Aclarubicin Plus Cyclophosphamide, Vincristine, and Prednisone (CAOP) in Patients With Previously Treated Cutaneous T-cell Lymphoma

Официальное название

A Multicenter, Open-Label, Phase 1/2 Clinical Study of the Safety and Efficacy of Aclarubicin Plus Cyclophosphamide, Vincristine, and Prednisone (CAOP) in Patients With Previously Treated Cutaneous T-cell Lymphoma

Обзор

Cutaneous T-cell lymphomas (CTCL) are a rare and heterogeneous group of extranidal T-cell lymphomas characterized by skin involvement. Current treatment options for CTCL are limited. Although responses have been demonstrated, their duration is often short, especially in patients with advanced stage disease. Additional treatment options are needed which demonstrate activity in cutaneous and extracutaneous sites. The traditional CHOP regimen (Cyclophosphamide, Hydroxydaunorubicin, Vincristine and Prednisone) has some efficacy for CTCL patients, but due to the cardiotoxicity of anthracyclines, patients can only receive a limited course of treatment. After stopping the regimen, most patients will experience relapse. Aclarubicin, also known as aclacinomycin A, is an anthracycline type of antibiotic with significant anti-cancer properties. Previous studies have shown that aclarubicin only induces histone eviction without causing DNA damage, and it stands out in pre-clinical models and clinical studies, as it potently kills AML cells. Meanwhile, aclarubicin lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Aclarubicin's treatment indications include malignant lymphoma, but actual clinical application experience is limited. The purpose of this study is to determine the maximum tolerated dose, safety and efficacy of aclarubicin combined with cyclophosphamide, vincristine, and prednisone (CAOP) for subjects with relapsed or refractory CTCL.

Подробное описание

The estimated incidence of CTCL in China is 6.9 per million, accounting for 75% to 80% of primary cutaneous lymphomas. CTCL has diverse subtypes, stages, and clinical manifestations, with mycosis fungoides (MF) being the most common subtype. The etiology of CTCL remains unclear, but it may be related to DNA damage, epigenetic regulation, programmed cell death, and abnormalities in the T-cell receptor (TCR) signaling pathway.

The diagnosis and classification of CTCL primarily refer to the 5th edition of the World Health Organization (WHO) Classification of Hematopoietic and Lymphoid Neoplasms. A definitive diagnosis requires a comprehensive assessment of the patient's clinical presentation, histopathological findings, immunohistochemical staining, and TCR gene rearrangement testing. Sézary syndrome (SS) is no longer classified as CTCL in 5th edition of the WHO Classification. However, due to its close association with MF, current treatment recommendations still do not separate SS from MF. Early skin manifestations of CTCL include patchy or plaque-like lesions. Advanced stages may develop tumors or erythroderma. Extracutaneous involvement may also occur, often with regional lymph node involvement and the presence of atypical lymphocytes in the peripheral blood. Prognostic factors for CTCL include the presence of extracutaneous involvement, the body surface area of affected skin, the type of skin lesion, and the pathological type. Currently, disease staging and treatment efficacy assessment are primarily based on the 2022 ISCL/USCC/EORTC recommended criteria.

Commonly used systemic therapies for CTCL include interferon α, oral retinoids, histone deacetylase inhibitors, CD30 antibody-drug conjugates (velutuximab), and CCR4 monoclonal antibodies (moglizumab). The global Phase III MAVORIC study of moglizumab demonstrated a median progression-free survival (PFS) of 7.7 months and a median time to next treatment (TTNT) of 11 months in adult patients with relapsed/refractory SS or stage III-IV MF. The objective response rate (ORR) in hematology was 68%, and the ORR in skin reached 42%. However, due to cost and accessibility, clinical application in China remains limited. For patients who have failed these systemic therapies, existing combination chemotherapy regimens, while effective, are limited by patient tolerance, toxicity, and comorbidities, making continued use difficult.

Aclarubicin (Acla) is an anthracycline anticancer drug. In vitro, Acla has demonstrated potent cytotoxicity against various lymphoma and T-lymphocytic leukemia cell lines. Mechanistic studies of anthracyclines have revealed that doxorubicin, epirubicin, daunorubicin, and idarubicin all induce tumor cell apoptosis through two mechanisms: 1. DNA damage: through inhibition of topoisomerase II (Topo II), leading to DNA double-strand breaks (DSBs); and 2. Chromatin damage: through histone removal, causing chromatin alterations at specific genomic loci. However, these dual mechanisms also lead to dose-dependent, irreversible cardiotoxicity. Compared with classic anthracyclines (such as doxorubicin and daunorubicin), Acla does not cause DNA damage and accumulates significantly in lymphoid tissues (spleen, thymus, and lymph nodes), with poor distribution to other tissues. Consequently, its cardiotoxicity is significantly reduced. Even at high cumulative doses, it is less likely to cause cardiac dysfunction. Therefore, Acla may offer a safer option for elderly patients or those with concomitant heart disease. Previous studies have shown that the combination of Acla and cytarabine (such as the CAG regimen) has some efficacy and is well tolerated in relapsed/refractory and elderly patients with acute myeloid leukemia. In the 1980s and 1990s, studies explored the use of Acla in chemotherapy regimens for non-Hodgkin's lymphoma and Hodgkin's lymphoma, demonstrating some activity. Small studies have shown that Acla monotherapy can achieve a response rate of approximately 30% in patients with advanced non-hedging lymphoma, without compromising cardiac function. Japanese researchers have found that combination chemotherapy regimens containing Acla in T-cell lymphomas exhibit superior efficacy.

