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

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

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Patritumab Deruxtecan

• Study Type: Interventional
• Enrollment (Actual): 184
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan, 277-8577
    • National Cancer Center Hospital East
  • Fukushima, Japan, 960-1295
    • Fukushima Medical University Hospital
  • Hiroshima, Japan, 730-518
    • Local Independent Administrative Corporation Hiroshima City Hospital Organization Hiroshima City Hiroshima Citizens Hospital
  • Kagoshima, Japan, 892-0833
    • Hakuaikai Social Medical Corporation Sagara Hospital
  • Kanagawa, Japan, 241-0815
    • Kanagawa cancer center
  • Kumamoto, Japan, 860-8556
    • Kumamoto University Hospital
  • Nagoya, Japan, 467-8602
    • Nagoya City University Hospital
  • Nagoya, Japan, 464-8681
    • Aichi Cancer Center Hospital
  • Osaka, Japan, 540-0006
    • National Hospital Organization Osaka National Hospital
  • Osaka, Japan, 589-8511
    • Kindai University Hospital
  • Osaka, Japan, 541-8567
    • Osaka International Cancer Institute
  • Saitama, Japan, 350-1298
    • Saitama Medical University International Medical Center
  • Saitama, Japan, 362 0806
    • Saitama Cancer Center
  • Tokyo, Japan, 104-0045
    • National Cancer Center Hospital
  • Tokyo, Japan, 135-8550
    • The Cancer Institute Hospital of Japanese Foundation for Cancer Research
  • Hokkaido
    • Sapporo-Shi, Hokkaido, Japan, 003-0804
      • National Hospital Organization Hokkaido Cancer Center
• United States
  • Georgia
    • Newnan, Georgia, United States, 30265
      • Southeastern Regional Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New York
    • Bronx, New York, United States, 10467
      • Albert Einstein College of Medicine
    • New York, New York, United States, 10022
      • Memorial Sloan Kettering Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Dallas, Texas, United States, 75231
      • Texas Oncology, P.A.
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Mays Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Is 18 Years and older in the United States or 20 Years and older in Japan
2. Has a pathologically documented advanced/unresectable or metastatic breast cancer
3. Documented HER3-positive disease measured by immunohistochemistry (IHC)
4. Has disease that is refractory to or intolerable with standard treatment, or for which standard treatment no longer is available
5. Has an Eastern Cooperative Oncology Group Performance Status 0-1
6. Has Left Ventricular Ejection Fraction ≥ 50%

7. 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:

8. 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:

9. Is able to submit a fresh tumor biopsy sample prior to starting study treatment if not already submitted for HER3 expression

10. 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:

11. 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
12. Has progressed after receiving 1 to 2 prior chemotherapy regimens for advanced/unresectable or metastatic breast cancer.

Exclusion Criteria:

1. Prior treatment with a HER3 antibody
2. Prior treatment with an antibody-drug conjugate (ADC) which consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, DS-8201)
3. Has a medical history of symptomatic congestive heart failure (New York Heart Association classes II-IV) or serious cardiac arrhythmia requiring treatment
4. Has a medical history of myocardial infarction or unstable angina
5. Has a corrected QT prolongation to > 450 millisecond (ms) in males and > 470 ms in females
6. 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

7. Has clinically significant corneal disease

   Additional Exclusion Criteria for Dose Expansion Part:

8. Prior treatment with an govitecan derivative (eg, IMMU-132).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation Part; 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; U3-1402 consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a); Other Names: U3-1402
Experimental: Dose Finding Part; 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; U3-1402 consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a); Other Names: U3-1402
Experimental: Dose Expansion Part; 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; U3-1402 consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a); Other Names: U3-1402

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Daiichi Sankyo Co., Ltd.
• Collaborators: Daiichi Sankyo, Inc.
• Investigators: Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2016
• Primary Completion (Actual): August 16, 2021
• Study Completion (Actual): September 7, 2023

Study Registration Dates

• First Submitted: November 28, 2016
• First Submitted That Met QC Criteria: November 30, 2016
• First Posted (Estimated): December 2, 2016

Study Record Updates

• Last Update Posted (Actual): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Oncology; Antibody drug conjugate; HER3; Developmental Phase I/II
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Patritumab deruxtecan
• Other Study ID Numbers: U31402-A-J101; JapicCTI-163401 (Registry Identifier: JapicCTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ .
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No