Valemetostat Tosylate (DS-3201b), an Enhancer of Zeste Homolog (EZH) 1/2 Dual Inhibitor, for Relapsed/Refractory Peripheral T-Cell Lymphoma (VALENTINE-PTCL01)

Relapsed/Refractory Peripheral T-Cell Lymphoma Clinical Trial

Official title:

Single-arm, Phase 2 Study of Valemetostat Tosylate Monotherapy in Subjects With Relapsed/Refractory Peripheral T-Cell Lymphoma (VALENTINE-PTCL01)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04703192
• Other study ID #: DS3201-A-U202
• Secondary ID: 2020-004954-31jR
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 3, 2021
• Est. completion date: September 8, 2025

Study information

• Verified date: April 2024
• Source: Daiichi Sankyo
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will characterize the safety and clinical benefit of valemetostat tosylate in participants with relapsed/refractory peripheral T-cell lymphoma, including relapsed/refractory adult T-cell leukemia/lymphoma.

Description:

This study was designed to evaluate the efficacy and safety of valemetostat tosylate monotherapy. The primary objective will evaluate objective response rate of valemetostat tosylate monotherapy as measured by blinded independent central review (BICR) in relapsed/refractory peripheral T-cell lymphoma.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 148
• Est. completion date: September 8, 2025
• Est. primary completion date: May 10, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Written informed consent
• Participants =18 years of age or the minimum legal adult age (whichever is greater) at the time the informed consent form is signed.
• Eastern Cooperative Oncology Group performance status of 0, 1, or 2
• Cohort 1 relapsed/refractory peripheral T-cell lymphoma (PTCL):
• Diagnosis should be confirmed by the local pathologist; local histological diagnosis will be used for eligibility determination. Participants with the following subtypes of PTCL are eligible according to 2016 WHO classification prior to the initiation of study drug. Any T-cell lymphoid malignancies not

listed are excluded. Eligible subtypes include:

• Enteropathy-associated T-cell lymphoma
• Monomorphic epitheliotropic intestinal T-cell lymphoma
• Hepatosplenic T-cell lymphoma
• Primary cutaneous ?d 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 T-follicular helper (TFH) phenotype
• Anaplastic large cell lymphoma, ALK positive
• Anaplastic large cell lymphoma, ALK negative
• Cohort 2 relapsed/refractory adult T-cell leukemia/lymphoma (ATL) acute, lymphoma, or unfavorable chronic type. Relapsed/refractory ATL should be confirmed by the local pathologist; local diagnosis will be used for eligibility determination. The positivity of anti-human T-cell leukemia virus type 1 (HTLV-1) antibody will be locally determined for eligibility.
• Must have at least one lesion which is 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 CRu for ATL) after first-line therapy
• Failure to reach at least PR after second-line therapy or beyond
• Must have at least 1 prior line of systemic therapy for PTCL or ATL.
• Participants must be considered hematopoietic cell transplantation (HCT) ineligible during screening due to disease status (active disease), comorbidities, or other factors; the reason for HCT ineligibility must be clearly documented.
• In the PTCL cohort, participants with anaplastic large cell lymphoma (ALCL) must have prior brentuximab vedotin treatment. Exclusion Criteria: Participants meeting any exclusion criteria for this study will be excluded from this

study. Below is a list of the key exclusion criteria:

• Diagnosis of mycosis fungoides, Sézary syndrome and primary cutaneous ALCL, and systemic dissemination of primary cutaneous ALCL
• Diagnosis of precursor T-cell 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 involvement of lymphoma
• History of autologous HCT within 60 days prior to the 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 prior or 5 half-lives of the drug, whichever is longer, 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 >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
• Participant has clinically relevant bradycardia of <50 bpm, unless the participant 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 craft implantation within 6 months prior to Screening
• Uncontrolled angina pectoris within 6 months prior to Screening
• New York Heart Association 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
• 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

