ARX788 for HER2-Positive Breast Cancer

(ACE-Breast03 Trial)

Not currently recruiting at 88 trial locations

Overseen By Trial Inquiry

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ambrx, Inc.

Disqualifiers: Lung disease, Heart failure, CNS metastases, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ARX788, an antibody-drug conjugate, for individuals with HER2-positive breast cancer that has spread and who have previously received T-DXd. The researchers aim to determine if ARX788 can manage the cancer more effectively than current treatments. Participants should have HER2-positive breast cancer that is either inoperable or has metastasized. This trial may suit those who have tried up to five treatments, including T-DXd, and are living with stable brain metastases. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have taken any other investigational or commercial anticancer agents within 14 days before starting the trial.

Is there any evidence suggesting that ARX788 is likely to be safe for humans?

Research has shown that ARX788 has a manageable safety profile based on past studies. In these studies, patients with HER2-positive and HER2-low breast cancer received ARX788 treatment, which they generally tolerated well. Most side effects were not severe.

One study found that the most common side effects were tiredness, nausea, and low blood cell counts, which were mostly mild to moderate. More serious side effects occurred less frequently.

Overall, these earlier studies suggest that ARX788 is safe. However, individual reactions to treatments can vary. Participants should discuss any concerns with the medical team conducting the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

ARX788 is unique because it is an investigational drug specifically targeting HER2-positive breast cancer with a new approach. Unlike traditional treatments like trastuzumab and pertuzumab, which are monoclonal antibodies, ARX788 is an antibody-drug conjugate (ADC). This means it combines an antibody that targets cancer cells with a powerful anti-cancer drug, allowing for more precise delivery of the medication directly to the tumor cells. Researchers are excited about ARX788 because this targeted delivery could potentially increase the treatment's effectiveness while minimizing side effects.

What evidence suggests that ARX788 might be an effective treatment for HER2-positive breast cancer?

Research shows that ARX788, the investigational treatment studied in this trial, has promising results for treating HER2-positive metastatic breast cancer. Studies have found that ARX788 can help patients live longer without their cancer worsening. Even in patients who have undergone many treatments, ARX788 demonstrated good anti-cancer effects, suggesting it might work when other treatments like T-DXd have not. This treatment targets cancer cells with high levels of HER2, a protein that can promote cancer growth. By focusing on these cancer cells, it helps protect normal cells, making it a potentially effective option for this type of breast cancer. ^{2 3 4 6 7}

Who Is on the Research Team?

Ambrx

Principal Investigator

Ambrx, Inc.

Are You a Good Fit for This Trial?

This trial is for adults with HER2-positive metastatic breast cancer who've had no more than 5 systemic treatments in the metastatic setting, including T-DXd. They must have stable brain metastases, resolved any acute toxicities to Grade ≤1 (except hair loss), and have a measurable lesion. People can't join if they've recently used other cancer treatments, have certain lung or heart conditions, severe uncontrolled diseases, active infections like COVID-19, or unstable brain metastases.

Inclusion Criteria

My side effects from previous cancer treatments have mostly gone away.

I've had 5 or fewer treatments for my cancer, including T-DXd.

I can carry out all my self-care but cannot do heavy physical work.

Exclusion Criteria

I haven't taken any cancer treatment drugs in the last 14 days.

I do not have any ongoing eye infections or long-term corneal problems.

I have severe nerve damage or pain in my hands or feet.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

ARX788 is administered every 3 weeks by intravenous infusion

2 years

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• ARX788

Trial Overview The study tests ARX788 on patients with advanced breast cancer who previously received T-DXd treatment. It's a global Phase 2 trial focusing on those whose disease has spread and are looking for new treatment options after traditional therapies.

How Is the Trial Designed?

Group I: ARX788 Experimental Treatment 1 Intervention

The investigational medicinal product (IMP), ARX788, will be administered every 3 weeks (Q3W) by intravenous (IV) infusion.

ARX788 is already approved in China, United States for the following indications:

Approved in China as ARX788 for:

• HER2-positive breast cancer

Approved in United States as ARX788 for:

• Advanced or metastatic HER2-positive breast cancer

Who Is Running the Clinical Trial?

Ambrx, Inc.

Lead Sponsor

Trials

8

Recruited

860+

Published Research Related to This Trial

Antibody-drug conjugates (ADCs) are a promising cancer treatment that combines targeted monoclonal antibodies with cytotoxic agents to deliver drugs directly to cancer cells, minimizing harm to healthy cells.

Despite their targeted approach, ADCs can still cause adverse events due to early payload release or target expression in normal cells, highlighting the need for careful monitoring and dose adjustments to optimize their safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for Mitigating Antibody-Drug Conjugate Related Adverse Events for Precision Therapy. Gouda, MA., Subbiah, V.[2022]

In a study of 2657 early breast cancer (EBC) and 535 metastatic breast cancer (MBC) patients, those with intermediate HER2 expression (IHC 2+) had significantly poorer recurrence-free survival compared to HER2-negative patients, particularly in those aged 55 and older.

Intermediate HER2 expression serves as an independent predictor of poor prognosis in both ER+ EBC and MBC patients aged 55 and older, suggesting that new HER2-targeting therapies like DS8201 may be particularly important for this high-risk group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermediate HER2 expression is associated with poor prognosis in estrogen receptor-positive breast cancer patients aged 55 years and older. Kim, MH., Kim, GM., Kim, JH., et al.[2020]

Trastuzumab deruxtecan (T-DXd) has shown effectiveness in treating HER2-low breast cancer, indicating its potential as a targeted therapy for this subtype.

