Ivarmacitinib in Advanced Solid Tumors: A Prospective, Two-Cohort, Two-Phase Exploratory Study in Patients Discontinued Due to Immune Intolerance

Обзор

This study is a Phase II, two-cohort, multicenter, two-stage clinical trial. It plans to enroll 72 subjects with solid tumors who discontinued prior ICI therapy due to irAE. Cohort 1 enrolls subjects with irAE resistant to or dependent on corticosteroid therapy. Subjects in Cohort 1 who achieve ≤ Grade 1 irAE resolution following treatment may then enroll in Cohort 2. Cohort 2 enrolls subjects with irAE achieving ≤ Grade 1 resolution following treatment, and deemed eligible for ICI re-initiation by the investigator. Phase I is the safety run-in phase, enrolling 6 subjects per cohort. Phase II is the expansion phase, enrolling 30 subjects per cohort.

Вмешательства

• Препарат Ivarmacitinib
  8 mg, orally, once daily. Cohort 1: Continue dosing until irAE resolves to ≤ Grade 1, with a maximum treatment duration of 28 days.
• Препарат Ivarmacitinib
  Cohort 2: Combination therapy with ICIs, with a maximum treatment duration not exceeding the duration of ICI administration.

Первичные конечные точки

• Response rate to adverse reactions during the treatment cycle [Срок оценки: In the study, treatment was administered on day 30 after the last dose.]
• Discontinuation rate due to irAE [Срок оценки: Follow-up visits were conducted every 30 days from the last dose of treatment until 90 days.]

Критерии участия

Критерии включения

• Age ≥ 18 years.
• ECOG performance status score 0-1.
• Expected survival ≥ 12 weeks.
• Solid tumor patients who have discontinued treatment with immune checkpoint inhibitors (ICIs).
• Treatment with ICIs may be administered as monotherapy or in combination with other therapies (including but not limited to radiotherapy, chemotherapy, targeted therapy, etc.).
• Current Status of irAE:

Cohort I:

• Patients currently diagnosed with steroid-resistant or steroid-dependent immune-related adverse events (immune myocarditis, immune colitis, immune myositis-arthritis, immune skin reactions, immune hepatitis, etc.);
• Patients with contraindications to steroid use, or who refuse continued steroid therapy due to adverse reactions following steroid administration.

Cohort II:

• Patients discontinued immunotherapy due to irAE (CTCAE 5.0) after receiving ≥1 line of treatment including ICIs;
• Time since discontinuation of immunotherapy due to irAE ≤3 months;
• irAE has resolved to ≤Grade 1.
• The patient still possesses certain organ and bone marrow functions:

Cohort 1:

• Hemoglobin ≥90 g/L, neutrophil count ≥1.0 × 10\^9/L, platelet count ≥75 × 10\^9/L; lymphocyte count ≥0.5 × 10\^9/L; coagulation function: INR, APTT, and PT all ≤1.5 × UNL;
• Liver function: Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN), aspartate aminotransferase (AST) ≤ 3 × ULN, alanine aminotransferase (ALT) ≤ 3 × ULN. For patients with immune hepatitis, specific liver function biochemical parameters are not restricted; adequate liver function is defined as Child-Pugh class A-B;
• Renal function: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min;
• Or patients assessed by the investigator as having adequate organ function.

Cohort II:

Organ function levels must meet the following requirements (no blood transfusion or hematopoietic growth factor therapy within 2 weeks prior to blood screening):

• ANC ≥ 1.5 × 10⁹/L;
• PLT ≥ 100 × 10⁹/L;
• Hb ≥ 90 g/L;
• TBIL ≤ 1.0 × ULN;
• ALT and AST ≤ 2.5 × ULN;
• BUN and Cr ≤ 1.5 × ULN.
• All women of childbearing potential must have a negative serum pregnancy test during the screening period and must use reliable contraception from signing the informed consent form until 3 months after the last dose.
• Subjects voluntarily participate in this study, sign the informed consent form prior to the screening process, demonstrate good compliance, and cooperate with safety follow-up.
• The subject is judged by the investigator to be able to adhere to the study protocol.

Критерии исключения

• 1\) Individuals with allergic diseases, a history of severe drug allergies, or potential hypersensitivity to Ivarmacitinib or its components; 2) Patients diagnosed with an embolic event within 3 months prior to enrollment, excluding superficial venous thrombosis (e.g., deep vein thrombosis, pulmonary embolism, embolic stroke, myocardial infarction, or peripheral arterial insufficiency); 3) Patients with severe non-irAE-related cardiac, hepatic, renal, or systemic diseases; 4) Patients with active tuberculosis or who received live vaccines during the illness period; 5) Patients with uncontrolled infectious diseases; 6) Patients with moderate to severe heart failure (NYHA Class III/IV); 7) Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive, with hepatitis B virus (HBV) deoxyribonucleic acid (DNA) exceeding 500 IU/mL or 1000 copies per milliliter (cps/mL); Hepatitis C virus (HCV) antibody (HCV-Ab) positive with HCV RNA quantitative levels exceeding the upper limit of normal for the assay; HIV antibody (Anti-HIV) positive; active syphilis. Meeting any one of the above criteria.

8\) Previous treatment with JAK inhibitors prior to enrollment (for Cohort 1: ≤30 days of prior JAK inhibitor use, irAE resolution ≤ Grade 1, and investigator assessment permitting ICI restart; eligible for Cohort 2); 9) Cohort 2 participants with prior ICI restart therapy, including but not limited to PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, etc.; 10) Patients receiving intravenous biologic therapy for other baseline autoimmune diseases; 11) Pregnant or lactating females, and males or females unwilling to use contraception; 12) Psychiatric disorders impairing study compliance; 13) Subjects deemed unsuitable for this study by the investigator shall be excluded, such as those judged to have other factors that may necessitate premature termination of the study. These include: - Concurrent treatment for other serious illnesses (including psychiatric disorders) - Severe laboratory abnormalities - Family or social circumstances that may compromise subject safety or interfere with data/sample collection.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Перекрёстный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07313202 · MA-SOLID-II-004

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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