A Study of Valemetostat Tosylate in Combination With DXd ADCs in Subjects With Solid Tumors

A Phase 1b, Multicenter, Open-Label Study of Valemetostat Tosylate in Combination With DXd ADCs in Subjects With Solid Tumors

This study will evaluate the safety, tolerability, and efficacy of valemetostat tosylate in combination with DXd ADC in patients with advanced solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: T-DXd; Drug: Valemetostat tosylate; Drug: Dato-DXd

Detailed Description

This is a 2-part study of valemetostat in combination with DXd ADCs in patients with HER2-positive gastric cancer, non-squamous NSCLC, or unresectable or metastatic HER2 low breast cancer. The study will begin with a Part 1 Dose-escalation Phase and will continue until the recommended dose for expansion "RDE" of valemetostat is determined and will then be followed by a Part 2 Dose-expansion Phase to further evaluate the safety and tolerability of the combination.

• Study Type: Interventional
• Enrollment (Estimated): 210
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Daiichi Sankyo Contact for Clinical Trial Information; Phone Number: 9089926400; Email: CTRinfo@dsi.com

Study Locations

• China
  • Beijing, China, 100191
    • Recruiting
    • Peking University Third Hospital
  • Guangzhou, China, 510060
    • Recruiting
    • SunYat-sen University Cancer Center
  • Guangzhou, China, 510060
    • Recruiting
    • Sun Yat-Sen University, Cancer Center
  • Heilongjiang, China, 150081
    • Recruiting
    • Harbin Medical Univeristy Cancer Hospital
  • Hunan, China, 410013
    • Recruiting
    • Hunan Cancer Hospital
  • Jilin, China, 130000
    • Recruiting
    • Jilin Cancer Hospital
  • Shandong, China, 240013
    • Recruiting
    • Jinana Center Hosptial
• Italy
  • Cesena, Italy, 47014
    • Recruiting
    • IRCCS Istituto Scientifico Romagnolo Per
• Japan
  • Chūōku, Japan, 104-0045
    • Recruiting
    • National Cancer Center Hospital
  • Fukuoka, Japan, 811-1395
    • Recruiting
    • National Hospital Org-Kyushu Cancer Center
  • Kashiwa, Japan, 277-8577
    • Recruiting
    • National Cancer Center Hospital East
    • Contact: Principal Investigator
  • Kōtoku, Japan, 135-8550
    • Recruiting
    • The Cancer Institute Hospital Of JFCR
  • Nagoya, Japan, 464-8681
    • Recruiting
    • Aichi Cancer Center Hospital
  • Osaka, Japan, 540-0008
    • Recruiting
    • Osaka International Cancer Institute
  • Shizuoka, Japan, 411-8777
    • Recruiting
    • Shizuoka Cancer Center
  • Suita, Japan, 565-0871
    • Recruiting
    • Osaka University Hospital
  • Yokohama, Japan, 241-8515
    • Recruiting
    • Kanagawa cancer center
  • Ōsaka-sayama, Japan, 589-8511
    • Recruiting
    • Kindai University Hospital
• United States
  • California
    • Irvine, California, United States, 92618
      • Recruiting
      • City of Hope at Orange County Lennar Foundation Cancer Center
    • Los Angeles, California, United States, 90067
      • Withdrawn
      • Valkyrie Clinical Trials
    • San Diego, California, United States, 92123
      • Recruiting
      • Sharp Memorial Hospital
  • Florida
    • Plantation, Florida, United States, 33322
      • Recruiting
      • Brcr Medical Center, Inc Dba Boca Raton Clinical Research
    • Tampa, Florida, United States, 33612
      • Withdrawn
      • H. Lee Moffitt Cancer Center and Research Institute, Inc
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Recruiting
      • University of Hawaii At Manoa
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • University of Chicago Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan-Kettering Cancer Center (MSKCC) - New York
    • Westbury, New York, United States, 11590
      • Recruiting
      • Clinical Research Alliance
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Recruiting
      • UNC Hospitals
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Active, not recruiting
      • The Cleveland Clinic Foundation
  • Oregon
    • Portland, Oregon, United States, 97213
      • Recruiting
      • Providence Portland Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • UT Southwestern Medical Center
    • Dallas, Texas, United States, 75230
      • Recruiting
      • Mary Crowley Cancer Research Centers
    • Houston, Texas, United States, 77030
      • Recruiting
      • University of Texas M. D. Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Next Virginia
      • Contact: Principal Investigator
    • Fairfax, Virginia, United States, 22031
      • Withdrawn
      • Inova Schar Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutchinson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria

All participants must meet all of the following criteria, as well as all criteria from the relevant sub-protocol to be eligible for enrollment:

• At least 18 years or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
• Has at least 1 measurable lesion based on investigator imaging assessment (computed tomography or magnetic resonance imaging) using RECIST v 1.1 at Screening.
• Is willing to provide an adequate tumor sample.
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening.

