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AzTrials

Breast CancerPhase 1NCT05633979

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

A Phase 1 study testing Trastuzumab deruxtecan and Valemetostat in people with Breast Cancer, run by M.D. Anderson Cancer Center at 1 site in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Breast Cancer
What is being tested?
Trastuzumab deruxtecan and Valemetostat
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
17 participants
Where
1 siteUnited States
Study dates
9 Feb 2023to 31 Dec 2032
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥18 years of age or the minimum legal adult age (whichever is greater) at the time the informed consent form (ICF) is signed.
  • 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.
  • MBC or locally progressive breast cancer that is not a surgical candidate.
  • Has progressed on and would no longer benefit from endocrine therapy in hormone receptor-positive subjects.
  • Has been treated with at least 1 prior line of chemotherapy in the metastatic or locally progressive setting.
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  • 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
  • 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).
  • Is willing to provide fresh tumor tissue via tumor biopsy only if the participant has a disease that can be safely accessed through a CT-guided/US-guided or percutaneous biopsy for multiple core biopsies judged by the investigator. If the participant doesn't have a disease that can be safely accessed, they are still eligible.
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
  • Negative serum pregnancy test within 72 hours of receiving the first dose of the study medication for women of childbearing potential as per institutional guidelines. Post-menopausal women (defined as having no menses for at least 1 year) and surgically sterilized women are not required to undergo pregnancy tests.
  • Subjects of childbearing potential must be willing to use effective birth control methods or be surgically sterile or abstain from heterosexual activity for the course of the study through at least 4 months after the last dose of the study drug (for males) and 7 months after last dose of study drug (for females). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for at least 1 year.
  • Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 3 months after the final study drug administration.
  • Male subjects must not freeze or donate sperm starting at Screening and throughout the study period, and for at least 3 months after the final study drug administration.
  • The patient must have adequate organ function as determined by the following laboratory values:
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × the upper limit of normal (ULN). For those with liver metastasis, ALT and AST ≤5.0 × ULN.
  • Total bilirubin ≤1.5 × ULN, except for subjects with Gilbert's syndrome (e.g., a gene mutation in UGT1A1), who can have total bilirubin <3.0 mg/dL.
  • Absolute neutrophil count (ANC) ≥1500/mm3 (granulocyte colony-stimulating factor administration is not allowed within 1 week prior to Screening assessment).
  • Hemoglobin ≥9.0 g/dL (red blood cell transfusion is not allowed within 1 week prior to Screening assessment).
  • Platelet count ≥100,000/mm3 (Platelet transfusion is not allowed within 1 week prior to Screening assessment).
  • Creatinine clearance ≥30 mL/min (measured by the Cockcroft-Gault equation*).
  • Female: ([140-age] × weight in kg)/(serum creatinine × 72) × 0.85 Male: ([140-age] × weight in kg)/(serum creatinine × 72)
  • Serum Albumin ≥ 2.5 g/dL
  • Acute non-hematologic toxic effects (as evaluated by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 5.0) of any prior therapy (except alopecia) resolved as shown below:
  • Peripheral neuropathy: Grade ≤2
  • Fatigue: Grade ≤2
  • All others: Grade ≤1

Who cannot join

  • Has previously been treated with any anti-HER2 therapy, including T-DXd, or EZH inhibitors.
  • 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.
  • 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
  • Uncontrolled or significant cardiovascular disease, including the following:
  • LVEF < 50% within 28 days
  • 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).
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  • 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 2-4 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 or right bundle branch block
  • Systemic treatment with corticosteroids (>10 mg daily prednisone equivalents). Note: Short-course systemic corticosteroids (e.g., prevention/treatment for transfusion reaction) or use for a non-cancer indication (e.g., adrenal replacement) is permissible.
  • Female who is pregnant or breastfeeding or intends to become pregnant during the study
  • Has known human immunodeficiency virus (HIV) infection or active hepatitis B or C infection (screen test is not required). Subjects positive for hepatitis C (HCV) antibody are eligible only if the polymerase chain reaction is negative for HCV RNA.
  • Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection requiring treatment with intravenous antibiotics, antivirals, or antifungals. Note: Subjects with localized fungal infections of skin or nails are eligible.
  • Any active uncontrolled systemic diseases or other medical conditions considered to be poorly controlled by the investigator, including, but not limited to, bleeding diatheses
  • A history of (noninfectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
  • Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study registration, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.).
  • Any autoimmune, connective tissue or inflammatory disorders (e.g., rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for subjects who are included in the study.
  • Current use of moderate or strong cytochrome P450 (CYP)3A inducers (Table 17)
  • Prior complete pneumonectomy
  • Medical history or complication considered inappropriate for participation in the study, or a serious physical or psychiatric disease, the risk of which may be increased by participation in the study in the investigator's opinion
  • A history of substance abuse or medical conditions such as clinically significant cardiac or pulmonary diseases or psychological conditions that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
  • Known or suspected hypersensitivity to valemetostat and T-DXd or any of the excipients.
  • Subjects with symptomatic brain metastases, or subjects with treated brain metastases that are no longer symptomatic but who require treatment with steroids.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

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.

Read the 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.
  1. To determine the CBR defined as SD ≥16 weeks + PR + CR.
  2. To evaluate safety of valemetostat in combination with T-DXd.
  3. To evaluate the pharmacokinetics (PK) of both the drugs in combination.
  4. 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.
Conditions
Breast Cancer
Being tested
Trastuzumab deruxtecan, Valemetostat
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Trastuzumab deruxtecanDrug

    Given by IV (vein)

  • ValemetostatDrug

    Given by PO

Study groups in NCT05633979
Study groupRoleWhat they receive
Group 1ExperimentalParticipants will receive the same drugs at the same schedule, and the same dose of trastuzumab deruxtecan
Receives: Drug: Trastuzumab deruxtecan; Drug: Valemetostat
Group 2ExperimentalParticipants will only receive 1 dose level of valemetostat.
Receives: Drug: Valemetostat

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The Overall Response Rate (ORR)

    Measured: through study completion; an average of 2-3 years.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Dec 2022
  2. Study start9 Feb 2023
  3. Primary completion31 Dec 2030 (estimated)
  4. Study completion31 Dec 2032 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
17 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05633979
Sponsor's protocol ID
2022-0315
Other IDs
NCI-2022-09968
Status last verified
Jul 2026
First submitted
21 Nov 2022
Last updated
16 Jul 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Trastuzumab deruxtecan and Valemetostat in people with Breast Cancer, run by M.D. Anderson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 29 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 16 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The Overall Response Rate (ORR) (time frame: through study completion; an average of 2-3 years.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05633979.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jul 2026.

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