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

• ClinicalTrials.gov Identifier: NCT04703192
• Recruitment Status: Active, not recruiting
• First Posted: January 11, 2021
• Last Update Posted: May 26, 2023
• Sponsor: Daiichi Sankyo, Inc.
• Information provided by (Responsible Party): Daiichi Sankyo, Inc.

Tracking Information

• First Submitted Date: January 7, 2021
• First Posted Date: January 11, 2021
• Last Update Posted Date: May 26, 2023
• Actual Study Start Date: June 3, 2021
• Actual Primary Completion Date: May 10, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 21, 2022)

• Percentage of Participants With Objective Response As Assessed by Blinded Independent Central Review After Administration of Valemetostat Tosylate Monotherapy (Cohort 1) [ Time Frame: From baseline until disease progression or death (whichever occurs first), up to approximately 56 months ]
  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.
• Number of Participants With Treatment-emergent Adverse Events After Administration of Valemetostat Tosylate Monotherapy (Cohort 2) [ Time Frame: From the time the informed consent form is signed up to 30 days after last dose ]
  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.

Original Primary Outcome Measures (submitted: January 7, 2021)

Percentage of Participants With Objective Response As Assessed by Blinded Independent Central Review After Administration of Valemetostat Tosylate Monotherapy [ Time Frame: From baseline until disease progression or death (whichever occurs first), up to approximately 56 months ]

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. For the adult T-cell leukemia/lymphoma cohort, ORR is defined as the proportion of participants with a BOR of CR, uncertified CR (CRu), or PR, assessed by BICR, among participants with positive anti-HTLV-1 antibody.

Current Secondary Outcome Measures (submitted: January 11, 2023)

• Plasma Concentrations of DS-3201a and CALZ-1809a After Administration of Valemetostat Tosylate Monotherapy [ Time Frame: 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) ]
  Total and unbound DS-3201a (free form of valemetostat tosylate) and total CALZ-1809a (major metabolite) concentration in plasma will be assessed.
• Duration of Response After Administration of Valemetostat Tosylate Monotherapy (Cohort 1) [ Time Frame: 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 ]
  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.
• Percentage of Participants With Complete Response After Administration of Valemetostat Tosylate Monotherapy (Cohort 1) [ Time Frame: From baseline to date of first documented objective response of CR, up to approximately 56 months ]
  Complete response rate is the percentage of participants achieving CR as the BOR based on BICR assessments.
• Duration of Complete Response After Administration of Valemetostat Tosylate Monotherapy (Cohort 1) [ Time Frame: 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 ]
  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.
• Percentage of Participants With Partial Response After Administration of Valemetostat Tosylate Monotherapy (Cohort 1) [ Time Frame: From baseline to date of first documented objective response of PR, up to approximately 56 months ]
  Partial response rate is the percentage of participants achieving PR as the BOR based on BICR assessment.
• Number of Participants With Treatment-emergent Adverse Events After Administration of Valemetostat Tosylate Monotherapy (Cohort 1) [ Time Frame: From the time the informed consent form is signed up to 30 days after last dose ]
  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.

Original Secondary Outcome Measures (submitted: January 7, 2021)

• Duration of Response After Administration of Valemetostat Tosylate Monotherapy [ Time Frame: Time from the date of first documented response (CR, CRu [ATL only], 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 ]
  Duration of response (DoR) is defined as the time from the date of the first documentation of objective response (CR, CRu [ATL only], 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.
• Percentage of Participants With Complete Response After Administration of Valemetostat Tosylate Monotherapy [ Time Frame: From baseline to date of first documented objective response of CR (CRu [ATL only]), up to approximately 56 months ]
  Complete response rate is the percentage of participants achieving CR (and CRu [ATL only]) as the BOR based on BICR assessments.
• Duration of Complete Response After Administration of Valemetostat Tosylate Monotherapy [ Time Frame: Time from the date of first documented CR (also CRu [ATL only]) 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 ]
  Duration of complete response is defined as the time from the date of the first documentation of CR (also CRu [ATL only]) 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.
• Percentage of Participants With Partial Response After Administration of Valemetostat Tosylate Monotherapy [ Time Frame: From baseline to date of first documented objective response of PR, up to approximately 56 months ]
  Partial response rate is the percentage of participants achieving PR as the BOR based on BICR assessment.
• Number of Participants With Treatment-emergent Adverse Events After Administration of Valemetostat Tosylate Monotherapy [ Time Frame: From the time the informed consent form is signed up to 30 days after last dose ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Valemetostat Tosylate (DS-3201b), an Enhancer of Zeste Homolog (EZH) 1/2 Dual Inhibitor, for Relapsed/Refractory Peripheral T-Cell Lymphoma (VALENTINE-PTCL01)
• Official Title: Single-arm, Phase 2 Study of Valemetostat Tosylate Monotherapy in Subjects With Relapsed/Refractory Peripheral T-Cell Lymphoma (VALENTINE-PTCL01)
• Brief 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.
• Detailed 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Other Name: DS-3201b

Study Arms

• Experimental: Cohort 1: Relapsed/Refractory Peripheral T-Cell Lymphoma
  Participants who will receive 200 mg/day valemetostat tosylate and had an eligible peripheral T-cell lymphoma subtype that was confirmed by independent hematopathology central review.
  Intervention: Drug: Valemetostat Tosylate
• Experimental: Cohort 2: Relapsed/Refractory Adult T-cell Leukemia/Lymphoma
  Participants who will receive 200 mg/day valemetostat tosylate and had an eligible adult T-cell leukemia/lymphoma subtype that was confirmed by the local pathologist/investigators and by documented positive anti-human T-cell leukemia virus type 1 (HTLV-1) antibody.
  Intervention: Drug: Valemetostat Tosylate

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: November 21, 2022): 148
• Original Estimated Enrollment (submitted: January 7, 2021): 176
• Estimated Study Completion Date: September 8, 2025
• Actual Primary Completion Date: May 10, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 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 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04703192
• Other Study ID Numbers: DS3201-A-U202; 2020-004954-31 ( EudraCT Number ); jRCT2071200095 ( Other Identifier: JAPIC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• URL: https://vivli.org/ourmember/daiichi-sankyo/

• Current Responsible Party: Daiichi Sankyo, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Global Clinical Leader; Daiichi Sankyo, Inc.

• PRS Account: Daiichi Sankyo, Inc.
• Verification Date: May 2023