A Study of HER3-DXd in Subjects With Locally Advanced or Metastatic Solid Tumors

HERTHENA-PanTumor01 (U31402-277): A Phase 2, Multicenter, Multicohort, Open-Label, Proof of Concept Study of Patritumab Deruxtecan (HER3-DXd; U3-1402) in Subjects With Locally Advanced or Metastatic Solid Tumors

This is a proof-of-concept study designed to investigate HER3-DXd monotherapy in locally advanced or metastatic solid tumors. Three initial cohorts of patients with an unmet medical need in the refractory setting are planned to be studied in this signal seeking study: melanoma (cutaneous/acral), squamous cell carcinomas of the head and neck (SCCHN), and HER2-negative gastric cancer.

Study Overview

• Status: Recruiting
• Conditions: Melanoma; Head and Neck Cancer; Gastric Cancer; Advanced Solid Tumor
• Intervention / Treatment: Drug: HER3-DXd

Detailed Description

This study is designed to assess the safety and efficacy of HER3-DXd monotherapy in subjects with refractory locally advanced or metastatic solid tumors who have been previously treated with ≥1 prior line of systemic anticancer therapy.

The primary objective of the study is to assess the efficacy of HER3-DXd monotherapy for each type of indicated locally advanced or metastatic tumor. Secondary objectives include the assessment of safety and tolerability, efficacy, and pharmacokinetics of HER3-DXd monotherapy for each type of indicated locally advanced or metastatic tumor. HER3 protein expression in tumor tissue and its relationship with HER3-DXd efficacy will also be evaluated.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Daiichi Sankyo Contact for Clinical Trial Information; Phone Number: 9089926400; Email: CTRinfo@dsi.com

Study Locations

• Japan
  • Tokyo, Japan, 135-0550
    • Recruiting
    • Cancer Institute Hospital of JFCR

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

Participants must meet all of the following criteria to be eligible for enrollment into the study:

1. Sign and date the informed consent form prior to the start of any study-specific qualification procedures. A separate tissue screening consent will be obtained from all subjects to meet the baseline tumor tissue requirement.
2. Is a male or female aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old).

3. Has locally advanced unresectable or metastatic disease (not curable by surgery or radiation) as follows:

   Cutaneous or acral melanoma

   1. Histologically or cytologically confirmed cutaneous or acral melanoma

   2. Disease progression after having received ≥1 prior line of anti-PD-1 or anti-PD-L1 based therapy.

      If the participant had BRAFm melanoma, they must have had disease progression on BRAF/MEK inhibitor therapy as well.

      OR

      Squamous cell carcinomas of the head and neck

   3. Squamous cell carcinoma of the head and neck that is human papillomavirus (HPV) positive or negative. Primary tumor site must have arisen initially from the oral cavity, oropharynx, hypopharynx, or larynx. Tumors arising from the nasopharynx are excluded.

   4. Disease progression after having received treatment with a PBC regimen with or without anti-PD-1 therapy

      OR

      Gastric or GEJ adenocarcinoma

   5. Tumor tissue must be confirmed as negative for HER2 expression (immunohistochemistry [IHC] 0/1+ or IHC 2+/in situ hybridization negative) as classified by ASCO-CAP guidelines and determined prior to enrollment by assessment in a local laboratory that is Clinical Laboratory Improvement Amendments certified (US sites) or accredited based on specific country regulations.
   6. Disease progression after having received treatment with a previous PBC with or without anti-PD-1 therapy.
4. Has ≥1 measurable lesion on CT or MRI as per RECIST v1.1 by investigator assessment.

5. Provides a pretreatment tumor tissue sample of sufficient quantity, as defined in the Study Laboratory Manual. The pretreatment tumor tissue can be provided as either

   1. Tissue collected from a biopsy performed since progression while on or after treatment with the most recent cancer therapy regimen and prior to signing of the tissue ICF

      OR

   2. Pretreatment tumor biopsy from ≥1 lesion not previously irradiated and amenable to sampling. The pretreatment tissue requirement may be waived after discussion and agreement with the Sponsor.
6. Has Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at screening.

Exclusion Criteria

Participants who meet any of the following criteria will be disqualified from entering the study:

1. Has HER2-positive gastric cancer as classified by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines and determined prior to enrollment by assessment in a local laboratory that is Clinical Laboratory Improvement Amendments certified (US sites) or accredited based on specific country regulations.
2. Has nasopharyngeal cancer.
3. Has mucosal or uveal melanoma.
4. Has any history of interstitial lung disease (ILD; including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have such disease by imaging during screening.
5. Has clinically severe respiratory compromise (based on the investigator's assessment) resulting from intercurrent pulmonary illnesses

6. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1 Day 1.

   Participants who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study.

7. Had prior treatment with an anti-HER3 antibody and/or antibody-drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan).

