ARX788 for Breast Cancer

Overseen By Amy Langdon

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Laura Huppert, MD, BA

Must not be taking: Auristatin analogues

Disqualifiers: Interstitial lung disease, Congestive heart failure, 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: 51

Duration: Up to 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of ARX788, a new treatment for certain types of advanced breast cancer. ARX788 targets and kills cancer cells by attaching a toxin to antibodies that bind to HER2, a protein on some breast cancer cells. The trial includes individuals with HER2-low breast cancer that cannot be surgically removed or has metastasized. It suits those who have already undergone at least one chemotherapy or similar treatment for advanced cancer. Participants will receive ARX788 intravenously every three weeks and may also use eye drops as part of the study. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have taken any investigational or commercial anti-cancer agents within 14 days before starting the trial, and anti-hormonal therapy can be used up to 7 days before the first dose.

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

Research has shown that ARX788 has been tested for safety in breast cancer patients, including those with HER2-low cancer, as in this trial. One study administered ARX788 to patients who had already tried many other treatments, and most tolerated it well. Common side effects included low blood counts, tiredness, and nausea, but these were usually manageable. Serious side effects occurred less frequently.

These findings suggest ARX788 is generally well-tolerated, even in those who have undergone many previous treatments. However, like any new treatment, risks may exist, and it is important to consider these when deciding to join a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about ARX788 for breast cancer because it offers a unique approach by targeting HER2-low cancers. Most treatments for breast cancer focus on either HER2-positive or hormone receptor-positive types, but ARX788 is designed to address the unmet need in HER2-low cases, which are harder to treat with current options. ARX788 is an antibody-drug conjugate, which means it combines a powerful cancer-killing drug with an antibody that specifically targets cancer cells, potentially leading to more effective and precise treatment with fewer side effects. Additionally, the trial includes an innovative ocular toxicity prevention sub-study, which aims to minimize potential eye-related side effects, showcasing the comprehensive approach to patient safety.

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

Research shows that ARX788, which participants in this trial will receive, may help treat breast cancer, particularly in patients with HER2-low tumors. In earlier studies, this treatment proved effective for patients who had already tried many other treatments. ARX788 is an antibody-drug conjugate, combining an antibody with a toxin to specifically target and kill cancer cells. Early results suggest it might work for both hormone receptor-positive and hormone receptor-negative breast cancer, studied in separate cohorts in this trial. This targeted approach aims to attach to HER2 proteins on some cancer cells and deliver the toxin directly to them, potentially slowing cancer growth. ^{1 2 3 6 7}

Who Is on the Research Team?

Laura Huppert, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for individuals with HER2-low breast cancer that has spread and cannot be removed by surgery. Participants should have a type of breast cancer that hasn't responded to other treatments or has come back.

Inclusion Criteria

Estimated life expectancy of at least at 6 months per investigator assessment

Hemoglobin ≥ 8 g/dL

Absolute neutrophil count ≥ 1.0 x 10^9/L

Exclusion Criteria

I do not have any mental or physical health conditions that would affect my participation in the study.

I have a history of eye diseases, but not glaucoma.

I have or had lung conditions not caused by cancer spread.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ARX788 intravenously over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Up to 1 year

Every 21 days

Ocular Toxicity Prevention Sub-study

The first 5 participants from Cohorts 1 and 2 will be given outpatient eye drops to use from home in conjunction with ARX788.

Throughout treatment and for 30 days after the last infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

1 year

30 days after treatment, then every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ARX788
• Biospecimen Collection
• Computed Tomography (CT)

Trial Overview The study tests ARX788, an antibody-drug conjugate given via infusion, designed to target and kill HER2-low breast cancer cells. The effectiveness and safety of this treatment are being evaluated in patients with advanced stages of the disease.

How Is the Trial Designed?

Group I: Ocular Toxicity Prevention Sub-study Experimental Treatment 4 Interventions

The first 5 participants from Cohorts 1 and 2 will be given outpatient eye drops to use from home in conjunction with ARX788. Participants will be drop applied to each eye 4 times a day starting on the day of first infusion and continuing daily throughout treatment and for 30 days after the last infusion.

