Phase I/II Study of U3-1402 in Subjects With Human Epidermal Growth Factor Receptor 3 (HER3) Positive Metastatic Breast Cancer

Study Overview
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Brief Summary
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This is an open-label, three-part, multiple-dose study to evaluate safety, tolerability, and efficacy of U3-1402 in patients with HER3-positive metastatic breast cancer. HER3 is a unique member of the human epidermal growth factor receptor, which defines a certain type of cancer. The number of patients and treatment cycles are not fixed in this study. Subjects who continue to derive clinical benefit from the study treatment in the absence of withdrawal of consent, progressive disease (PD), unacceptable toxicity, or death may continue the study treatment until the end of the trial.

Official Title
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Phase 1/2, Multicenter, Open-label, Multiple-Dose First-in-human Study of U3-1402, in Subjects With HER3 Positive Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Patritumab Deruxtecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is 18 Years and older in the United States or 20 Years and older in Japan Has a pathologically documented advanced/unresectable or metastatic breast cancer Documented HER3-positive disease measured by immunohistochemistry (IHC) Has disease that is refractory to or intolerable with standard treatment, or for which standard treatment no longer is available Has an Eastern Cooperative Oncology Group Performance Status 0-1 Has Left Ventricular Ejection Fraction ≥ 50% Has measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Additional Inclusion Criteria for Dose Finding Part and Dose Expansion Part: Has received 2-6 prior chemotherapy regimens for breast cancer, at least 2 of which were administered for treatment of advanced/unresectable or metastatic disease. At least 1 prior chemotherapeutic regimen must have included a taxane, administered in the neoadjuvant, adjuvant, or advanced setting. (With exception of Dose Expansion Part TNBC cohort. See additional inclusion criteria for Dose Expansion Part TNBC cohort.) Additional Inclusion Criteria for Dose Expansion Part Only: Is able to submit a fresh tumor biopsy sample prior to starting study treatment if not already submitted for HER3 expression Has documented hormone (estrogen and/or progesterone) receptor (HR)-positive and HER2 negative expression according to American Society of Clinical Oncology - College of American Pathologists (ASCO-CAP) guidelines. (With exception of Dose Expansion Part TNBC cohort. See additional inclusion criteria for Dose Expansion Part TNBC cohort.) Additional Inclusion Criteria for Dose Expansion Part TNBC cohort Only: Has documented hormone (estrogen and progesterone) receptor (HR)-negative and HER2 negative expression according to American Society of Clinical Oncology - College of American Pathologists (ASCO-CAP) guidelines Has progressed after receiving 1 to 2 prior chemotherapy regimens for advanced/unresectable or metastatic breast cancer. Exclusion Criteria: Prior treatment with a HER3 antibody Prior treatment with an antibody-drug conjugate (ADC) which consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, DS-8201) Has a medical history of symptomatic congestive heart failure (New York Heart Association classes II-IV) or serious cardiac arrhythmia requiring treatment Has a medical history of myocardial infarction or unstable angina Has a corrected QT prolongation to > 450 millisecond (ms) in males and > 470 ms in females Has a medical history of clinically significant lung diseases (eg, interstitial pneumonia, pneumonitis, pulmonary fibrosis, and radiation pneumonitis) or who are suspected to have these diseases by imaging at screening period Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Part: Prior treatment with an govitecan derivative (eg, IMMU-132).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Part<br>Participants receive U3-1402 from 1.6 mg/kg to 9.6 mg/kg, administered via intravenous (IV) solution at 3-week intervals. | Drug: Patritumab Deruxtecan<br>* U3-1402 consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a)<br>* Other names: U3-1402;|
