without exceeding dose limits for risk organs.
(10) If there is a history of radiation therapy, the following conditions (A) or (B) must be met:
(A) For unresectable esophageal cancer:
(i) No prior radiation therapy for esophageal cancer.
(ii) If there is a history of radiation therapy, including the lung as the irradiation field for other cancer types, at least 52 weeks have passed since the last radiation treatment until the registration date.
(iii) If there is a history of radiation therapy not including the lung as the irradiation field for other cancer
(B) For recurrent esophageal cancer:
(i) If there is a history of radiation therapy, including the lung as the irradiation field for esophageal cancer or other cancer types, at least 52 weeks have passed since the last radiation treatment until the registration date.
(ii) If there is a history of radiation therapy not including the lung as the irradiation field for esophageal cancer or other cancer.
(11) There is no history of pharmacotherapy for unresectable or recurrent esophageal cancer. If there is a history of chemotherapy for the initial esophageal cancer, the recurrence must occur more than 24 weeks (168 days) after the end of chemotherapy.
(12) There is no history of immune checkpoint inhibitor therapy.
(13) If antibiotics were administered before registration, more than 7 days must have passed since the last administration of antibiotics.
(14) If a blood transfusion was received before registration, more than 7 days must have passed since the last blood transfusion.
(15) No concomitant interstitial pneumonia was diagnosed by chest CT. However, a history of radiation pneumonitis or organizing pneumonia is acceptable.
(16) There is no pneumonitis of Grade 2 or higher.
(17) There is no history of autoimmune disease or chronic or recurrent autoimmune disease.
(18) The latest test values within 14 days before registration meet all of the following criteria:
(A) White blood cell count <= 8,600/mm3 or neutrophil to lymphocyte ratio <= 5.
(B) Neutrophil count >= 1,000/mm3.
(C) Platelet count >= 100,000/mm3.
(D) Total bilirubin <= 2.0 mg/dL.
(E) AST <= 100 U/L.
(F) ALT <= 100 U/L.
(G) Serum creatinine <= 1.5 mg/dL.
(19) Written consent for participation in the study has been obtained from the patient.

Exclude criteria

(1) Presence of active multiple cancers (synchronous multiple cancers/multiple cancers requiring treatment within a disease-free period of 2 years or less).
(2) Presence of an infection requiring systemic treatment.
(3) Fever of 38.0C or higher at registration.
(4) Women who are pregnant, may be pregnant, within 28 days postpartum, or breastfeeding. Men who wish their partner to become pregnant.
(5) Presence of a mental disorder or psychiatric symptoms that interfere with daily life and make participation in the trial difficult.
(6) Continuous systemic administration (oral or intravenous) of steroid drugs in a dose higher than prednisolone 10 mg/day or other immunosuppressive drugs (e.g., infliximab, cyclophosphamide, mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, tocilizumab).
(7) Presence of uncontrolled diabetes despite appropriate treatment.
(8) History of cerebrovascular accident (stroke, cerebral hemorrhage, subarachnoid hemorrhage) within the past year, or a history of two or more transient ischemic attacks.
(9) Presence of symptomatic congestive heart failure, unstable angina, or a history of myocardial infarction within the past 6 months.
(10) Presence of uncontrolled valvular disease, dilated cardiomyopathy, or hypertrophic cardiomyopathy.
(11) Positive for HBs antigen.
(12) Positive for HIV antibody (testing for HIV antibody is not required).
(13) Hypersensitivity to nivolumab, ipilimumab, polysorbate 80, or any other component or additive of these drugs.
(14) Presence of pulmonary fibrosis, severe emphysema, or both as diagnosed by chest CT.

Related Information

• Primary Sponsor: TSUSHIMA Takahiro
• Source(s) of Monetary Support: National Cancer Center Japan