ARX788 for HER2-Positive Breast Cancer

(ACE-Breast03 Trial)

Recruiting in Palo Alto (17 mi)

+78 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Ambrx, Inc.

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

No Placebo Group

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests ARX788, a new IV medicine, for patients with HER2-positive metastatic breast cancer who did not respond well to T-DXd. The medicine targets a specific protein on cancer cells to help stop their growth.

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.

What data supports the effectiveness of the drug ARX788 for HER2-Positive Breast Cancer?

ARX788 is a new type of drug that combines a targeted antibody with a powerful cancer-fighting agent, and early studies show it has antitumor activity in patients with HER2-positive metastatic breast cancer. Similar drugs, like trastuzumab deruxtecan, have been effective in treating breast cancer with low HER2 expression, suggesting that ARX788 might also be effective in similar cases. ^{1 2 3 4 5}

Is ARX788 safe for humans?

ARX788 has shown a favorable safety profile in early studies, with no major adverse side effects observed in animal studies and a high level of stability, which reduces the risk of off-target toxicity. It was well-tolerated in monkeys at doses higher than those needed for effectiveness, supporting its safety for further clinical development. ^{2 3 6 7 8}

What makes the drug ARX788 unique for treating HER2-positive breast cancer?

ARX788 is a next-generation antibody-drug conjugate (ADC) that uses a unique technology to attach a powerful cancer-killing agent to an antibody targeting HER2, making it more stable and effective, especially in cases resistant to other treatments like T-DM1. It shows strong activity in both high and low HER2-expressing tumors, offering a new option for patients who may not respond to existing therapies. ^{2 3 6 7 9}

Research Team

Ambrx

Principal Investigator

Ambrx, Inc.

Eligibility Criteria

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 am 18 years old or older.

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

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.

Trial Timeline

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

Treatment Details

Interventions

• ARX788 (Monoclonal Antibodies)

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.

Participant Groups

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 for the following indications:

Approved in China as ARX788 for:

• HER2-positive breast cancer

Who Is Running the Clinical Trial?

Ambrx, Inc.

Lead Sponsor

Trials

8

Recruited

860+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

References

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

Antibody-drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment. [2023]

2. United States 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. [2022]

3. Netherlands 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. [2020]

4. China pubmed.ncbi.nlm.nih.gov

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

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

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

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

Nonclinical Development of Next-generation Site-specific HER2-targeting Antibody-drug Conjugate (ARX788) for Breast Cancer Treatment. [2021]

7. United States 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. [2021]

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

Strategies for Mitigating Antibody-Drug Conjugate Related Adverse Events for Precision Therapy. [2022]

9. Ireland 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. [2020]