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Phase 1b Study of EZH1/2 Inhibitor Valemetostat in Combination With Trastuzumab Deruxtecan in Subjects With HER2 Low/Ultra-low/Null Metastatic Breast Cancer | Clinical Trials | Clareo Health

ACTIVE_NOT_RECRUITINGPHASE1

Phase 1b Study of EZH1/2 Inhibitor Valemetostat in Combination With Trastuzumab Deruxtecan in Subjects With HER2 Low/Ultra-low/Null Metastatic Breast Cancer

NCT05633979•M.D. Anderson Cancer Center

View on ClinicalTrials.gov

Summary

To find a recommended dose of valemetostat that can be given in combination with trastuzumab deruxtecan to patients with low/ultra-low HER2-expressing metastatic breast cancer.

Detailed Description

Primary Objectives: Dose escalation part: 1. To evaluate the safety and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of valemetostat in combination with trastuzumab deruxtecan (T-DXd). Dose expansion part: 2. To evaluate the objective response rate (ORR) of valemetostat at the RDE in combination with T-DXd. Secondary Objectives: Dose escalation: 1. To determine ORR; defined as a percentage of subjects who achieve complete response (CR) or partial response (PR) by RECIST 1.1 criteria. 2. To determine survival outcomes, including duration of response (DoR), progression free survival (PFS), and overall survival (OS). 3. To determine the Clinical Benefit Rate (CBR) defined as stable disease (SD) ≥ 16 weeks + PR + CR. Dose expansion: 1. To determine survival outcomes, including DoR, PFS, and OS. * DOR of the proposed treatment: the time from observing response to the valemetostat treatment until objective tumor progression (PD) * PFS: the time from starting valemetostat treatment until objective tumor progression (PD) or death due to any cause. * Overall survival (OS): the time from starting valemetostat treatment until death due to any cause. 2. To determine the CBR defined as SD ≥16 weeks + PR + CR. 3. To evaluate safety of valemetostat in combination with T-DXd. 4. To evaluate the pharmacokinetics (PK) of both the drugs in combination. 5. To evaluate the immunogenicity of T-DXd Exploratory Objectives: 1. To investigate pharmacodynamic biomarkers. 2. To investigate biomarkers that may aid in identifying subjects who may derive clinical benefit.

Eligibility

Age

18 - No limit years

Sex

ALL

Healthy Volunteers

Inclusion Criteria

•1. ≥18 years of age or the minimum legal adult age (whichever is greater) at the time the informed consent form (ICF) is signed.
•2. Pathologically confirmed HER2 low/ultra-low/null breast cancer. HER2 low is defined as IHC 2+/ISH- or IHC 1+/(ISH- or undefined), HER2 ultra-low is defined as IHC 0 with detectable faint/barely perceptible incomplete staining in ≤10% tumor cells and HER2 null is defined as IHC 0 without any observed tumor cell staining, regardless of hormone receptor expression status, and as determined by the Ventana 4B5 IHC assay The accrual numbers of HER2 ultra-low/null and HER2 low should be approximately 1:1 in the dose-escalation and dose-expansion cohort (i.e., 6 subjects for HER2 ultra-low/null and 6 subjects for HER2 low in dose-escalation cohort, 10 subjects for HER2 ultra-low/null and 10 subjects for HER2 low in dose-expansion cohort). Initial subject inclusion may be based on previously obtained HER2 testing results, however final HER2 status determination (HER2 low, ultra-low, or null) will be based on centralized pathologist (re)evaluation of HER2 IHC staining using the Ventana 4B5 assay at MDA Department of Pathology laboratory.
•If HER2 eligibility assessment and subject inclusion are based on results from a previous HER2 IHC test performed with an IHC assay different from the Ventana 4B5 assay, or if the IHC slides from the initial test are not available for re-evaluation, adequate material for HER2 testing using the Ventana 4B5 assay must be provided to MDA Department of Pathology laboratory.
•3. MBC or locally progressive breast cancer that is not a surgical candidate.
•4. Has progressed on and would no longer benefit from endocrine therapy in hormone receptor-positive subjects.
•5. Has been treated with at least 1 prior line of chemotherapy in the metastatic or locally progressive setting.
•6. Has adequate treatment washout period by the time of enrollment, defined as:
•Treatment Washout Period Major surgery ≥ 4 weeks Radiation therapy including palliative stereotactic radiation to chest ≥ 4 weeks Palliative stereotactic radiation therapy to other anatomic areas ≥ 2 weeks Anti-cancer chemotherapy (Immunotherapy \[non-antibody based therapy\]), retinoid therapy, hormonal therapy
•* 3 weeks Targeted agents and small molecules ≥ 2 weeks or 5 half-lives, whichever is longer Nitrosoureas or mitomycin C ≥ 6 weeks Antibody-based anti-cancer therapy ≥ 4 weeks Chloroquine/Hydroxychloroquine \>14 days
•7. Has at least one measurable lesion per RECIST (except for up to the first 5 subjects who enroll in dose escalation part where the measurable lesions meeting RECIST definition are not mandatory).
+40 more criteria

Exclusion Criteria

•1. Has previously been treated with any anti-HER2 therapy, including T-DXd, or EZH inhibitors.
•2. 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. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study registration.
•3. 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
•4. Uncontrolled or significant cardiovascular disease, including the following:
•1. LVEF \< 50% within 28 days
•2. Evidence of prolongation of QT/QTc (e.g., repeated episodes of QT corrected for heart rate using Fridericia's method \[QTcF\] \>450 ms) (average of triplicate determinations; over a 5 min time window when the subject has been supine position for at least 10 min without any environmental stimuli).
•3. Diagnosed or suspected long QT syndrome, or known family history of long QT syndrome
•4. History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes
•5. Uncontrolled arrhythmia (subjects with asymptomatic, controllable atrial fibrillation may be enrolled), or asymptomatic persistent ventricular tachycardia
•6. Subject has clinically relevant bradycardia of 50 bpm unless the subject has a pacemaker

Locations (1)

M D Anderson Cancer Center

Houston, Texas, United States

Key Dates

Start Date

February 9, 2023

Primary Completion Date

December 31, 2030

Completion Date

December 31, 2032

Last Updated

January 20, 2026

Enrollment

ACTUAL participants

Conditions

Breast Cancer

Interventions

Trastuzumab deruxtecan

DRUG

Valemetostat

DRUG

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Data Source & Attribution

This clinical trial information is sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

ClinicalTrials.gov last update: January 20, 2026Data synced to Clareo: March 29, 2026

Modifications: This data has been reformatted for display purposes. Eligibility criteria have been parsed into inclusion/exclusion sections. Location data has been geocoded to enable distance-based search. For the authoritative and most current information, please visit ClinicalTrials.gov.

Neither the United States Government nor Clareo Health make any warranties regarding the data. Check ClinicalTrials.gov frequently for updates.

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Phase 1b Study of EZH1/2 Inhibitor Valemetostat in Combination With Trastuzumab Deruxtecan in Subjects With HER2 Low/Ultra-low/Null Metastatic Breast Cancer

Inclusion Criteria

Exclusion Criteria

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