Valemetostat + Trastuzumab Deruxtecan for Breast Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Senthil Damodaran, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anti-HER2, EZH inhibitors

Disqualifiers: Active CNS metastases, Cardiovascular disease, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called valemetostat with an existing drug, trastuzumab deruxtecan, for patients with a specific type of breast cancer that doesn't respond well to usual treatments. The combination aims to stop cancer cell growth and deliver chemotherapy directly to the cancer cells.

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.

What data supports the effectiveness of the drug Trastuzumab Deruxtecan for breast cancer?

Trastuzumab deruxtecan has shown effectiveness in treating advanced HER2-positive breast cancer, with a majority of patients responding to the drug and a median response duration of 20.7 months. It has also been approved in the USA for patients with HER2-positive breast cancer who have received prior treatments, based on the results of the phase 2 DESTINY-Breast01 trial. ^{1 2 3 4 5}

Is the combination of Valemetostat and Trastuzumab Deruxtecan safe for humans?

Trastuzumab Deruxtecan (also known as Enhertu or DS-8201a) has been shown to have a generally manageable safety profile in patients with HER2-positive breast cancer, but it can cause serious side effects like interstitial lung disease (lung inflammation) and neutropenia (low white blood cell count). Common side effects include nausea, fatigue, and hair loss. There is no specific safety data available for the combination with Valemetostat. ^{2 3 6 7 8}

What makes the drug Valemetostat + Trastuzumab Deruxtecan unique for breast cancer treatment?

This drug combination is unique because it combines trastuzumab deruxtecan, a novel HER2-targeted antibody-drug conjugate that links an anti-HER2 antibody with a potent cancer-killing agent, with valemetostat, which may offer a new approach to treating HER2-positive breast cancer, especially in patients who have already tried other treatments. ^{1 3 4 5 6}

Research Team

Senthil Damodaran, MD, PhD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Trastuzumab deruxtecan (Monoclonal Antibodies)
• Valemetostat (EZH2 Inhibitor)

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.

Participant Groups

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 Japan for the following indications:

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+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. [2020]

2. United States 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. [2023]

3. England 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. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. [2021]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. [2020]

6. France pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. [2022]

8. England 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. [2023]