This finding highlights the importance of developing treatments that can specifically target and benefit patients with lower levels of HER2 expression, expanding options for breast cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan Is Effective in HER2-Low Breast Cancer. [2021]

ARX788, a new anti-HER2 antibody-drug conjugate, demonstrated significant effectiveness against T-DM1-resistant HER2-positive breast and gastric cancer cell lines, showing a pronounced growth inhibitory effect and inducing more apoptosis compared to T-DM1.

In xenograft models, tumors resistant to T-DM1 responded well to ARX788 treatment, with many tumors disappearing and improved survival rates in mice treated with ARX788, suggesting it could be a promising option for patients whose cancers progress during T-DM1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ARX788, a novel anti-HER2 antibody-drug conjugate, shows anti-tumor effects in preclinical models of trastuzumab emtansine-resistant HER2-positive breast cancer and gastric cancer. Barok, M., Le Joncour, V., Martins, A., et al.[2020]

ARX788 is a novel antibody-drug conjugate that uses site-specific conjugation to achieve a stable drug-to-antibody ratio, resulting in improved stability and reduced side effects compared to conventional ADCs.

In preclinical studies, ARX788 showed significant antitumor activity against HER2-expressing tumors and demonstrated a favorable safety profile, with a nonseverely toxic dose of 10 mg/kg, well above the effective dose, supporting its potential for clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical Development of Next-generation Site-specific HER2-targeting Antibody-drug Conjugate (ARX788) for Breast Cancer Treatment. Nagaraja Shastri, P., Zhu, J., Skidmore, L., et al.[2021]

In a phase I study involving 69 patients with HER2-positive metastatic breast cancer, ARX788 showed a promising objective response rate of 65.5% and a disease control rate of 100% at the recommended dose of 1.5 mg/kg every 3 weeks.

The safety profile of ARX788 was manageable, with no dose-limiting toxicities or drug-related deaths reported, although 97.1% of patients experienced treatment-related adverse events, primarily mild to moderate in severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of a Novel Anti-HER2 Antibody-Drug Conjugate, ARX788, for the Treatment of HER2-Positive Metastatic Breast Cancer. Zhang, J., Ji, D., Shen, W., et al.[2022]

Antibody-drug conjugates (ADCs) combine the targeting ability of monoclonal antibodies with potent cytotoxic drugs, leading to improved treatment efficacy for breast cancer by specifically delivering the drug to tumor cells while also potentially affecting neighboring cells.

Three ADCs are currently approved for breast cancer treatment, showing significant efficacy and becoming part of standard regimens, although challenges remain in patient selection, managing side effects, and overcoming resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment. Nader-Marta, G., Molinelli, C., Debien, V., et al.[2023]

Antibody-drug conjugates (ADCs) are effective targeted therapies that link cytotoxic drugs to monoclonal antibodies, allowing for specific delivery to tumor cells while minimizing side effects, with 14 ADCs approved globally as of September 2022.

The successful use of ADCs in clinical settings relies on understanding their molecular characteristics, appropriate dosing, and management of adverse reactions, prompting the need for updated clinical guidelines to optimize their application in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Expert consensus on the clinical application of antibody drug conjugates in the treatment of malignant tumors (2023 edition)]. [2023]

ARX788 is a next-generation antibody-drug conjugate (ADC) that shows improved stability and efficacy compared to first-generation ADCs, with a drug-to-antibody ratio of 1.9 and a half-life of 12.5 days in mice.

In preclinical studies, ARX788 demonstrated superior tumor growth inhibition in both HER2-high and HER2-low expressing cancer models, including those resistant to T-DM1, suggesting it could be an effective treatment for patients with various HER2 expression levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ARX788, a Site-specific Anti-HER2 Antibody-Drug Conjugate, Demonstrates Potent and Selective Activity in HER2-low and T-DM1-resistant Breast and Gastric Cancers. Skidmore, L., Sakamuri, S., Knudsen, NA., et al.[2021]

Citations

1. ambrx.com ambrx.com/wp-content/uploads/P01-04-01-SABCS-2023-ARX788-CLINICAL.pdf

P01-04-01-SABCS-2023-ARX788-CLINICAL.pdf Here we present safety data and preliminary efficacy data in heavily pre-treated patients with HER2+ and HER2-low breast cancer treated with ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS1112

Targeting HER2-positive metastatic breast cancer with ... A global, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04829604?spons=COVERAGE%5BFullMatch%5DEXPANSION%5BNone%5D(%22Ambrx,%20Inc.%22)&viewType=Table&rank=3

Study Details | NCT04829604 | ARX788 in HER2-positive, ... A Global, Single Arm, Phase 2 Study of ARX788 in HER2-positive Metastatic Breast Cancer Patients who were previously treated with T-DXd. The ARX788 will be ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/28/19/4212/709299/Phase-I-Trial-of-a-Novel-Anti-HER2-Antibody-Drug

Phase I Trial of a Novel Anti-HER2 Antibody–Drug Conjugate ... Herein, we present the results of a phase I study of the safety, pharmacokinetics, and antitumor activity of ARX788 in patients with HER2-positive metastatic ...

5. onclive.com onclive.com/view/arx788-meets-pfs-end-point-in-her2-metastatic-breast-cancer

ARX788 Meets PFS End Point in HER2+ Metastatic Breast ... ARX788 was found to significantly improve progression-free survival compared with an active control in patients with HER2-positive locally advanced or ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06224673

NCT06224673 | ARX788 for Treating Patients With HER2- ... Giving ARX788 may be safe and effective in treating patients with HER2-low locally advanced unresectable metastatic breast cancer. Detailed Description. PRIMARY ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS1123

ACE-BREAST-03: A phase 2 trial evaluating ARX788 ... A phase 2 trial evaluating ARX788, an anti-HER2 antibody drug conjugate (ADC), for the treatment of HER2+ metastatic breast cancer (mBC)