A phase 1 study of ACE-Breast-01 [ZMC-ARX788111 (CTR20171162)] to test the safety, PK, and antitumor activity of ARX788 in patients in China with HER2-positive metastatic breast cancer (MBC) whose disease had progressed on prior anti-HER2 treatments. The study includes dose escalation(N=69) to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) in patients with HER2-positive MBC.

The MTD of ARX788 was not reached at doses of up to 1.50 mg/kg every 3 weeks. the RP2D in breast cancer studies was determined to be 1.50 mg/kg every 3 weeks. 33 of the 69 (47.83%) patients had an objective partial tumor response. For ARX788 1.50 mg/kg every 3 weeks, the objective response rate was 65.52% [19/29, 95% confidence interval (CI), 45.70-82.10], the disease control rate was 100.00% (95% CI, 81.20-100.00), and the median progression-free survival was 17.02 months (95% CI, 10.09-not reached).

A phase 1 study in HER2-positive advanced ug/GEJ adenocarcinoma was initiated to evaluate the safety and efficacy of ARX788. There were 22 males (73.3%) and 8 females (26.7%). Twenty-two (73.3%) had gastric adenocarcinoma,and the rest (26.7%) had GEJ adenocarcinoma. Twenty-seven patients (90%) underwent prior trastuzumab-containing therapy,eight of whom progressed within 6 months in the adjuvant or neoadjuvant phase. Twelve (40%) were treated with 2 or more lines of therapy (26) and eight of whom had 3 or more lines. All patients were treated with platinum-based and fluorouracil regimens,and eight with taxanes and three with irinotecan. Most participants (73.3%) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1. All of them had at least one dose of ARX788,of whom 9 patients received 1.3 mg/kg,14 received 1.5 mg/kg,and 7 received 1.7 mg/kg ARX788.

Incurable, locally advanced, or metastatic HER2-positive (immunohistochemistry [IHC] 3+ and/or fluorescence in situ 1 hybridization [FISH]-positive) breast cancer that progressed on greater and or 2 equal to two prior anti-HER2 treatment(s) in the advanced disease setting and 3 who provided written informed consent, patients had an Eastern 4 Cooperative Oncology Group (ECOG) performance status of 0-1.

Patients with HER2-positive MBC received ARX788 at doses of 0.33, 0.66, 0.88, 1.10, 1.30, or 1.50 mg/kg every 3 weeks, or 0.88, 1.10, or 1.30 mg/kg every 4 weeks. The dose-limiting toxicity (DLT) was assessed for 84 days for pulmonary toxicity and at a duration of one cycle (21 or 28 days) for other toxicities. In total, 69 patients were enrolled. No DLT or drug-related deaths occurred.

Eligibility requires HER2-positive (IHC 3+ or 2+/FISH+) stage II-III breast cancer patients (females, 18-75 years, ECOG 0-1) with adequate organ function. Key exclusions: prior antitumor therapy, metastatic/active malignancies (last 5 years), untreated infections, severe cardiac/pulmonary diseases, pregnancy, or uncontrolled comorbidities like hypertension/diabetes.

Eligible subjects &ge;18 years with HER2+ metastatic breast cancer (&le;5 prior therapies including T-DXd), measurable disease per RECIST 1.1, and stable brain metastases. Key exclusions: ILD/pneumonitis history, significant cardiac/ocular conditions, uncontrolled systemic diseases, recent radiotherapy (<7 days), active COVID-19, or investigational drug use within 14 days prior. Adequate organ function and stable prior toxicity (Grade &le;1) required.

Eligibility requires HER2-positive (IHC 3+ or 2+/FISH+) stage II-III breast cancer patients (females, 18-75 years, ECOG 0-1) with adequate organ function. Key exclusions: prior antitumor therapy, metastatic/active malignancies (last 5 years), untreated infections, severe cardiac/pulmonary diseases, pregnancy, or uncontrolled comorbidities like hypertension/diabetes.

