Phase 2 Evaluation of Valemetostat Tosylate Monotherapy in Relapsed/Refractory Peripheral T-Cell Lymphoma Patients

Trial ID: 2023-507381-13-00
Protocol: DS3201-A-U202
Sponsor: Daiichi Sankyo Inc.

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Diseases & Conditions

Lymphoma

Objectives

The primary objective of this study is to estimate the **objective response rate (ORR)** with valemetostat tosylate monotherapy treatment in patients with **relapsed/refractory peripheral T-cell lymphoma (R/R PTCL)** in Cohort 1. Additionally, for Cohort 2, the study aims to assess the safety and tolerability of valemetostat tosylate monotherapy. These objectives are clinically relevant as they aim to determine the efficacy and safety profile of valemetostat tosylate, which could potentially offer a new therapeutic option for patients with limited treatment alternatives.

Secondary objectives include:

Evaluating the pharmacokinetics (PK) of valemetostat and its major metabolite (CALZ-1809a) across all cohorts.
For Cohort 1 only, assessing the duration of response (DoR), complete response (CR) rate, duration of CR (DoCR), partial response (PR) rate, and the safety and tolerability of valemetostat tosylate monotherapy.

Participants

The clinical trial involves a total of **101 participants** diagnosed with **Relapsed/Refractory Peripheral T-Cell Lymphoma**. The study population includes both male and female subjects, aged 18 years and older, with an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0, 1, or 2. Participants were selected based on their confirmed diagnosis by a local pathologist, and they must have documented refractory, relapsed, or progressive disease after at least one prior line of systemic therapy. The trial includes individuals who are considered ineligible for hematopoietic cell transplantation due to active disease, comorbidities, or other factors. The study population is characterized by a vulnerable group, and the selection criteria ensure that participants have measurable lesions and have undergone prior systemic therapy. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

Plans and Procedures

The clinical trial is a **Phase II** study designed to evaluate the efficacy and safety of **Valemetostat Tosylate** monotherapy in subjects with **relapsed/refractory peripheral T-cell lymphoma** (R/R PTCL). The trial employs a single-arm design, focusing on two cohorts: Cohort 1 aims to estimate the objective response rate (ORR) in subjects with R/R PTCL, while Cohort 2 assesses the safety and tolerability of the treatment. The study is expected to run from June 16, 2021, to March 2, 2026, with a maximum treatment period of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and histological diagnosis. Eligible subtypes of PTCL include, but are not limited to, enteropathy-associated T-cell lymphoma and angioimmunoblastic T-cell lymphoma. Following the screening, participants will receive **Valemetostat Tosylate** orally, with a maximum daily dose of 200 mg. Regular follow-up visits will be conducted to monitor safety, efficacy, and any adverse events, with assessments including laboratory tests, vital signs, and ECGs.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoints focus on the ORR for Cohort 1 and comprehensive safety assessments for Cohort 2. Secondary endpoints include the duration of response (DoR), progression-free survival (PFS), and overall survival (OS) for Cohort 1. The expected length of participant involvement is up to 24 months, contingent on individual response and tolerability.

Treatment

The clinical trial involves the administration of **Valemetostat Tosylate**, a chemical compound provided in the form of a film-coated tablet. The active substance, **valemetostat tosylate**, is manufactured by Daiichi Sankyo, Inc. The pharmaceutical form is specifically designed for oral administration. Participants in the trial will receive a maximum daily dose of 200 mg, with the total dose not exceeding 200 mg per day. The treatment period is set for a maximum of 24 weeks. The medication is not formulated for pediatric use and is designated as an orphan drug under the designation number EU/3/22/2572. The sponsor product code for this investigational drug is DS-3201b.

In this single-arm, Phase 2 study, **Valemetostat Tosylate** is used as a monotherapy for subjects with relapsed/refractory peripheral T-cell lymphoma (R/R PTCL). The trial aims to estimate the objective response rate (ORR) and assess the safety and tolerability of the treatment. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. Compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen.

Efficacy

The efficacy of Valemetostat Tosylate in the treatment of **Relapsed/Refractory Peripheral T-Cell Lymphoma (R/R PTCL)** will be assessed through a series of primary and secondary endpoints. The primary endpoint for Cohort 1 is the Objective Response Rate (ORR), defined as the proportion of subjects achieving a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR), as assessed by Blinded Independent Central Review (BICR). For Cohort 2, the primary focus is on safety assessments, including adverse event reporting and laboratory evaluations.

Secondary endpoints for Cohort 1 include Duration of Response (DoR), CR rate, Duration of Complete Response (DoCR), PR rate, Progression-Free Survival (PFS), and Overall Survival (OS). DoR is measured from the first documentation of objective response to disease progression or death. CR and PR rates are determined based on BICR assessments. PFS is defined as the time from the first dose to disease progression or death, while OS is the time from the first dose to death from any cause.

