Valemetostat + DXd ADCs for Solid Tumors

Recruiting at 43 trial locations

Overseen By Daiichi Sankyo Contact for Clinical Trial Information

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Daiichi Sankyo

Must not be taking: CYP3A inducers, Corticosteroids

Disqualifiers: Cardiovascular disease, CNS metastases, others

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

Compensation: Varies

Number of Visits: 24

210 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for advanced solid tumors. The study examines the safety and effectiveness of valemetostat (a potential cancer therapy) and DXd ADCs (antibody-drug conjugates) when used together. Different parts of the trial focus on breast cancer, stomach cancer, and lung cancer, specifically for patients whose cancers have not responded well to previous treatments. Those with metastatic breast cancer, stomach cancer not helped by trastuzumab, or advanced lung cancer after other treatments may find this trial suitable. 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 does not specify if you need to stop taking your current medications, but you cannot use moderate or strong CYP3A inducers or take more than 10 mg of prednisone (a type of steroid) daily.

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

Research shows that the combination of valemetostat with DXd ADCs is under careful study for safety. In earlier studies, researchers tested this combination on patients with various advanced cancers. Some patients experienced side effects, but these were generally manageable.

For instance, studies have included the combination of valemetostat with T-DXd or Dato-DXd. Patients exhibited varying levels of tolerance, but most found the combination tolerable. Common side effects included tiredness and nausea, typical for cancer treatments.

These studies are ongoing, and researchers continue to gather information. The early phase of this trial focuses primarily on ensuring the treatment's safety for more participants, a crucial step before assessing its effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Valemetostat and DXd ADCs because these treatments offer a novel approach to targeting cancer. Unlike traditional chemotherapy, which affects both healthy and cancerous cells, these drugs specifically target cancer cells, potentially reducing side effects. Valemetostat is a dual inhibitor targeting EZH1 and EZH2, enzymes involved in cancer cell growth, while DXd ADCs deliver a potent chemotherapy directly to the cancer cells. This targeted delivery can enhance the treatment's effectiveness while minimizing damage to healthy tissues.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors?

Studies have shown that trastuzumab deruxtecan (T-DXd), a targeted cancer treatment, can significantly improve survival in patients with HER2-low metastatic breast cancer. In the DESTINY-Breast04 trial, patients treated with T-DXd lived longer and experienced more time without cancer progression compared to those receiving standard therapy. In this trial, participants will receive valemetostat combined with T-DXd in various treatment arms to explore its potential to enhance treatment effects. Research suggests that this combination shows promise in patients with advanced cancers like stomach cancer. Specifically, previous patients demonstrated that this combination can effectively target and fight certain types of tumors. Overall, researchers are exploring the combination of valemetostat with DXd ADCs for its potential to effectively treat various advanced solid tumors. ^{1 4 6 7 8}

Who Is on the Research Team?

Global Clinical Leader

Principal Investigator

Daiichi Sankyo

Are You a Good Fit for This Trial?

Adults with advanced solid tumors who have at least one measurable lesion, can provide a tumor sample, and are in good physical condition (ECOG PS of 0 or 1). Specifically for those with certain types of gastric cancer or non-squamous NSCLC that's progressed after specific treatments.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

Is willing to provide an adequate tumor sample

I have a tumor that can be measured by scans.

Exclusion Criteria

My cancer has spread to the lining of my brain and spinal cord.

I have severe lung problems due to another lung illness.

History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive valemetostat in combination with DXd ADCs to determine the recommended dose for expansion

6 weeks

Every 6 weeks

Dose Expansion

Participants receive valemetostat at the recommended dose in combination with DXd ADCs to further evaluate safety and tolerability

12 weeks

Every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 5 years

Every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• DXd ADCs
• Valemetostat

Trial Overview The trial is testing the combination of valemetostat tosylate with two antibody-drug conjugates (DXd ADCs), T-DXd and Dato-DXd, to see if they're safe and effective against advanced solid tumors.

How Is the Trial Designed?

Group I: Part 2: Dose Expansion (Sub-protocol C) Experimental Treatment 2 Interventions

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).

Group II: Part 2: Dose Expansion (Sub-protocol B) Experimental Treatment 2 Interventions

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.

Group III: Part 2: Dose Expansion (Sub-protocol A) Experimental Treatment 2 Interventions

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.

Group IV: Part 1: Dose Escalation Phase (Sub-protocol C) Experimental Treatment 2 Interventions

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).