Related Conditions & MeSH terms

• Adult T Cell Leukemia/Lymphoma
• Leukemia, T-Cell
• Leukemia-Lymphoma, Adult T-Cell
• Lymphoma
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Peripheral
• Relapsed/Refractory Peripheral T-Cell Lymphoma

Intervention

Drug:
• Valemetostat Tosylate
Oral administration of valemetostat tosylate at a dose of 200 mg once daily starting at Cycle 1, Day 1 (continuous for 28-day cycles), until disease progression or unacceptable toxicity

Locations

Country	Name	City	State
Australia	Epworth Healthcare	Richmond
Canada	Ottawa Hospital Research Institute	Ottawa
Canada	University Health Network Princess Margaret Hospital	Toronto
Canada	BC Cancer - Vancouver Centre	Vancouver	British Columbia
France	CHU de Dijon	Dijon
France	CHRU de Lille - Hôpital Claude Huriez - Maladies du Sang	Lille
France	Centre Lyon Berard - Medical Oncology	Lyon
France	APHP - Hopital Saint Louis	Paris
France	Hôpital Necker	Paris
France	Centre Hospitalier Lyon Sud - Hématologie	Pierre-Bénite
France	Institut Universitaire du Cancer de Toulouse-Oncopole (IUCT-Oncopole)	Toulouse
Germany	Universitätsklinikum Halle (Saale) - Klinik und Poliklinik für Innere Medizin IV	Halle
Italy	ASST Papa Giovanni XXIII - Medicina Trasfusionale ed Ematologia - Bergamo	Bergamo
Italy	A.O.di Bologna Policl.S.Orsola	Bologna
Italy	PO San Gerardo, ASST Monza	Monza
Italy	Fondazione Pascale, IRCCS, Istituto Nazionale dei Tumori	Napoli
Italy	Ospedale S.Maria della Misericordia, AO di Perugia, Università degli Studi di Perugia	Perugia
Japan	National Cancer Center Hospital	Chuo Ku	Tokyo
Japan	Kyushu University Hospital	Fukuoka
Japan	Kagoshima University Hospital	Kagoshima
Japan	National Cancer Center Hospital East	Kashiwa	Chiba
Japan	University Hospital - Kyoto Prefectural University of Medicine	Kyoto
Japan	Nagasaki University Hospital	Nagasaki
Japan	Nagoya City University Hospital	Nagoya	Aichi
Japan	National Hospital Organization Nagoya Medical Center - Hematology	Nagoya	Aichi
Japan	Okayama University Hospital	Okayama
Japan	Hokkaido University Hospital - Medical Oncology Center	Sapporo	Hokkaido
Korea, Republic of	Asan Medical Center - Oncology	Seoul
Korea, Republic of	Samsung Medical Center - Hematology-Oncology	Seoul
Korea, Republic of	Seoul National University Hospital - Department of Internal	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul	Seoul Teugbyeolsi
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Netherlands	Leids Universitair Medisch Centrum (LUMC) (Leiden University Medical Center)	Leiden
Netherlands	Universiteit Maastricht Academisch Ziekenhuis Maastricht	Maastricht
Spain	Hospital Universitario Vall d'Hebrón	Barcelona
Spain	ICO Hospital Duran i Reynals	Barcelona
Spain	Hospital Universitario Fundación Jiménez Díaz	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Taiwan	Chang Gung Medical Foundation - Kaohsiung Chang Gung Memorial Hospital - Hemato-Oncology	Kaohsiung
Taiwan	National Cheng Kung University Hospital - Internal Medicine	Tainan
Taiwan	National Taiwan University Hospital - Hematology And Oncology	Taipei
Taiwan	Chang Gung Medical Foundation - LinKou Chang Gung Memorial Hospital - Hematology and Oncology - Hematology and Oncology	Taoyuan City
United Kingdom	University College London Hospital	London
United Kingdom	Nottingham City Hospital - Clinical Haematology	Nottingham
United Kingdom	Churchill Hospital	Oxford
United States	Emory University Hospital - Winship Cancer Institute	Atlanta	Georgia
United States	University Of Colorado Cancer Center	Aurora	Colorado
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Northwestern University - Feinberg School of Medicine	Chicago	Illinois
United States	City Of Hope National Medical Center	Duarte	California
United States	Duke Cancer Center	Durham	North Carolina
United States	Hackensack University Medical Center - John Theurer Cancer Center	Hackensack	New Jersey
United States	Memorial Sloan-Kettering Cancer Center at Memorial Hospital	New York	New York
United States	Weill Cornell Medicine	New York	New York
United States	Stanford University Medical Center - Cancer Clinical Trials Office - ONCOLOGY	Palo Alto	California