Eligible subjects are adults (&ge;18 years) with HER2-positive advanced cancers (breast, gastric, or other solid tumors) refractory to prior HER2-targeted therapies. Phase 1b requires measurable disease (RECIST v1.1), ECOG 0-1, resolved prior toxicities (&le;Grade 1), and adequate organ function. Exclusions include severe cardiac/neuropathy history, active infections (e.g., COVID-19/HIV/HBV/HCV), recent anticancer therapies (<14 days), or uncontrolled comorbidities. Contraception is mandated for participants.

Experimental: ARX788 Phase 1a (Dose Escalation), ARX788 will be administered every 3 weeks (Q3W) or every 4 weeks (Q4W) via intravenous (IV) infusion. Patients will be enrolled into escalating dose levels during Dose Escalation period.Experimental: ARX788 Phase 1b (Dose Expansion), ARX788 will be administered every 3 weeks (Q3W) via intravenous (IV) infusion. Patients will receive the maximum tolerated dose during the Dose Expansion period of the study.

Eligible subjects &ge;18 years with HER2+ metastatic breast cancer (&le;5 prior therapies including T-DXd), measurable disease per RECIST 1.1, and stable brain metastases. Key exclusions: ILD/pneumonitis history, significant cardiac/ocular conditions, uncontrolled systemic diseases, recent radiotherapy (<7 days), active COVID-19, or investigational drug use within 14 days prior. Adequate organ function and stable prior toxicity (Grade &le;1) required.

Eligible subjects are adults (&ge;18 years) with HER2-positive advanced cancers (breast, gastric, or other solid tumors) refractory to prior HER2-targeted therapies. Phase 1b requires measurable disease (RECIST v1.1), ECOG 0-1, resolved prior toxicities (&le;Grade 1), and adequate organ function. Exclusions include severe cardiac/neuropathy history, active infections (e.g., COVID-19/HIV/HBV/HCV), recent anticancer therapies (<14 days), or uncontrolled comorbidities. Contraception is mandated for participants.

Experimental: ARX788 Phase 1a (Dose Escalation), ARX788 will be administered every 3 weeks (Q3W) or every 4 weeks (Q4W) via intravenous (IV) infusion. Patients will be enrolled into escalating dose levels during Dose Escalation period.Experimental: ARX788 Phase 1b (Dose Expansion), ARX788 will be administered every 3 weeks (Q3W) via intravenous (IV) infusion. Patients will receive the maximum tolerated dose during the Dose Expansion period of the study.

Eligibility requires HER2-positive (IHC 3+ or 2+/FISH+) stage II-III breast cancer patients (females, 18-75 years, ECOG 0-1) with adequate organ function. Key exclusions: prior antitumor therapy, metastatic/active malignancies (last 5 years), untreated infections, severe cardiac/pulmonary diseases, pregnancy, or uncontrolled comorbidities like hypertension/diabetes.

Eligible patients are adults (18-75 years) with HR&plusmn;/HER2-low metastatic breast cancer (IHC 1+ or 2+/FISH-), prior systemic therapy exposure, measurable lesions, ECOG 0-1, and adequate organ function. Key exclusions include HER2-ADC pretreatment, active CNS metastases, uncontrolled comorbidities, interstitial lung disease, ocular disorders, recent anticancer therapies, pregnancy, or impaired trial compliance. Organ function thresholds and resolved prior toxicity (Grade &le;1) are required for enrollment.

Secondary endpoints include Progression-Free Survival (PFS), Overall Survival (OS), Disease Control Rate (DCR), and Duration of Response (DOR), all evaluated within 2 years from treatment initiation. PFS measures time from first dose to progression/death; OS tracks survival from treatment start; DCR combines ORR with stable disease cases; DOR assesses sustained response in CR/PR patients.

Eligibility includes HR+/HER2+ metastatic breast cancer patients (18-75 years, ECOG 0-2) with untreated brain metastases, prior trastuzumab/taxane/EGFR-TKI exposure, and adequate organ function. Key exclusions: pneumomeningeal/cystic metastases, interstitial lung disease, recent antitumor therapies (within 1-2 weeks), active infections, severe allergies, pregnancy, or uncontrolled comorbidities.