Group V: Part 1: Dose Escalation Phase (Sub-protocol B) Experimental Treatment 2 Interventions

Participants with previously treated, advanced, or metastatic HER2-positive gastric or gastro-esophageal junction (GEJ) adenocarcinoma will receive valemetostat in combination with T-DXd.

Group VI: Part 1: Dose Escalation (Sub-protocol A) Experimental Treatment 2 Interventions

Participants with unresectable or metastatic HER2-low IHC\]1+ or IHC 2+/ISH-negative breast cancer will receive valemetostat in combination with T-DXd.

DXd ADCs is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as ENHERTU for:

• Breast cancer
• Gastric cancer

Approved in United States as ENHERTU for:

• Breast cancer
• Gastric cancer

Approved in Japan as ENHERTU for:

• Breast cancer
• Gastric cancer

Who Is Running the Clinical Trial?

Daiichi Sankyo

Lead 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.

Lead 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

In a real-world study of 143 patients with HER2+ metastatic breast cancer, trastuzumab deruxtecan (T-DXd) demonstrated a high overall response rate of 68% and a median progression-free survival of 16 months, confirming its efficacy in routine clinical practice.

The safety profile of T-DXd was consistent with previous studies, with 59% of patients experiencing any-grade toxicity, primarily nausea and neutropenia, but no new safety concerns were identified, indicating it is a well-tolerated treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Outcomes of Trastuzumab Deruxtecan in Patients With HER2+ Metastatic Breast Cancer: The DE-REAL Study. Botticelli, A., Caputo, R., Scagnoli, S., et al.[2023]

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that combines an anti-HER2 antibody with a topoisomerase I inhibitor, showing a stable drug-to-antibody ratio in vivo compared to other similar drugs.

In a study involving monkeys, the concentrations of the drug and antibody decreased over time after administration, with the drug-to-antibody ratio dropping to about 2.5 over 21 days, indicating a gradual release of the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transition of average drug-to-antibody ratio of trastuzumab deruxtecan in systemic circulation in monkeys using a hybrid affinity capture liquid chromatography-tandem mass spectrometry. Habara, H., Okamoto, H., Nagai, Y., et al.[2023]

Trastuzumab deruxtecan (T-DXd) is a promising new antibody-drug conjugate that has been approved for treating HER2-positive metastatic breast cancer and gastric cancer, showing potential for use in other solid tumors as well.

T-DXd is expected to become the standard second-line treatment for HER2-positive metastatic breast cancer and may also benefit patients with hormone receptor-positive and triple-negative breast cancer that express low levels of HER2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. Perez, J., Garrigós, L., Gion, M., et al.[2022]

Trastuzumab-deruxtecan (T-DXd) is a promising antibody-drug conjugate that shows clinically relevant activity in heavily pretreated patients with HER2-positive metastatic breast cancer, particularly those who have progressed on T-DM1.

While T-DXd demonstrates efficacy, it is important to monitor for interstitial lung disease, which occurred in about 13% of patients, highlighting the need for careful patient management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab-deruxtecan: an investigational agent for the treatment of HER2-positive breast cancer. Bartsch, R.[2022]

In a phase II study involving 152 patients with HER2-mutant metastatic non-small-cell lung cancer, trastuzumab deruxtecan (T-DXd) showed a confirmed objective response rate of 49% at 5.4 mg/kg and 56% at 6.4 mg/kg, indicating robust antitumor activity.

The safety profile of T-DXd was generally manageable, with fewer severe adverse events reported in the 5.4 mg/kg group compared to the 6.4 mg/kg group, suggesting that the lower dose may be preferable for patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. Goto, K., Goto, Y., Kubo, T., et al.[2023]

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]

Trastuzumab deruxtecan (T-DXd) has shown superior efficacy compared to capecitabine-based chemotherapy and T-DM1 in patients with metastatic HER2-positive breast cancer, based on the latest phase III data from the DESTINY-Breast02 and DESTINY-Breast03 trials.

T-DXd may also be effective as a neoadjuvant treatment for HER2-low breast cancer, suggesting its potential for broader applications in HER2-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-DXd Keeps Shining in Breast Cancer. [2023]

Trastuzumab deruxtecan (T-DXd) is a promising HER2-targeted therapy that has shown significant anti-tumor activity in heavily pre-treated patients with HER2-positive breast and gastric cancers, and preliminary data suggest it may also be effective in HER2-positive non-small cell lung cancer (NSCLC) and colorectal cancer.