8. Has history of other active malignancy within 3 years prior to Cycle 1 Day 1, except the following:

   1. Adequately treated nonmelanoma skin cancer
   2. Adequately treated intraepithelial carcinoma of the cervix
   3. Any other curatively treated in situ disease
9. Has any evidence of severe or uncontrolled diseases (eg, active bleeding diatheses, active serious infection) psychiatric illness/social situations, geographical factors, substance abuse, or other factors that, in the investigator's opinion, make it high risk for the subject to participate in the study or that would jeopardize compliance with the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HER3-DXd Monotherapy; Participants with locally advanced or metastatic cancer (melanoma, head and neck, and gastric cancer) will receive an intravenous infusion of HER3-DXd monotherapy 5.6 mg/kg every 3 weeks (Q3W).	Drug: HER3-DXd; Intravenous infusion 5.6 mg/kg administered Q3W on Day 1 of each 21-day cycle; Other Names: U3-1402; Patritumab Deruxtecan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Objective Response Rate Assessed by Investigator Following HER3-DXd Monotherapy	Confirmed objective response rate (ORR) is defined as the sum of the complete response (CR) rate and partial response (PR) rate based on investigator by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1.	Baseline up until documented progressive disease, death, lost to follow-up, or withdrawal by the participant, up to approximately 27 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Number of Participants With Treatment-emergent Adverse Events Following HER3-DXd Monotherapy	Adverse events (AEs) will be coded using MedDRA and AEs and will be graded by using NCI-CTCAE v5.0.	Baseline up to 27 months
Duration of Response As Assessed by Investigator Following HER3-DXd Monotherapy	Duration of response (DoR) is defined as the time from the date of the first documentation of objective response (complete response [CR] or partial response [PR]) to the date of the first documentation of progressive disease (PD) or death. The DoR will be calculated for responding participants (PR or CR) only.	From the date of first documentation of confirmed response (CR or PR) to the first documentation of objective progression or to death due to any cause, whichever occurs first, up to approximately 27 months
Clinical Benefit Rate As Assessed by Investigator Following HER3-DXd Monotherapy	Clinical benefit rate (CBR) is the proportion of participants with a best overall response of confirmed CR, confirmed PR, or SD lasting ≥183 days.	Baseline up until documented progressive disease, death, lost to follow-up, or withdrawal by the participant, up to approximately 27 months
Disease Control Rate As Assessed by Investigator Following HER3-DXd Monotherapy	Disease control rate is defined as the proportion of participants who have achieved a best overall response of confirmed CR, confirmed PR, or SD (or non-CR/non-PD) by investigator assessment per RECIST v1.1.	Baseline up until documented progressive disease, death, lost to follow-up, or withdrawal by the participant, up to approximately 27 months
Time to Response As Assessed by Investigator Following HER3-DXd Monotherapy	Time to response (TTR) will be calculated for confirmed responders only.	From the start date of study drug to the date of the first documentation of response (CR or PR) that is subsequently confirmed, up to approximately 27 months
Progression-free Survival As Assessed by Investigator Following HER3-DXd Monotherapy		From the start date of study drug to the earlier date of the first objective documentation of radiographic disease progression as assessed by investigator per RECIST v1.1 or death due to any cause, whichever occurs first, up to approximately 27 months
Overall Survival Following HER3-DXd Monotherapy		From the start date of study drug to the date of death due to any cause, whichever occurs first, up to approximately 27 months
Pharmacokinetic Parameter Maximum Serum Concentration for HER3-DXd	Maximum serum concentration (Cmax) will be assessed using non-compartmental methods.	Cycles 1-4, 6, 8: Day 1, predose and postdose; Cycles 1 and 3: Day 1, 2 hours and 4 hours postdose; Cycles 1 and 3: Day 8; Cycle 1: Day 15 (each cycle is 21 days)
Pharmacokinetic Parameter Time to Maximum Serum Concentration for HER3-DXd	Time to maximum serum concentration (Tmax) will be assessed using non-compartmental methods.	Cycles 1-4, 6, 8: Day 1, predose and postdose; Cycles 1 and 3: Day 1, 2 hours and 4 hours postdose; Cycles 1 and 3: Day 8; Cycle 1: Day 15 (each cycle is 21 days)
Pharmacokinetic Parameter Trough Serum Concentration (Ctrough) for HER3-DXd	Trough serum concentration (Ctrough) will be assessed using non-compartmental methods.	Cycles 1-4, 6, 8: Day 1, predose and postdose; Cycles 1 and 3: Day 1, 2 hours and 4 hours postdose; Cycles 1 and 3: Day 8; Cycle 1: Day 15 (each cycle is 21 days)
Pharmacokinetic Parameter Area Under the Concentration Curve for HER3-DXd	Area under the concentration-time curve up to the last quantifiable time (AUClast) and Area under the concentration-time curve during dosing interval (AUCtau) will be assessed using non-compartmental methods.	Cycles 1-4, 6, 8: Day 1, predose and postdose; Cycles 1 and 3: Day 1, 2 hours and 4 hours postdose; Cycles 1 and 3: Day 8; Cycle 1: Day 15 (each cycle is 21 days)

Collaborators and Investigators

• Sponsor: Daiichi Sankyo
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Global Clinical Leader, Daiichi Sankyo

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2024
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: December 7, 2023
• First Submitted That Met QC Criteria: December 7, 2023
• First Posted (Actual): December 15, 2023

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Head and Neck Cancer; Gastric Cancer; Melanoma; Advanced Solid Tumor; HER3-DXd; Patritumab Deruxtecan; U3-1402
• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Stomach Neoplasms; Head and Neck Neoplasms; Melanoma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Patritumab deruxtecan
• Other Study ID Numbers: U31402-277

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) on completed studies 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: Completed studies that has reached a global end or completion with all data set collected and analyzed, and 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 on completed 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; ICF

Drug and device information, study documents

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