In this study, the investigators will replace doxorubicin in the traditional CHOP regimen with aclarubicin, a drug with proven efficacy and low cardiotoxicity, to create a novel aclarubicin, cyclophosphamide, vincristine, and prednisone (CAOP) regimen for patients with relapsed/refractory CTCL and SS who have received at least one prior systemic therapy. This combination chemotherapy regimen may improve efficacy while balancing tolerability and safety, providing a new treatment option for elderly patients with CTCL.

Вмешательства

• Препарат Aclarubicin
  Cycle 1-6: Phase I starting dose 20mg/m\^2/D, D1-2 (dose group 1), D1-3 (dose group 2), D1-4 (dose group 3), QD, ivgtt The Phase II dose was determined based on the Phase I results Cycle 7-10: Phase I starting dose 20mg/ m\^2/D, D1-2 (dose group 1), D1-3 (dose group 2), D1-4 (dose group 3), QD, ivgtt The Phase II dose was determined based on the Phase I results
• Препарат Cyclophosphamide
  Cycle 1-6 750 mg/m\^2, D1, QD, ivgtt Cycle 7-10 750 mg/m\^2, D1, QD, ivgtt
• Препарат Vincristine
  Cycle 1-6 1.4 mg/m\^2, D1 (maximum 2mg/d), QD, iv Cycle 7-10 1.4 mg/m\^2, D1 (maximum 2mg/d), QD, iv
• Препарат Prednisone
  Cycle 1-6 60 mg/m\^2, D1-5 (maximum 100mg/d), QD, Po Cycle 7-10 60 mg/m\^2, D1-5 (maximum 100mg/d), QD, Po

Первичные конечные точки

• Maximum tolerated dose (MTD) [Срок оценки: 28 days after first dose of aclarubicin]
• Recommended Phase 2 Dose (RP2D) [Срок оценки: 28 days after first dose of aclarubicin]
• Objective response rate (ORR) [Срок оценки: At the end of induction cycle 6 (each cycle is about 28 days)]

Вторичные конечные точки (6)

• Objective response rate (ORR) [Срок оценки: At the end of induction cycle 6 (each cycle is about 28 days)]
• Progression Free Survival [Срок оценки: All enrolled patients were followed up for at least 12 months or had an event]
• Time to Next Treatment (TTNT) [Срок оценки: All enrolled patients were followed up for at least 12 months or had an event]
• Adverse Events [Срок оценки: From enrollment to 28 days after the end of treatment]
• Change in quality of life as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) global health status score [Срок оценки: From enrollment to 28 days after the end of treatment]
• Cancer-related fatigue as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue score [Срок оценки: From enrollment to 28 days after the end of treatment]

Критерии участия

Критерии включения

• Understand and voluntarily sign the informed consent form
• Age ≥ 60 years at enrollment
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Histologically confirmed primary cutaneous T-cell lymphoma (CTCL) or Sézary syndrome (SS) (according to the fifth edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid System)
• Stage II-B, III, or IV (referring to the Olsen criteria of the International Society for Cancer Research (ISCL)/USCC/EORTC, 2022)
• Patients who have failed at least one systemic therapy; psoralen combined with ultraviolet radiation therapy (PUVA) is not considered a systemic therapy
• All clinically significant toxicities caused by previous anticancer therapy have resolved to ≤ Grade 1 (according to NCI-CTCAE v5.0 criteria)
• Hematological, renal, and liver function tests meet the following requirements:

• Absolute neutrophil count (ANC) ≥ 1,500 cells/μL
• Platelet count ≥ 100,000 cells/μL
• For patients with known bone marrow involvement, ANC ≥ 1,000 cells/μL and platelets ≥ 75,000 cells/μL
• Total bilirubin ≤ 1.5 times the institutional upper limit of normal (ULN) (except for patients with Gilbert syndrome)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN; if liver involvement is known in C TCL, ≤ 5.0 × ULN
• Serum creatinine ≤ 1.5 × ULN, or creatinine clearance calculated by the Cockcroft-Gault formula > 50 mL/min

Критерии исключения

• Patients diagnosed with a malignancy within the past two years. Exclude the following situation: non-melanoma skin cancer, melanoma in situ, localized prostate cancer (current PSA <0.1 ng/mL), treated thyroid cancer; or cervical carcinoma in situ or breast ductal/lobular carcinoma in situ diagnosed within the past two years, as long as there is no current evidence of active disease.
• Clinical evidence of central nervous system (CNS) infiltration.
• Large cell transformation (LCT). Patients with a history of LCT but no current invasive disease and no evidence of LCT on skin or lymph node pathology may be enrolled.
• Psychiatric illness, disability, or social circumstances that may affect the subject's safety, ability to provide informed consent, or poor compliance.
• Patients with significant uncontrolled comorbidities or infections, as follows:

• Uncontrolled infection requiring intravenous antibiotics
• Clinically significant heart disease (New York Heart Association class III or IV), unstable angina
• History of angioplasty, stent implantation, or myocardial infarction within 6 months
• Uncontrolled hypertension despite treatment with two antihypertensive medications (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg, measured on two consecutive occasions, one week apart)
• Clinically significant arrhythmias
• Uncontrolled diabetes mellitus
• Known or tested positive for human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV-1), hepatitis B, or hepatitis C.
• Active herpes simplex or herpes zoster. Patients who have started antiviral prophylaxis ≥30 days prior to the pretreatment visit, have no signs of active infection, and whose last active infection occurred more than 6 months ago may be enrolled and must continue taking prescribed medications during the study.
• Known active autoimmune disease (e.g., Graves' disease, systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, psoriasis).
• Allergic reaction to study medications.
• History of allogeneic transplantation.
• Pregnancy (confirmed by β-hCG) or lactation.

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

Китай · 2 центра

• Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai — Шанхай
• Ruijin Hospital Wuxi Branch — Wuxi

Идентификаторы

NCT: NCT07535710 · Acla-CTCL

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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