Eligible participants include adults (&ge;18 years, ECOG 0-2) with HER2-low (IHC 1+/2+/FISH-) unresectable/metastatic breast cancer (HR+ or HR- cohorts), measurable lesions by RECIST 1.1, and controlled brain metastases if treated. Key exclusions: prior ARX-788/auristatin exposure, active ILD/pneumonitis, uncontrolled cardiac/pulmonary conditions, QTc prolongation (>450-470 ms), ocular diseases (keratitis), pregnancy, or malignancies requiring treatment within 3 years (exceptions: cured skin/thyroid cancers).

Secondary objectives include duration of response (DOR), best overall response (BOR), disease control rate (DCR), median progression-free survival (PFS), median overall survival (OS), treatment-emergent AEs, ocular AE monitoring with visual/keratitis assessments, and adherence to preventive eye drop regimen - all analyzed within 1-2 years with 95% CIs where applicable.

Exclusion criteria encompass known ARX788 hypersensitivity, active CNS metastases requiring treatment, symptomatic effusions requiring intervention, significant pulmonary/cardiac/ophthalmic comorbidities, uncontrolled hypertension, recent live vaccinations, pregnancy/breastfeeding, recent antitumor therapy (<28 days), cognitive impairments affecting consent comprehension, and any investigator-assessed conditions potentially compromising patient safety or protocol compliance.

The study evaluates key efficacy parameters including objective response rate (ORR) based on RECIST 1.1, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and incidence of treatment-emergent adverse events (TEAEs) assessed by CTCAE v5.0. Pharmacokinetic parameters such as Cmax, tmax, t1/2, AUC (0-inf), AUC (0-last), λz, CL, Vz, Vss, and Ctrough are measured at specified cycle endpoints to characterize drug exposure and metabolism.

Eligible participants aged 18-75 with HER2-positive (IHC3+ or FISH+) unresectable locally advanced, recurrent, or metastatic breast cancer who have received ≤2 prior chemotherapy lines (excluding hormonal therapy) and have ≥1 measurable lesion per RECIST1.1. Required criteria include recovery from prior treatment toxicities (≤Grade 1), adequate organ function, ECOG 0-1, and willingness to comply with study procedures and contraception requirements.

Eligible subjects must have life expectancy >12 weeks, BMI 18-32 kg/m2, HER2-positive advanced cancer with prior HER2-targeted therapy (where applicable), measurable disease per RECIST v1.1 (Phase 1b), and adequate organ function. Exclusions include severe allergies, uncontrolled CNS metastases, heart conditions, neuropathy, electrolyte imbalances, recent anticancer therapy/surgery/radiation, pregnancy, or inability to consent.

Eligible patients have untreated, measurable (&ge;2.5cm) stage II-III breast cancer with biomarker profiles matching study arms. Key requirements include adequate organ function, no distant metastases, and compatible MRI eligibility. Exclusions involve prior chemotherapy/radiation for current malignancy, uncontrolled comorbidities, or investigational drug use within 30 days.

The primary endpoint is Objective Response Rate (ORR) assessed by BICR per RECIST 1.1, defined as the proportion of subjects achieving CR or PR. Secondary endpoints include Duration of Response (DOR), Best Overall Response (BOR), Disease Control Rate (DCR), Progression-Free Survival (PFS), Overall Survival (OS), Time to Response (TTR), pharmacokinetic parameters (Cmax and Ctrough for ARX788, total antibody, and metabolites), and incidence of anti-drug antibodies (ADAs).

Eligibility criteria include age ≥18, life expectancy >3 months, ECOG ≤1, and HER2 status confirmed via CLIA-certified lab. Cohorts 1, 2, and A require HER2 mutations in NSCLC, breast cancer, or other tumors without prior HER2 ADC treatment. Cohorts 3-5 include HER2-amplified BTC, CRC, ovarian, endometrial, NSCLC, and other tumors, with Cohort 5 allowing prior HER2 ADC. Subjects must have stable brain metastases and adequate organ function.