While T-DXd has an acceptable safety profile, there are concerns about serious treatment-emergent adverse events, highlighting the need for careful monitoring in clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors. Indini, A., Rijavec, E., Grossi, F.[2021]

Trastuzumab deruxtecan (T-DXd) showed promising antitumor activity in patients with advanced HER2-low breast cancer, achieving a 37% objective response rate in a study of 54 patients who had undergone a median of 7.5 prior therapies.

While T-DXd demonstrated efficacy, it also presented significant safety concerns, with 98% of patients experiencing treatment-emergent adverse events, including severe cases of interstitial lung disease (ILD) that led to fatalities, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. Modi, S., Park, H., Murthy, RK., et al.[2021]

Trastuzumab deruxtecan (T-DXd) shows comparable pharmacokinetics between Japanese and Western patients with HER2-positive advanced gastric cancer, suggesting similar drug exposure and effectiveness across populations.

In Western patients, T-DXd demonstrated a confirmed objective response rate of 28.6%, which is lower than the 40.1% observed in Japanese patients, potentially due to differences in prior treatments, while maintaining a manageable safety profile with a lower incidence of interstitial lung disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Real-World Evidence in a Virtual Bridging Analysis for a Human Epidermal Growth Factor Receptor 2-Targeted Antibody-Drug Conjugate in Gastric Cancer. Lu, Z., Wada, R., Salas, M., et al.[2023]

Trastuzumab deruxtecan (T-DXd) was evaluated for safety in 1457 patients across 8 clinical trials, revealing that gastrointestinal disorders and blood-related issues were the most common adverse events, with neutropenia being the most severe (21.4% incidence).

The study highlighted significant concerns regarding interstitial lung disease (10.9% incidence) and decreased left ventricular ejection fraction (1.2% incidence), suggesting that while T-DXd is generally well tolerated, these specific side effects require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of trastuzumab deruxtecan: A meta-analysis and pharmacovigilance study. Guo, Z., Ding, Y., Wang, M., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06244485

NCT06244485 | A Study of Valemetostat Tosylate in ... This study will evaluate the safety, tolerability, and efficacy of valemetostat tosylate in combination with DXd ADC in patients with advanced solid tumors.

2. daiichisankyo.com daiichisankyo.com/files/news/pressrelease/pdf/202510/20251013_E.pdf

Press Release Results of these two landmark trials will showcase the potential of ENHERTU® (trastuzumab deruxtecan) to become a foundational treatment in ...

3. datasourcebydaiichisankyo.com datasourcebydaiichisankyo.com/documents/d/datahub/jbcs-2025_naito_vale_t-dxd_presentation_final

Valemetostat and T-DXd for HER2-Low, Previously Treated ... Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) composed of 3 parts: 1-3. − A humanized anti-human epidermal growth ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.TPS508

Valemetostat and trastuzumab deruxtecan (T-DXd) in ... This study evaluates the clinical activity and safety of valemetostat in combination with T-DXd in patients with GC or GEJ adenocarcinoma as part of a Master ...

5. datasourcebydaiichisankyo.com datasourcebydaiichisankyo.com/documents/d/datahub/jsmo-2025_val-t-dxd-or-dato-dxd_naito_poster_final

Valemetostat Plus Trastuzumab Deruxtecan (T-DXd) or ... AstraZeneca. Enhertu significantly improved both progression-free and overall survival in DESTINY-Breast04 trial in patients with. HER2-low metastatic breast ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS4180

A phase 1b, multicenter, open-label study of valemetostat ... This study will combine valemetostat with topoisomerase-I inhibitor ADCs, T-DXd or Dato-DXd, for the first time in patients (pts) with HER2-positive (HER2+) ...

7. jto.org jto.org/article/S1556-0864(24)01313-3/fulltext

P2.10A.04 Valemetostat and Datopotamab Deruxtecan in ... This study is structured as a Master Protocol trial evaluating the clinical activity and safety of valemetostat in combination with DXd-ADCs.

8. daiichisankyo.us daiichisankyo.us/press-releases/-/article/daiichi-sankyo-continues-to-transform-standards-of-care-for-patients-with-three-landmark-breast-cancer-trials-and-additional-data-across-industry-leading-adc-portfolio-at-esmo

Press Releases Phase 1b study of valemetostat in combination with datopotamab deruxtecan (Dato-DXd) in advanced non-squamous non-small cell lung cancer: ...