United States	University of Pennsylvania Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Objective Response As Assessed by Blinded Independent Central Review After Administration of Valemetostat Tosylate Monotherapy (Cohort 1)	For the relapsed/refractory peripheral T-cell lymphoma (PTCL) cohort, objective response rate (ORR) is defined as the proportion of participants with a best overall response (BOR) of complete response (CR) or partial response (PR), assessed by blinded independent central review (BICR), among participants with centrally confirmed PTCL eligible histology.	From baseline until disease progression or death (whichever occurs first), up to approximately 56 months
Primary	Number of Participants With Treatment-emergent Adverse Events After Administration of Valemetostat Tosylate Monotherapy (Cohort 2)	Treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), severe events (Grades 3 and 4), fatal events, TEAEs associated with treatment discontinuation, interruption, or reduction, and adverse events of special interest (AESIs) will be assessed.	From the time the informed consent form is signed up to 30 days after last dose
Secondary	Plasma Concentrations of DS-3201a and CALZ-1809a After Administration of Valemetostat Tosylate Monotherapy	Total and unbound DS-3201a (free form of valemetostat tosylate) and total CALZ-1809a (major metabolite) concentration in plasma will be assessed.	Cycle 1 Day 1, 8, 15 Predose; Cycle 1 Day 1 (1, 2, 4, 5 hours Postdose); Cycle 2 Day 1 Predose; Cycle 3 Day 1 to Cycle 13 Day 1 Predose; Cycle 25 Day 1 Predose & every 3 cycles thereafter up to approximately 56 months (each cycle is 28 days)
Secondary	Duration of Response After Administration of Valemetostat Tosylate Monotherapy (Cohort 1)	Duration of response (DoR) is defined as the time from the date of the first documentation of objective response (CR or PR) to the date of the first documentation of disease progression (progressive or relapsed disease) based on BICR assessments or to death due to any cause, whichever occurs first.	Time from the date of first documented response (CR or PR) until documented disease progression (progressive or relapsed disease) based on BICR assessments or death from any cause (whichever occurs first), up to approximately 56 months
Secondary	Percentage of Participants With Complete Response After Administration of Valemetostat Tosylate Monotherapy (Cohort 1)	Complete response rate is the percentage of participants achieving CR as the BOR based on BICR assessments.	From baseline to date of first documented objective response of CR, up to approximately 56 months
Secondary	Duration of Complete Response After Administration of Valemetostat Tosylate Monotherapy (Cohort 1)	Duration of complete response is defined as the time from the date of the first documentation of CR to the date of the first documentation of disease progression (progressive or relapsed disease) based on BICR assessments or to death due to any cause, whichever occurs first.	Time from the date of first documented CR until documented disease progression (progressive or relapsed disease) based on BICR assessments or death from any cause (whichever occurs first), up to approximately 56 months
Secondary	Percentage of Participants With Partial Response After Administration of Valemetostat Tosylate Monotherapy (Cohort 1)	Partial response rate is the percentage of participants achieving PR as the BOR based on BICR assessment.	From baseline to date of first documented objective response of PR, up to approximately 56 months
Secondary	Number of Participants With Treatment-emergent Adverse Events After Administration of Valemetostat Tosylate Monotherapy (Cohort 1)	Treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), severe events (Grades 3 and 4), fatal events, TEAEs associated with treatment discontinuation, interruption, or reduction, and adverse events of special interest (AESIs) will be assessed.	From the time the informed consent form is signed up to 30 days after last dose