Valemetostat + Trastuzumab Deruxtecan for Breast Cancer

Overseen By Senthil Damodaran, MD, PHD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anti-HER2, EZH inhibitors

Disqualifiers: Active CNS metastases, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, valemetostat and trastuzumab deruxtecan (an antibody-drug conjugate), for individuals with metastatic breast cancer showing low or ultra-low levels of the HER2 protein. The goal is to determine a safe dose of valemetostat when combined with trastuzumab deruxtecan. It targets those whose cancer has progressed after at least one prior chemotherapy and who are not candidates for surgery. Individuals with breast cancer meeting these criteria and who have not benefited from hormone therapy may be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for various treatments before enrollment. For example, you need to stop anti-cancer chemotherapy at least 3 weeks before, and antibody-based therapy at least 4 weeks before joining the trial. Please discuss with the trial team to understand how this applies to your specific medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier studies have shown that valemetostat is safe for patients, including those with certain cancers like peripheral T-cell lymphoma. Most patients tolerate it well, experiencing few severe side effects.

Research has shown that trastuzumab deruxtecan is also safe for patients with advanced breast cancer. However, some patients experienced a decrease in white blood cells, which can weaken the immune system. Despite this, trastuzumab deruxtecan is considered manageable and effective.

Both treatments have been safely used in other conditions, suggesting they might be safe in this trial as well. Since this trial is in the early stages, researchers are closely monitoring for any safety issues to ensure the best care for participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Valemetostat and Trastuzumab Deruxtecan for breast cancer because it introduces a novel approach to targeting cancer cells. Trastuzumab Deruxtecan is an antibody-drug conjugate that specifically targets and delivers chemotherapy directly to cancer cells, which can enhance its effectiveness while sparing healthy cells. On the other hand, Valemetostat is a unique inhibitor that targets specific enzymes involved in cancer cell growth. This dual-action strategy is promising because it aims to tackle cancer cells from different angles, potentially leading to improved outcomes compared to existing treatments that often focus on singular pathways.

What evidence suggests that this trial's treatments could be effective for breast cancer?

Research has shown that trastuzumab deruxtecan (T-DXd) effectively treats advanced breast cancer. Patients using T-DXd experienced a 31% lower risk of death, and it performed well in large studies. T-DXd is known for significantly improving survival rates for breast cancer patients. In this trial, participants in Group 1 will receive T-DXd. Valemetostat has also controlled tumors effectively, with high success rates in past studies. Participants in Group 2 will receive valemetostat. While valemetostat appears promising, researchers are primarily testing its potential when combined with T-DXd. Together, these treatments offer hope for better outcomes in breast cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Senthil Damodaran, MD, PhD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with metastatic breast cancer that expresses low levels of HER2 and who have already tried at least one chemotherapy. They must be in good physical condition, not planning to become pregnant, willing to use birth control if necessary, and able to provide a tumor tissue sample. People with serious health issues, brain metastases requiring steroids, uncontrolled infections or diseases like HIV/hepatitis B/C, or those who've had certain treatments are excluded.

Inclusion Criteria

Any side effects from my previous treatments have gone away.

Subjects of childbearing potential must be willing to use effective birth control methods or be surgically sterile or abstain from heterosexual activity

I am willing to undergo a biopsy for my cancer if it's safe.

Exclusion Criteria

I do not have any uncontrolled illnesses.

I do not have any serious health or mental conditions that would prevent me from joining the study.

I have brain metastases but am not currently experiencing symptoms.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Evaluate the safety and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of valemetostat in combination with trastuzumab deruxtecan

8-12 weeks

Dose Expansion

Evaluate the objective response rate (ORR) of valemetostat at the RDE in combination with trastuzumab deruxtecan

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

16 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Trastuzumab deruxtecan
• Valemetostat

Trial Overview The study aims to determine the safe dosage when combining valemetostat with trastuzumab deruxtecan in patients whose breast cancer has low HER2 expression. It's an early-phase trial focusing on finding the right balance of these two drugs for effective treatment.

How Is the Trial Designed?

Group I: Group 2 Experimental Treatment 1 Intervention

Participants will only receive 1 dose level of valemetostat.

Group II: Group 1 Experimental Treatment 2 Interventions

Participants will receive the same drugs at the same schedule, and the same dose of trastuzumab deruxtecan

Trastuzumab deruxtecan is already approved in United States, European Union, Japan for the following indications:

Approved in United States as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma
• Unresectable or metastatic HER2-low breast cancer
• Unresectable or metastatic HER2-positive solid tumors

Approved in European Union as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

Approved in Japan as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Daiichi Sankyo

Industry Sponsor

Trials

443

Recruited

493,000+

Hiroyuki Okuzawa

Daiichi Sankyo

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Yuki Abe

Daiichi Sankyo

Chief Medical Officer since 2023

MD

Daiichi Sankyo, Inc.

Industry Sponsor

Trials

390

Recruited

442,000+

Yuki Abe

Daiichi Sankyo, Inc.

Chief Medical Officer since 2022

MD

Hiroyuki Okuzawa

Daiichi Sankyo, Inc.

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Published Research Related to This Trial

Trastuzumab deruxtecan (Enhertu®) has been shown to significantly improve progression-free survival in adults with unresectable or metastatic HER2-positive breast cancer compared to the previous standard treatment, trastuzumab emtansine, in a pivotal phase 3 trial.

The treatment has a generally manageable safety profile, although it is associated with common adverse events like hematological and gastrointestinal disorders, and requires careful monitoring for interstitial lung disease (ILD)/pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. Nie, T., Blair, HA.[2023]

In a phase 1 trial involving 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer, trastuzumab deruxtecan demonstrated a manageable safety profile, with the most common serious side effects being anemia and decreases in blood cell counts, but no drug-related deaths were reported.

