Aclarubicin Plus Cyclophosphamide, Vincristine, and Prednisone (CAOP) in Patients With Previously Untreated Peripheral T-Cell Lymphoma

Официальное название

A Prospective, Single-Arm, Multi-center, Phase 2 Study of Aclarubicin Plus Cyclophosphamide, Vincristine, and Prednisone (CAOP) in Patients With Previously Untreated Peripheral T-Cell Lymphoma

Обзор

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare disorders that result from clonal proliferation of mature post-thymic lymphocytes. These T-cell neoplasms account for approximately 10-15% of all lymphomas. The most common subtype of PTCL is classified as "not otherwise specified" (NOS) which accounts for 30-40%. PTCLs have been treated similarly with CHOP (Cyclophosphamide, Hydroxydaunorubicin, Vincristine and Prednisone), often with etoposide (CHOEP), followed by high-dose therapy and autologous stem cell transplantation (ASCT) in first remission. However, \<50% of the patients are cured with CHOP alone, and the progression-free survival rates at 5 years are as low as 20% for PTCLs. Meanwhile, for elderly patients who can't endure CHOPE and proceed ASCT, the long-term survival is even worse. Aclarubicin is an anthracycline which showed good safety profile in the treatment of both myeloid and lymphocytic leukemia. 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. The purpose of this study is to determine the efficacy of Aclarubicin, Cyclophosphamide, Vincristine, and Prednisone (CAOP) in elderly patients with newly diagnosed PTCLs. The investigators hope to try to replace doxorubicin in CHOP with aclarubicin, which is less toxic, without reducing the efficacy of patients while ensuring safety.

Подробное описание

Peripheral T-cell lymphoma (PTCL) is a rare and highly heterogeneous group of hematologic malignancies, belonging to the T-cell tumor category of non-Hodgkin lymphoma (NHL). Compared to B-cell tumors, current understanding of T-cell leukemia and lymphoma remains relatively underdeveloped, and a significant proportion of patients are diagnosed at an advanced stage. Therefore, PTCL patients have not experienced the same level of prognostic improvement over the past 20 to 30 years. In recent years, however, with a deeper understanding of the molecular pathogenesis of PTCLs and the approval of numerous new drugs (including various epigenetic modifiers and biologics), the prognosis for T-cell lymphoma patients may be further improved.

Although histone deacetylase inhibitors (HDACi), PD-1/PD-L1 inhibitors, EZH2 inhibitors, and demethylating agents have made some progress in clinical research on PTCLs, their clinical application still relies heavily on CHOP-based chemotherapy regimens. A study of 239 patients with localized nodular PTCL showed that among patients receiving CHOP-like therapy ± radiotherapy, the 5-year overall survival (OS) was 58%, and the 5-year progression-free survival (PFS) was 53%. Multivariate analysis indicated that age ≥60 years and presence of B symptoms at onset were poor prognostic factors, while ALK-positive anaplastic large T-cell lymphoma had a better prognosis. Therefore, for elderly PTCL patients, there is an urgent need to find a low-toxicity, tolerable, and effective basic chemotherapy regimen.

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, which has good efficacy and low cardiotoxicity, to create a novel CAOP (aclarubicin, cyclophosphamide, vincristine, and prednisone) regimen for elderly patients newly diagnosed with PTCL. This combination chemotherapy regimen may improve efficacy while also considering tolerability and safety, providing a new treatment option for elderly patients with PTCLs.

Вмешательства

• Препарат Aclarubicin
  20mg/m\^2/D, D1-4, QD, ivgtt
• Препарат Cyclophosphamide
  750 mg/m\^2, D1, ivgtt
• Препарат Vincristine
  1.4 mg/m\^2, D1 (maximum 2mg/d), IV
• Препарат Prednisone
  60 mg/m\^2, D1-5 (maximum 100mg/d), Po

Первичные конечные точки

• Complete remission rate (CR) [Срок оценки: After a maximum of 6 cycles of CAOP regimen (each cycle is 28 days)]

Вторичные конечные точки (5)

• Progression Free Survival [Срок оценки: Maximum follow-up period is 2 years after the end of treatment.]
• Overall Survival [Срок оценки: maximum follow-up period is 2 years after the end of treatment.]
• 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 ≥ 65 years at enrollment
• ECOG performance status score ≤ 2
• Able to comply with the research visit plan and other protocol requirements
• Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) who have not previously received treatment

The following subtypes as defined by the World Health Organization (WHO) classification (2022) are eligible, with Ann Arbor stage I-IV, and pathological immunohistochemical CD30 negative:

• Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS)
• Nodal T-follicular helper cell lymphoma (TFH)
• Anaplastic large cell lymphoma, ALK-negative (ALCL)
• Life expectancy ≥ 3 months
• Hematological, renal, and hepatic function all meet the requirements:

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

Критерии исключения

• Mental illness, disability, or social circumstances that may affect participant safety, ability to provide informed consent, or poor adherence
• Other types of lymphoma
• Previous immunotherapy or chemotherapy for PTCL, excluding those who used corticosteroids (≤8 days) prior to enrollment
• Previous radiotherapy for PTCL, excluding those confined to a single lymph node region
• Pathological immunohistochemistry showing CD30 positivity and/or ALK positivity
• Patients planning to receive autologous or allogeneic transplantation as first-line consolidation therapy
• Confirmed central nervous system/meningeal involvement
• Significant uncontrolled comorbidities or infections, specifically:

• Uncontrolled infection requiring intravenous antibiotics
• Clinically significant heart disease (NYHA Class III or IV), unstable angina
• History of angioplasty, stent implantation, or myocardial infarction within the past 6 months
• Uncontrolled hypertension (systolic blood pressure >160 mmHg) despite using two antihypertensive medications. (or diastolic blood pressure >100 mmHg, measured twice consecutively, one week apart)
• Clinically significant cardiac arrhythmias
• Uncontrolled diabetes
• Known or detected positive for human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV-1), hepatitis B, or hepatitis C.
• Patients diagnosed with malignancy within the past two years. However, the following are excluded: 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 within the past two years, provided there is currently no evidence of active disease.

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: NCT07535762 · Acla-PTCL

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