Additional secondary endpoints involve pharmacokinetic assessments, measuring total and unbound concentrations of DS-3201a (the free form of Valemetostat Tosylate) and its major metabolite CALZ-1809a in plasma. These measurements will be conducted at specified intervals throughout the trial to evaluate the drug's pharmacokinetic profile.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent
Subjects ≥18 years of age or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
Cohort 1 (R/R PTCL): Diagnosis should be confirmed by the local pathologist; local histological diagnosis will be used for eligibility determination. Subjects with the following subtypes of PTCL are eligible, according to 2016 World Health Organization classification prior to the initiation of study drug. Any T-cell lymphoid malignancies not listed below are excluded. Below is the complete list of eligible subtypes: - Enteropathy-associated T-cell lymphoma - Monomorphic epitheliotropic intestinal T-cell lymphoma - Hepatosplenic T-cell lymphoma - Primary cutaneous γδ T-cell lymphoma - Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma - PTCL, not otherwise specified - Angioimmunoblastic T-cell lymphoma - Follicular T-cell lymphoma - Nodal PTCL with TFH phenotype - Anaplastic large cell lymphoma, ALK positive - Anaplastic large cell lymphoma, ALK negative
Cohort 2 (R/R ATL): Acute, lymphoma, or unfavorable chronic type. R/R ATL should be confirmed by the local pathologist; local diagnosis will be used for eligibility determination. The positivity of anti-HTLV-1 antibody will be locally determined for eligibility
Must have at least one of the following lesions which are measurable in 2 perpendicular dimensions on computed tomography (or magnetic resonance imaging) based on local radiological read
Documented refractory, relapsed, or progressive disease after at least 1 prior line of systemic therapy. Refractory is defined as - Failure to achieve CR (or uncertified CR [CRu] for ATL) after first-line therapy; or - Failure to reach at least PR or stable disease) after second-line therapy or beyond
Must have at least 1 prior line of systemic therapy for PTCL or ATL. - Subjects must also be considered as HCT ineligible during Screening due to disease status (active disease), comorbidities, or other factors; the reason for HCT ineligibility must be clearly documented - In Cohort 1, subjects with ALCL must have prior brentuximab vedotin treatment

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Exclusion Criteria

Diagnosis of mycosis fungoides, Sézary syndrome, and primary cutaneous ALCL and systemic dissemination of primary cutaneous ALCL
Diagnosis of precursor T-cell lymphoblastic leukemia and lymphoma (T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma), T-cell prolymphocytic leukemia, or T-cell large granular lymphocytic leukemia
Prior malignancy active within the previous 2 years except for locally curable cancer that is currently considered as cured, such as cutaneous basal or squamous cell carcinoma, superficial bladder cancer, or cervical carcinoma in situ, or an incidental histological finding of prostate cancer
Presence of active central nervous system (CNS) involvement of lymphoma
History of autologous HCT within 60 days prior to first dose of study drug
History of allogeneic HCT within 90 days prior to the first dose of study drug
Clinically significant graft-versus-host disease (GVHD) or GVHD requiring systemic immunosuppressive prophylaxis or treatment
Inadequate washout period from prior lymphoma-directed therapy before enrollment, defined as follows: - Prior systemic therapy (eg, chemotherapy, immunomodulatory therapy, or monoclonal antibody therapy) within 3 weeks or 5 half-lives of the drug, whichever is longer, prior to the first dose of study drug - Had curative radiation therapy or major surgery within 4 weeks or palliative radiation therapy within 2 weeks prior to the first dose of study drug
Uncontrolled or significant cardiovascular disease, including: - Evidence of prolongation of QT/QTc interval (eg, repeated episodes of QT corrected for heart rate using Fridericia's method [QTcF] >450 ms) (average of triplicate determinations) - Diagnosed or suspected long QT syndrome, or known family history of long QT syndrome - History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes - Uncontrolled arrhythmia (subjects with asymptomatic, controllable atrial fibrillation may be enrolled), or asymptomatic persistent ventricular tachycardia - Subject has clinically relevant bradycardia of ≤ 50 bpm unless the subject has a pacemaker - History of second- or third-degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers, and have no history of fainting or clinically relevant arrhythmia with pacemakers, within 6 months prior to Screening - Myocardial infarction within 6 months prior to Screening - Angioplasty or stent graft implantation within 6 months prior to Screening - Uncontrolled angina pectoris within 6 months prior to Screening - New York Heart Association (NYHA) Class 3 or 4 congestive heart failure - Coronary/peripheral artery bypass graft within 6 months prior to Screening - Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) - Complete left bundle branch block
History of treatment with other EZH inhibitors
Current use of moderate or strong cytochrome P450 (CYP)3A inducers (Table 10.4)
Systemic treatment with corticosteroids (>10 mg daily prednisone equivalents). Note: Short-course systemic corticosteroids (eg, prevention/treatment for transfusion reaction) or use for a non-cancer indication (eg, adrenal replacement) is permissible
Known or suspected hypersensitivity to valemetostat tosylate or any of the excipients