The treatment showed promising preliminary activity, with 43.2% of patients achieving a confirmed objective response, indicating its potential effectiveness in patients who had previously been treated with trastuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Shitara, K., Iwata, H., Takahashi, S., et al.[2020]

In a phase 2 study involving 184 patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a significant response rate of 60.9%, with a median response duration of 14.8 months.

While trastuzumab deruxtecan showed promising efficacy, it was associated with notable adverse effects, including interstitial lung disease in 13.6% of patients, highlighting the need for careful monitoring of pulmonary symptoms during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi, S., Saura, C., Yamashita, T., et al.[2021]

In the DESTINY-Breast03 trial, trastuzumab deruxtecan (T-DXd) demonstrated superior progression-free survival and overall survival compared to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer, while maintaining quality of life (QoL) throughout treatment.

Patients receiving T-DXd experienced a median time to first hospitalization that was three times longer than those on T-DM1, indicating better overall health management and fewer hospital visits during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. Curigliano, G., Dunton, K., Rosenlund, M., et al.[2023]

In a phase 1 trial involving 115 patients with HER2-positive breast cancer previously treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a manageable safety profile, with 59.5% of patients achieving a confirmed objective response.

Despite some serious treatment-emergent adverse events, including cases of interstitial lung disease and pneumonitis, the preliminary efficacy results suggest that trastuzumab deruxtecan is a promising treatment option, warranting further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Tamura, K., Tsurutani, J., Takahashi, S., et al.[2020]

Fam-trastuzumab deruxtecan-nxki (T-DXd) has been approved for treating HER2-low metastatic breast cancer, showing significant improvements in progression-free survival (PFS) and overall survival (OS) in a phase III trial with 557 patients.

The study demonstrated a 50% reduction in the risk of disease progression and a 36% reduction in the risk of death compared to standard chemotherapy, with a safety profile consistent with previous uses of T-DXd and no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

US Food and Drug Administration Approval Summary: Fam-Trastuzumab Deruxtecan-nxki for Human Epidermal Growth Factor Receptor 2-Low Unresectable or Metastatic Breast Cancer. Narayan, P., Dilawari, A., Osgood, C., et al.[2023]

Trastuzumab deruxtecan (ENHERTU®) is an innovative treatment that combines an antibody targeting HER2 with a DNA topoisomerase I inhibitor, specifically designed for HER2-expressing solid tumors, including various types of cancer.

It received accelerated approval in the USA based on the promising results from the phase 2 DESTINY-Breast01 trial, which focused on patients with advanced HER2-positive breast cancer who had already undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. Keam, SJ.[2020]

Fam-trastuzumab deruxtecan-nxki (ENHERTU) received accelerated FDA approval for treating HER2-positive breast cancer in patients who have already undergone two or more anti-HER2 therapies, based on a study involving 184 patients that showed a confirmed overall response rate of 60.3%.

While ENHERTU is effective, it carries significant risks, including severe interstitial lung disease and neutropenia, highlighting the importance of monitoring for serious side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. Narayan, P., Osgood, CL., Singh, H., et al.[2022]

Citations

1. enhertuhcp.com enhertuhcp.com/en/breast/efficacy/efficacy-data

Efficacy data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU.

2. nature.com nature.com/articles/s41591-025-03981-4

Trastuzumab deruxtecan in HER2-low metastatic breast ... Patients treated with T-DXd had a 31% reduction in the risk of death in both the overall and HR+ cohorts and a 42% reduction in risk of death in ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40947843/

Real-world safety and efficacy of trastuzumab deruxtecan ... Our study confirms the efficacy and safety of T-DXd in daily clinical practice. Further research and longer patient follow-up are needed to ...

4. esmoopen.com esmoopen.com/article/S2059-7029(25)01199-8/fulltext

Outcomes with trastuzumab deruxtecan by biomarker ... In a large (n = 1490) real-world dataset, T-DXd exhibited favorable activity for metastatic breast cancer (MBC).

5. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-demonstrated-highly-statistically-significant-and-clinically-meaningful-improvement-in-invasive-disease-free-survival-vs-T-DM1-in-DESTINY-Breast05-Phase-III-trial-in-patients-with-high-risk-early-breast-cancer-following-neoadjuvant-therapy.html

ENHERTU® (fam-trastuzumab deruxtecan-nxki) ... ENHERTU® (fam-trastuzumab deruxtecan-nxki) demonstrated highly statistically significant and clinically meaningful improvement in invasive ...

6. enhertuhcp.com enhertuhcp.com/en/breast/safety

Safety Data | ENHERTU® (fam-trastuzumab deruxtecan- ... In patients with metastatic breast cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11178646/

Safety profile of trastuzumab deruxtecan in advanced breast ... The article covers various aspects of T-DXd treatment, including its clinical efficacy, safety profile, and dosing considerations, and provides practical ...

8. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-reduced-the-risk-of-disease-recurrence-or-death-by-53-percent-vs-T-DM1-in-patients-with-high-risk-HER2-positive-early-breast-cancer-following-neoadjuvant-therapy-in-DESTINY-Breast05-Phase-III-trial.html

ENHERTU® (fam-trastuzumab deruxtecan-nxki) reduced ... The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least 1 dose of ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e13023

Efficacy and safety of trastuzumab deruxtecan in HER2+ ... Our study supports the efficacy and safety of T-DXd in India in a real-world clinical setting with results being consistent across published literature.

10. sciencedirect.com sciencedirect.com/science/article/pii/S2949820124000730

Real-world safety and effectiveness data of trastuzumab ... Real-world safety and effectiveness data of trastuzumab deruxtecan and sacituzumab govitecan in breast cancer: a Hellenic Cooperative Oncology Group study.