Immunotherapy in Patients With Early dMMR Rectal Cancer

Обзор

The purpose of this investigator-initiated, multicenter phase II trial is to evaluate the efficacy and tolerability of nivolumab and ipilimumab in patients with stage 1-3 MSI/dMMR rectal cancer. The primary objective is: Number of patients with complete clinical response after one or two cycles of immunotherapy. Patients will be treated with 1 or 2 cycles of combination immunotherapy: Cycle 1: Nivolumab 3 mg/kg days 1 and 15 \& ipilimumab 1 mg/kg day 1 Cycle 2: Nivolumab 3 mg/kg days 50 and 65 \& ipilimumab 1 mg/kg day 50

Вмешательства

• Препарат Nivolumab
  Nivolumab is a highly selective fully humanized, IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1) (17). PD-1 is an inhibitory receptor expressed on the surface of T-cells, B cells, macrophages, and NK cells. Endogenous binding of PD-1 with one of its two ligands PD-L1 and PD-L2 results in production of an inhibitory signal which results in reduction of T-cell proliferation, cytokine production, and cytotoxic activity. This results in significant dampening of the immune response. N
• Препарат Ipilimumab
  Ipilimumab is a fully humanized monoclonal anti-CTLA-4 antibody that acts as an antineoplastic ICI by selectively binding to cytotoxic T-lymphocyte-associated antigen 4, a molecule located on the surface of cytotoxic T-cells, suppressing the immune response (17). Ipilimumab blocks CTLA-4, leading to a continuously active immune response in malignant cells.

Первичные конечные точки

• Complete clinical response [Срок оценки: Evaluated at day 93 (+/- 7 days) after one or two cycles of immunotherapy. (Each cycle is 7 weeks)]

Вторичные конечные точки (7)

• Complete biological response [Срок оценки: Evaluated at day 93 (+/- 7 days) after one or two cycles of immunotherapy. (Each cycle is 7 weeks)]
• 12 months recurrence [Срок оценки: after 12 months]
• Respons rate [Срок оценки: after 1 or 2 cycles of immunotherapy. (Each cycle is 7 weeks)]
• Adverse events [Срок оценки: after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks)]
• Bio-marker predictive models for treatment response and survival. [Срок оценки: after 1 or 2 cycles of immunotherapy. (Each cycle is 7 weeks)]
• Quality of life (EORCT QLQ-C30) [Срок оценки: after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks)]
• Quality of life (EORCT QLQ-CR29) [Срок оценки: after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks)]

Критерии участия

Критерии включения

• Age ≥ 18 years.
• Histologically verified non-metastatic rectal cancer stage 1-3.
• No indication for local therapy like TEM.
• Histologically verified dMMR or MSI.
• Performance status (WHO) of 0-1.
• No previous chemotherapy, radiotherapy or immunotherapy for colorectal cancer
• Adequate haematological function defined as neutrophils ≥ 1.5 x 109/l and platelets ≥ 100 x 109/l.
• Adequate organ function (bilirubin ≤ 1.5 x UNL (upper normal limit), GFR (may be calculated) > 30 ml/min.
• Women of childbearing potential must have been tested negative in a serum pregnancy test within five days prior to registration. Fertile patients must agree to use a highly effective method of birth control. (i.e., pregnancy rate of less than 1 % per year) (Appendix 1) during the study and for six months after the discontinuation of study medication.
• Has provided written informed consent prior to performance of any study procedure.
• Written informed consent must be obtained according to the local Ethics Committee requirements.

Критерии исключения

• Any other condition or therapy, which in the investigator's opinion may pose a risk to the patient or interfere with the study objectives.
• Concomitant use of systemic glucocorticoids more than the equivalent dose to tablet prednisolone 10 mg/day. Treatment with systemic glucocorticoids must end no later than two weeks before inclusion.
• Subjects with active, known, or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol.
• Known allergy or intolerance to any of the drugs used (nivolumab and ipilimumab).

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Дания · 5 центров

• Aalborg University Hospital — Aalborg
• Aarhus University Hospital — Aarhus
• Rigshospitalet — Copenhagen
• Department of Oncology, Odense University Hospital — Odense
• Zealand University Hospital — Roskilde

Идентификаторы

NCT: NCT05732389 · KFE nr. 22.20

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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