Additional Key Inclusion for Sub-Protocol A:

• Diagnosed with pathologically documented breast cancer that:

  1. Is unresectable or metastatic.
  2. Has progressed on and would no longer benefit from endocrine therapy in hormone receptor-positive subjects in the opinion of the investigator.
  3. Has been treated with at least 1 and at most 2 prior lines of chemotherapy in the recurrent or metastatic setting.
  4. Has a history of low HER2 expression, defined as IHC 2+ /ISH-negative or IHC 1+ (ISH-negative or untested). ), as classified by the American Society of Clinical Oncology/College of American Pathologists 2018 HER2 testing guidelines.

  5. Was never previously HER2-positive (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per American Society of Clinical Oncology/College of American Pathologists guidelines

     Additional Key Inclusion for Sub-Protocol B:

     • Gastric or GEJ adenocarcinoma that is (a) unresectable or metastatic or (b) has progressed on trastuzumab or approved trastuzumab biosimilar-containing regimen.

     Additional Key Inclusion for Sub-Protocol C:

• Pathologically documented Stage IIIB, IIIC, or IV non-squamous NSCLC with or without AGA at the time of enrollment.

• Must meet prior therapy requirements:

  • Participants without AGA: (a) received platinum-based chemotherapy in combination with α-PD-1/α -PD-L1 mAb as a prior line of therapy or (b) received platinum-based chemotherapy and α -PD-1/ α -PD-L1 mAb (in either order) sequentially as 2 prior lines of therapy.
  • Participants with AGA: (a) has been treated with at least 1 or 2 prior lines of applicable targeted therapy that is locally approved for participant's genomic alteration at the time of Screening, (b) participants who have received platinum-based chemotherapy as a prior line of cytotoxic therapy, (c) may have received α -PD-1/α -PD-L1 mAb alone or in combination with a cytotoxic agent

Key Exclusion Criteria

• Has previously been treated with any enhancer of zeste homolog inhibitors.
• Uncontrolled or significant cardiovascular disease.
• Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
• Has leptomeningeal carcinomatosis or metastasis.
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses.
• Current use of moderate or strong cytochrome P450 (CYP)3A inducers.
• Systemic treatment with corticosteroids (>10 mg daily prednisone equivalents).
• History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).
• Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection requiring treatment with intravenous (IV) antibiotics, antivirals, or antifungals.
• Female who is pregnant or breastfeeding or intends to become pregnant during the study.
• Psychological, social, familial, or geographical factors that would prevent regular follow-up.

Additional Key Exclusion for Sub-Protocol A:

• Has previously received any anti-HER2 therapy in the metastatic setting.
• Has received prior treatment with an antibody-drug conjugate that consists of an exatecan derivative that is a topoisomerase I inhibitor, including either as part of prior treatment history or within prior participation in a clinical study.

Additional Key Exclusion for Sub-Protocol B:

* Participants who have received an antibody-drug conjugate consisting of an exatecan derivative that is a topoisomerase I inhibitor.

Additional Key Exclusion for Sub-Protocol C:

* Has received any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase I or TROP2-targeted therapy including Dato-DXD

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Dose Escalation Phase (Sub-protocol B); Participants with previously treated, advanced, or metastatic HER2-positive gastric or gastro-esophageal junction (GEJ) adenocarcinoma will receive valemetostat in combination with T-DXd.	Drug: T-DXd; One IV infusion Q3W on Day 1 of each 21-day cycle; Other Names: DS-8201a; ENHERTU; Drug: Valemetostat tosylate; Administered orally once daily; Other Names: DS-3201b
Experimental: Part 1: Dose Escalation Phase (Sub-protocol C); Participants with previously treated, locally advanced, unresectable, or metastatic non-squamous non-small cell lung cancer (NSCLC) with or without actionable genomic alteration(s) will receive valemetostat in combination with datopotamab deruxtecan (Dato-DXd).	Drug: Valemetostat tosylate; Administered orally once daily; Other Names: DS-3201b; Drug: Dato-DXd; One IV infusion Q3W on Day 1 of each 21-day cycle.; Other Names: DS-1062a
Experimental: Part 2: Dose Expansion (Sub-protocol B); Participants with previously treated, advanced, or metastatic HER2-positive gastric or gastro-esophageal junction (GEJ) adenocarcinoma will receive valemetostat at the RDE in combination with T-DXd at RDE.	Drug: T-DXd; One IV infusion Q3W on Day 1 of each 21-day cycle; Other Names: DS-8201a; ENHERTU; Drug: Valemetostat tosylate; Administered orally once daily; Other Names: DS-3201b
Experimental: Part 2: Dose Expansion (Sub-protocol C); Participants with previously treated, locally advanced, unresectable, or metastatic non-squamous non-small cell lung cancer (NSCLC) with or without actionable genomic alteration(s) will receive valemetostat at the RDE in combination with datopotamab deruxtecan (Dato-DXd).	Drug: Valemetostat tosylate; Administered orally once daily; Other Names: DS-3201b; Drug: Dato-DXd; One IV infusion Q3W on Day 1 of each 21-day cycle.; Other Names: DS-1062a
Experimental: Part 1: Dose Escalation (Sub-protocol A); Participants with unresectable or metastatic HER2-low IHC]1+ or IHC 2+/ISH-negative breast cancer will receive valemetostat in combination with T-DXd.	Drug: T-DXd; One IV infusion Q3W on Day 1 of each 21-day cycle; Other Names: DS-8201a; ENHERTU; Drug: Valemetostat tosylate; Administered orally once daily; Other Names: DS-3201b
Experimental: Part 2: Dose Expansion (Sub-protocol A); Participants with unresectable or metastatic HER2-low IHC]1+ or IHC 2+/ISH-negative breast cancer will receive valemetostat at the RDE in combination with T-DXd at RDE.	Drug: T-DXd; One IV infusion Q3W on Day 1 of each 21-day cycle; Other Names: DS-8201a; ENHERTU; Drug: Valemetostat tosylate; Administered orally once daily; Other Names: DS-3201b

