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

• ClinicalTrials.gov Identifier: NCT02980341
• Recruitment Status: Completed
• First Posted: December 2, 2016
• Last Update Posted: December 15, 2023
• Sponsor: Daiichi Sankyo Co., Ltd.
• Collaborator: Daiichi Sankyo
• Information provided by (Responsible Party): Daiichi Sankyo ( Daiichi Sankyo Co., Ltd. )

Tracking Information

• First Submitted Date: November 28, 2016
• First Posted Date: December 2, 2016
• Last Update Posted Date: December 15, 2023
• Actual Study Start Date: November 28, 2016
• Actual Primary Completion Date: August 16, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 24, 2018)

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

Original Primary Outcome Measures (submitted: November 30, 2016)

• Number of participants experiencing adverse events [ Time Frame: From signing of informed consent form (ICF) through 28 days after last dose, within about 6 months ]
  To investigate the safety of U3-1402 reporting on frequency and seriousness of treatment emergent adverse events.
• Number of participants with tumor response throughout the study using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 [ Time Frame: From screening until disease progresses, within about 6 months ]
  Assessment of tumor response is conducted every 6 weeks in the first 24 weeks and thereafter every 12 weeks until progressive disease to evaluate the efficacy of U3-1402.

Current Secondary Outcome Measures (submitted: September 4, 2018)

• Dose Escalation Part: Area under the serum concentration time curve (AUC) of U3-1402 [ Time Frame: Cycle 1, Day 1 to Cycle 8, Day 1 (148 days) ]
  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
• Dose Finding Part: AUC of U3-1402 [ Time Frame: Cycle 1, Day 1 to Cycle 8, Day 1 (148 days) ]
  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
• Dose Expansion Part: AUC of U3-1402 [ Time Frame: Cycle 1, Day 1 to Cycle 8, Day 1 (148 days) ]
  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
• Dose Escalation Part: Maximum plasma concentration (Cmax) of U3-1402 [ Time Frame: within 148 days ]
• Dose Finding Part: Cmax of U3-1402 [ Time Frame: within 148 days ]
• Dose Expansion Part: Cmax of U3-1402 [ Time Frame: within 148 days ]
• Dose Escalation Part: Time to maximum plasma concentration (Tmax) of U3-1402 [ Time Frame: within 148 days ]
• Dose Finding Part: Tmax of U3-1402 [ Time Frame: within 148 days ]
• Dose Expansion Part: Tmax of U3-1402 [ Time Frame: within 148 days ]
• Dose Escalation Part: Change in Total anti-HER3 antibody from U3-1402 [ Time Frame: Baseline, 6 months ]
• Dose Finding Part: Change in Total anti-HER3 antibody from U3-1402 [ Time Frame: Baseline, 6 months ]
• Dose Expansion Part: Change in Total anti-HER3 antibody from U3-1402 [ Time Frame: Baseline, 6 months ]
• Dose Escalation Part: Change in MAAA-1181 level from U3-1402 [ Time Frame: within 148 days ]
• Dose Finding Part: Change in MAAA-1181 level from U3-1402 [ Time Frame: within 148 days ]
• Dose Expansion Part: Change in MAAA-1181 level from U3-1402 [ Time Frame: within 148 days ]

Original Secondary Outcome Measures (submitted: November 30, 2016)

• Change in area under the serum concentration time curve (AUC) of U3-1402 [ Time Frame: From first dose to Cycle 8, within 24 weeks ]
  Area under curve at Cycle 1, Days 1, 2, 4, 8, 15; Cycle 2, Days 1, 8, 15; Cycle 3, Days 1, 2, 4, 8, 15; Cycle 4,6,8; Day 1
• Change in the maximum plasma concentration (Cmax) of U3-1402 [ Time Frame: From first dose to Cycle 8, within 24 weeks ]
  Maximum plasma concentration at Cycle 1, Days 1, 2, 4, 8, 15; Cycle 2, Days 1, 8, 15; Cycle 3, Days 1, 2, 4, 8, 15; Cycle 4,6,8; Day 1
• Change in the time to maximum plasma concentration (Tmax) of U3-1402 [ Time Frame: From first dose to Cycle 8, within 24 weeks ]
  Time of maximum plasma concentration at Cycle 1, Days 1, 2, 4, 8, 15; Cycle 2, Days 1, 8, 15; Cycle 3, Days 1, 2, 4, 8, 15; Cycle 4,6,8; Day 1
• Change in the total anti-HER3 antibody from U3-1402 [ Time Frame: From first dose to Cycle 8, within 24 weeks ]
  Cycle 1, Days 1, 2, 4, 8, 15; Cycle 2, Days 1, 8, 15; Cycle 3, Days 1, 2, 4, 8, 15; Cycle 4,6,8; Day 1
• Change in the MAAA-1181 level from U3-1402 [ Time Frame: From first dose to Cycle 8, within 24 weeks ]
  To determine the change in MAAA-1181 level from first dose to Cycle 8 at Cycle 1, Days 1, 2, 4, 8, 15; Cycle 2, Days 1, 8, 15; Cycle 3, Days 1, 2, 4, 8, 15; Cycle 4,6,8; Day 1

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase I/II Study of U3-1402 in Subjects With Human Epidermal Growth Factor Receptor 3 (HER3) Positive Metastatic Breast Cancer
• Official Title: Phase 1/2, Multicenter, Open-label, Multiple-Dose First-in-human Study of U3-1402, in Subjects With HER3 Positive Metastatic Breast Cancer

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Breast Cancer

Intervention

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 Name: U3-1402

Study Arms

• 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.
  Intervention: Drug: Patritumab Deruxtecan
• 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.
  Intervention: Drug: Patritumab Deruxtecan
• 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.
  Intervention: Drug: Patritumab Deruxtecan

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 27, 2021): 184
• Original Estimated Enrollment (submitted: November 30, 2016): 80
• Actual Study Completion Date: September 7, 2023
• Actual Primary Completion Date: August 16, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan, United States

Administrative Information

• NCT Number: NCT02980341
• Other Study ID Numbers: U31402-A-J101; JapicCTI-163401 ( Registry Identifier: JapicCTI )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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/ .
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• 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.
• 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.
• URL: https://vivli.org/ourmember/daiichi-sankyo/

• Current Responsible Party: Daiichi Sankyo ( Daiichi Sankyo Co., Ltd. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo Co., Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Daiichi Sankyo

Investigators

• Study Director: Global Clinical Leader; Daiichi Sankyo

• PRS Account: Daiichi Sankyo
• Verification Date: December 2023