Phase I-II Study of Romidepsin Combined with CHOEP for Initial Treatment in Young Patients with Nodal Peripheral T-Cell Lymphomas Prior to Hematopoietic Stem Cell Transplantation

The primary objective of this study is to determine the **maximum tolerated dose (MTD)** of Ro-CHOEP-21 in Phase I and to evaluate its efficacy in terms of **Progression Free Survival (PFS)** in Phase II. This is clinically relevant as it aims to optimize the dosing regimen and assess the treatment's effectiveness in prolonging the time patients with nodal peripheral T-cell lymphomas remain free from disease progression.

Secondary objectives include:

• Phase I: Assessing the feasibility of the Ro-CHOEP-21 treatment strategy combined with **stem cell transplantation (SCT)**.
• Phase II: Evaluating the overall response rate (ORR) and complete response (CR) rate before and after SCT.
• Phase II: Assessing **event-free survival (EFS)** and overall survival (OS).
• Phase II: Evaluating the safety of the treatment.
• Phase II: Evaluating the outcome of early allogeneic SCT in patients in partial response (PR) at the end of the induction phase.
• Phase II: Estimating the treatment-related mortality (TRM).
• Phase II: Evaluating the incidence of acute and chronic **graft-versus-host disease (GVHD)** in allografted patients.
• Phase II: Improving knowledge on the diagnosis, classification, and biology of peripheral T-cell lymphomas (PTCL).

The sponsor does not provide information regarding the total number of participants in this clinical trial. The study population comprises both **male** and **female** subjects, aged between 18 and 65 years, who are diagnosed with specific types of **Peripheral T-cell Lymphoma**, including Anaplastic Large T-cell Lymphoma ALK negative, Angioimmunoblastic T-cell Lymphoma, and Peripheral T-cell lymphoma, NOS. Participants are required to have a general health status that includes normal liver function tests, adequate cardiac and pulmonary function, and no active, uncontrolled infections. The trial excludes individuals with psychiatric illnesses that impair understanding of the trial, those with prior lymphoma treatment, and those with Central Nervous System involvement. Lifestyle considerations include the use of effective contraceptive methods for participants of child-bearing potential. The trial does not involve a vulnerable population, and all participants must provide written informed consent and have histological material available for central review and pathobiological studies.

The clinical trial is designed as a **Phase I-II** study to evaluate the safety and efficacy of **Romidepsin** in combination with CHOEP as a first-line treatment before hematopoietic stem cell transplantation in young patients with nodal peripheral T-cell lymphomas. The trial is structured as a randomized, double-blind, controlled study. The estimated duration of the trial spans from September 2014 to March 2025, with the primary objective of Phase I being to define the maximum tolerated dose (MTD) of Ro-CHOEP-21, and Phase II focusing on evaluating the efficacy in terms of progression-free survival (PFS).

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, liver function, cardiac health, and absence of active infections. Following successful screening, participants will be enrolled and randomized into the study. The trial includes multiple follow-up visits to monitor the incidence of dose-limiting toxicity (DLT) and overall response rate (ORR) according to the Lugano Classification 2014 response criteria. The end-of-study visit will evaluate the primary and secondary endpoints, including event-free survival (EFS) and overall survival (OS).

The expected length of participant involvement is approximately 18 months, with conditions for early termination including the development of any grade ≥3 non-hematological toxicity or a delay of more than 15 days in the planned cycle date, as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Participants may also be withdrawn if they experience disease progression, relapse, or death from any cause. The study aims to provide comprehensive data on the safety and efficacy of the treatment regimen, contributing valuable insights into the management of peripheral T-cell lymphomas.

The clinical trial involves the administration of **Romidepsin**, a **histone deacetylase inhibitor**, as part of the experimental treatment regimen. Romidepsin is provided in the form of a **solution for injection** and is administered **intravenously**. The active substance, romidepsin, is chemically synthesized and is also known by other names such as depsipeptide, FK228, FR901228, and NSC630176. The pharmaceutical product is manufactured by Celgene Corporation. The trial aims to determine the maximum tolerated dose and evaluate the efficacy of the treatment in terms of progression-free survival in young patients with nodal peripheral T-cell lymphomas.

In addition to Romidepsin, the study incorporates a combination therapy known as CHOEP, which is a standard-of-care regimen for the treatment of lymphomas. CHOEP consists of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone. This combination is administered according to established dosing schedules and protocols. The frequency and route of administration for each component of CHOEP are consistent with standard clinical practice for lymphoma treatment. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of the clinical trial involving **Romidepsin** in combination with CHOEP as a first-line treatment for young patients with nodal peripheral T-cell lymphomas will be assessed through several primary and secondary endpoints. In Phase I, the primary endpoint is the incidence of dose-limiting toxicity (DLT) of Ro-CHOEP-21, defined as any grade ≥ 3 non-hematological toxicity or a delay of more than 15 days in the planned cycle date, as per the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. In Phase II, the primary endpoint is Progression-Free Survival (PFS) evaluated at 18 months, defined as the time from enrollment to disease progression, relapse, or death from any cause.

Secondary endpoints include the proportion of patients reaching stem cell transplantation (SCT), overall response rate (ORR) and complete response (CR) according to the Lugano Classification 2014, event-free survival (EFS), and overall survival (OS). EFS is defined as the time from enrollment to treatment discontinuation for any reason, while OS is the time from enrollment to death from any cause. Additional assessments include PFS and OS in patients not responding to the first three courses of Ro-CHOEP-21, evaluation of any grade III or higher toxicities during interim analyses and the pretransplant phase, treatment-related mortality, and the incidence of acute and chronic graft-versus-host disease (GVHD) in allografted patients.