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Reporting Dose-limiting Toxicities (Part 1 Dose Escalation)		Cycle 1 Day 1 up to Day 21 (each cycle is 21 days)
Number of Participants Reporting Treatment-emergent Adverse Events (Part 1 Dose Escalation)		Screening up to 40 days after last dose
Objective Response Rate Based on Investigator Assessment (Part 2 Dose Expansion)	Objective response rate (ORR) is defined as the proportion of participants with a best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST v 1.1 criteria. CR is defined as a disappearance of all target lesions and PR is defined as at least a 30% decrease in the sum of diameters of target lesions.	Baseline (Screening), at every 6 weeks from Cycle 1 Day 1 in the first year, and every 12 weeks thereafter until disease progression or until the start of a new anticancer treatment, up to approximately 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival		Date of enrollment up to date of death due to any cause, up to approximately 5 years
Progression-free Survival	Disease progression will be determined by investigator assessment of tumor scans and using RECIST v 1.1 criteria.	Date of enrollment up to date of radiographic disease progression or death due to any cause (whichever occurs first), up to approximately 5 years
Duration of Response (DoR)	CR is defined as a disappearance of all target lesions and PR is defined as at least a 30% decrease in the sum of diameters of target lesions.	Date of first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of objective tumor progression or to death due to any cause (whichever occurs first), up to approximately 5 years
Objective Response Rate Based on Investigator Assessment (Part 1 Dose Escalation)	Objective response rate (ORR) is defined as the proportion of participants with a best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST v 1.1 criteria. CR is defined as a disappearance of all target lesions and PR is defined as at least a 30% decrease in the sum of diameters of target lesions.	Baseline (Screening), at every 6 weeks from Cycle 1 Day 1 in the first year, and every 12 weeks thereafter until disease progression or until the start of a new anticancer treatment, up to approximately 5 years
Number of Participants Reporting Treatment-emergent Adverse Events (Part 2 Dose Expansion)		Screening up to 40 days after last dose
Total and Unbound Plasma Concentration of Valemetostat		Cycle 1, Day 1: Predose, 1 hour (hr), 2 hr, 4 hr, and 5 hr postdose; Cycle 1, Day 8 and Day 15: Predose; Cycles 2, 3, 4, Day 1: Predose (each cycle is 21 days)
Plasma Concentration of DXd Antibody-Drug Conjugates		Cycle 1, Day 1: Predose, 1 hour (hr), 2 hr, 4 hr, and 5 hr postdose; Cycle 1, Day 8 and Day 15: Predose; Cycles 2, 3, 4, Day 1: Predose (each cycle is 21 days)

Collaborators and Investigators

• Sponsor: Daiichi Sankyo
• Investigators: Study Director: Global Clinical Leader, Daiichi Sankyo

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2024
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): November 1, 2028

Study Registration Dates

• First Submitted: January 29, 2024
• First Submitted That Met QC Criteria: January 29, 2024
• First Posted (Actual): February 6, 2024

Study Record Updates

• Last Update Posted (Actual): February 4, 2026
• Last Update Submitted That Met QC Criteria: February 2, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Advanced Solid Tumor; Valemetostat tosylate; DXD Antibody-drug Conjugates
• Additional Relevant MeSH Terms: Neoplasms; Immunologic Factors; Physiological Effects of Drugs; Immunoconjugates; trastuzumab deruxtecan
• Other Study ID Numbers: DS3201-324

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) on completed studies 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/
• IPD Sharing Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and 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.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No