Group II: Cohort 2: HR-/HER2-low Experimental Treatment 3 Interventions

Participants with confirmed HR negative (HR-)/human epidermal growth factor receptor 2 (HER2)-low will receive ARX788 intravenously over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants also undergo CT, PET/CT, and collection of blood samples throughout the study.

Group III: Cohort 1: HR+/HER2-low Experimental Treatment 3 Interventions

Participants with locally advanced, unresectable MBC that is hormone receptor (HR) positive (HR+) /human epidermal growth factor receptor 2 (HER2)-low will receive ARX788 intravenously over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants also undergo CT, PET/CT, and collection of blood samples throughout the study.

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?

Laura Huppert, MD, BA

Lead Sponsor

Trials

1

Recruited

40+

Ambrx, Inc.

Industry Sponsor

Trials

8

Recruited

860+

Published Research Related to This Trial

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]

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 a new class of targeted cancer treatments that combine the tumor-targeting ability of antibodies with the powerful effects of cytotoxic drugs, significantly improving treatment options for certain breast cancer subtypes.

While ADCs generally have favorable safety profiles, they can cause specific adverse reactions such as thrombocytopenia and hepatotoxicity, necessitating careful monitoring and management by healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chinese expert consensus of antibody-drug conjugate toxicity management for breast cancer]. [2022]

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) 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]

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]

PF-06650808, an anti-Notch3 antibody-drug conjugate, was generally well tolerated in a phase I study with 40 patients, showing no dose-limiting toxicities at doses up to 2.0 mg/kg, and an estimated maximum tolerated dose of 2.4 mg/kg.

The treatment showed early signs of antitumor activity, with 5 patients achieving partial responses and 51.6% of patients experiencing stable disease, particularly in those with estrogen receptor-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody-drug conjugate, in patients with breast cancer and other advanced solid tumors. Rosen, LS., Wesolowski, R., Baffa, R., et al.[2022]

Antibody-drug conjugates (ADCs) are a promising treatment for breast cancer, effectively delivering cytotoxic drugs directly to tumors while minimizing systemic toxicity, making them generally well tolerated.

Despite their benefits, ADCs can cause predictable side effects such as neutropenia and nausea, which require careful monitoring and management to prevent treatment interruptions or dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity profile of antibody-drug conjugates in breast cancer: practical considerations. D'Arienzo, A., Verrazzo, A., Pagliuca, M., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06224673

NCT06224673 | ARX788 for Treating Patients With HER2- ... This phase II trial tests how well ARX788 works in treating patients diagnosed with HER2-low, locally advanced unresectable or metastatic breast cancer.

2. 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 ...

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

ACE-BREAST-03: A phase 2 trial evaluating ARX788 ... ARX788 has shown antitumor activity in heavily pretreated patients with HER2+ and HER2-low mBC, including those with prior T-DXd exposure.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11830773/

ACE-Breast-02: a randomized phase III trial of ARX788 versus ... The clinical benefit of ARX788 in patients with HER2-positive advanced breast cancer (ABC) was reported in a phase I trial conducted in China, ...

5. withpower.com withpower.com/trial/phase-2-her2-low-breast-carcinoma-2-2024-bee63

ARX788 for Breast Cancer · Info for Participants This phase II trial tests how well ARX788 works in treating patients diagnosed with HER2-low, locally advanced unresectable or metastatic breast cancer.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32669315/

ARX788, a Site-specific Anti-HER2 Antibody-Drug ... Breast and gastric cancer patient-derived xenograft studies confirmed strong antitumor activity of ARX788 in HER2-positive and HER2-low expression tumors, as ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.1038

Safety and unique pharmacokinetic profile of ARX788, a ... ARX788 demonstrated promising activity in HER2-positive, HER2-low, and T-DM1 resistant tumors in preclinical studies. Here we present the phase ...