| Experimental: Dose Finding Part<br>Participants receive 1 of 5 different U3-1402 dosing regimens, administered via IV solution at 2 or 3-week intervals at doses at or lower than those studied in the Dose Escalation Part. | Drug: Patritumab Deruxtecan<br>* U3-1402 consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a)<br>* Other names: U3-1402;|
| Experimental: Dose Expansion Part<br>Participants with HER3 high, HER2 negative, HR positive status receive 4.8 mg/kg or 6.4 mg/kg of U3-1402 administered via intravenous (IV) solution at 3-week intervals. Participants with HER3 low, HER2 negative, HR positive status receive 6.4 mg/kg of U3-1402 administered via intravenous (IV) solution at 3-week intervals. Participants with HER3 high, HER2 negative, HR negative status receive 6.4 mg/kg of U3-1402 administration via intravenous (IV) solution at 3-week intervals. | Drug: Patritumab Deruxtecan<br>* U3-1402 consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a)<br>* Other names: U3-1402;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants experiencing adverse events (AEs) | AEs will be collected systematically from signing of the informed consent form (ICF) through 28 days after last dose | within about 6 months | 
| Number of participants with tumor response throughout the study using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 |  | From screening until disease progresses, within about 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Part: Area under the serum concentration time curve (AUC) of U3-1402 | Samples are obtained for all secondary outcome measures in the Dose Escalation Part at Cycle 1: Days 1, 2, 4, 8, 15; Cycle 2: Days 1, 8, 15; Cycle 3: Days 1, 2, 4, 8, 15; Cycles 4, 6, 8: Day 1 | Cycle 1, Day 1 to Cycle 8, Day 1 (148 days) | 
| Dose Finding Part: AUC of U3-1402 | Samples are obtained for all secondary outcome measures in the Dose Finding Part for the following categories: Cohorts 1 and 2: at Cycle 1: Days 1, 2, 4, 8, 15; Cycle 2: Day 1; Cycle 3: Days 1, 8, 15; Cycles 4, 5, 6, 8: Day 1 Cohort 3: at Cycles 1, 2, 3: Days 1, 8, 15; Cycles 4, 5, 6, 8: Day 1 Cohorts 4 and 5: at Cycle 1: Days 1, 4, 8; Cycle 2: Day 1; Cycle 3: Days 1, 4, 8; Cycle 4: Days 1, 8, 15; Cycles 5, 6, 8: Day 1 | Cycle 1, Day 1 to Cycle 8, Day 1 (148 days) | 
| Dose Expansion Part: AUC of U3-1402 | Samples are obtained for all secondary outcome measures in the Dose Expansion Part at Cycle 1, Days 1, 2, 4, 8, 15; Cycle 2, Day 1; Cycle 3, Days 1, 8, 15; Cycles 4, 6, 8; Day 1 | Cycle 1, Day 1 to Cycle 8, Day 1 (148 days) | 
| Dose Escalation Part: Maximum plasma concentration (Cmax) of U3-1402 |  | within 148 days | 
| Dose Finding Part: Cmax of U3-1402 |  | within 148 days | 
| Dose Expansion Part: Cmax of U3-1402 |  | within 148 days | 
| Dose Escalation Part: Time to maximum plasma concentration (Tmax) of U3-1402 |  | within 148 days | 
| Dose Finding Part: Tmax of U3-1402 |  | within 148 days | 
| Dose Expansion Part: Tmax of U3-1402 |  | within 148 days | 
| Dose Escalation Part: Change in Total anti-HER3 antibody from U3-1402 |  | Baseline, 6 months | 
| Dose Finding Part: Change in Total anti-HER3 antibody from U3-1402 |  | Baseline, 6 months | 
| Dose Expansion Part: Change in Total anti-HER3 antibody from U3-1402 |  | Baseline, 6 months | 
| Dose Escalation Part: Change in MAAA-1181 level from U3-1402 |  | within 148 days | 
| Dose Finding Part: Change in MAAA-1181 level from U3-1402 |  | within 148 days | 
| Dose Expansion Part: Change in MAAA-1181 level from U3-1402 |  | within 148 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncology, HER3, Antibody drug conjugate, Developmental Phase I/II