Phase 2 Multicenter Study of Patritumab Deruxtecan in Patients with Locally Advanced or Metastatic Solid Tumors

Trial ID: 2023-507641-29-00
Protocol: U31402-277
Sponsor: Daiichi Sankyo Inc.

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Diseases & Conditions

Neoplasm

Objectives

The primary objective of this study is to assess the **efficacy** of HER3-DXd monotherapy in patients with locally advanced or metastatic solid tumors. This evaluation is clinically relevant as it aims to determine the therapeutic potential of HER3-DXd, which could offer a new treatment option for patients with these challenging cancer types.

Secondary objectives include:

To assess the safety and tolerability of HER3-DXd monotherapy, which is crucial for understanding the risk-benefit profile of the treatment.
To further assess the efficacy of HER3-DXd monotherapy, providing additional insights into its therapeutic impact.
To evaluate the pharmacokinetics (PK) of HER3-DXd monotherapy, which will help in understanding the drug's absorption, distribution, metabolism, and excretion.
To evaluate HER3 protein expression in tumor tissue and its relationship with HER3-DXd efficacy, which may identify potential biomarkers for treatment response.

Participants

The clinical trial involves a total of **320 participants** diagnosed with **locally advanced or metastatic solid tumors**. The study population includes both male and female subjects aged **18 years and older**, with no upper age limit specified. Participants were selected based on their ability to comply with study procedures and their health status, which includes having an Eastern Cooperative Oncology Group performance status of 0 or 1 at screening. The trial population is not restricted by gender, and both male and female subjects are included. Participants are required to have adequate bone marrow reserve and organ function, as determined by local laboratory data. Lifestyle considerations such as diet and physical activity are not specified, but participants must be physically able to participate in study-related activities. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these individuals. Key inclusion criteria include having at least one measurable lesion on computed tomography or magnetic resonance imaging and providing a pretreatment tumor tissue sample. The trial aims to assess the efficacy of HER3-DXd monotherapy in this specific patient population.

Plans and Procedures

The clinical trial is a **Phase 2**, multicenter, multicohort, open-label study designed to evaluate the efficacy and safety of **HER3-DXd** monotherapy in subjects with **locally advanced or metastatic solid tumors**. The trial aims to assess the overall response rate (ORR) as the primary endpoint, with secondary endpoints including safety parameters, duration of response, and progression-free survival. The study is expected to commence recruitment on May 29, 2024, and conclude by October 31, 2026.

Participants will be administered **Patritumab deruxtecan** via **intravenous infusion**. The maximum treatment period is 16 cycles, with a maximum daily dose of 5.60 mg/kg. The trial will include several study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, disease status, and organ function. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments conducted using **RECIST v1.1** criteria. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment.

Participant involvement is expected to last until the completion of the treatment period or until disease progression, unacceptable toxicity, or withdrawal of consent occurs. Conditions that may lead to early termination from the study include non-compliance with study procedures or the emergence of significant adverse events. The trial is not categorized as low intervention and is designed to provide insights into the therapeutic potential of HER3-DXd in a diverse patient population.

Treatment

The clinical trial involves the administration of **Patritumab deruxtecan**, a novel therapeutic agent under investigation. This experimental medication is provided in the form of a **solution for infusion**. The active substance, **patritumab deruxtecan**, is a protein-based compound classified under the category "Protein - Other." The pharmaceutical form is specifically designed for **intravenous infusion**, ensuring direct delivery into the bloodstream. The dosing regimen for Patritumab deruxtecan is calculated based on body weight, with a maximum daily dose of 5.60 mg/kg. The total dose administered over the course of the treatment should not exceed 6272 mg/kg. The maximum treatment period is set at 16 weeks, during which the efficacy of the monotherapy will be assessed. The product is not formulated for pediatric use and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on evaluating the efficacy of Patritumab deruxtecan as a monotherapy. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the therapeutic outcomes. The trial is conducted under the sponsorship of Daiichi Sankyo, Inc., and follows rigorous clinical guidelines to maintain the integrity and reliability of the study results.

Efficacy

The efficacy of **Patritumab deruxtecan** in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint for most cohorts, except the prostate cancer cohort, is the Objective Response Rate (ORR) as evaluated by the investigator according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). For the prostate cancer cohort, the primary endpoint is the PSA50 response rate, which is defined as the proportion of patients experiencing a ≥50% decrease in PSA levels from baseline, confirmed by a consecutive PSA assessment at least three weeks later.

Secondary endpoints include the assessment of Treatment-Emergent Adverse Events (TEAEs) and other safety parameters, Duration of Response (DoR), Clinical Benefit Rate (CBR), Disease Control Rate (DCR), Time to Response (TTR), and Progression-Free Survival (PFS) evaluated by the investigator per RECIST v1.1. Overall Survival (OS) will also be measured, including in the prostate cancer cohort. Pharmacokinetic (PK) endpoints and the correlation between HER3 protein expression at baseline, as determined by HER3 IHC assay, and efficacy will be evaluated. Specific to the prostate cancer cohort, additional secondary endpoints include radiographic Progression-Free Survival (rPFS) according to PCWG3, PSA30 response rate, Time to First Subsequent Anticancer Therapy (TFST), and Time to First Symptomatic Skeletal-Related Event (SSRE).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Sign and date the ICF, 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.
Subject aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old
Has locally advanced unresectable or metastatic disease (not curable by surgery or radiation) (see details on page 99)
Has ≥1 measurable lesion on computed tomography (CT) or magnetic resonance imaging (MRI) as per RECIST v1.1 by investigator assessment. Prostate cancer subjects with bone only disease may be eligible.
Provides a pretreatment tumor tissue sample that meets 1 of the collection requirements (see details on page 103)
Has Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at screening
Has adequate bone marrow reserve and organ function based on local laboratory data within 7days prior to Cycle 1 Day (see table starting on page 103)
If the subject is a female of childbearing potential, she must have a negative serum pregnancy test at screening and must be willing to use highly effective birth control upon enrolment, during the Treatment Period, and for 7 months following the last dose of study drug (see table on page 103).
Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study Treatment Period and for ≥7 months after the final study drug administration.
A male, subject capable of producing sperm is eligible to participate if he agrees to the following, during the intervention period, and for at least the time needed the trial intervention. The length of time required to continue contraception after last dose for the trial intervention is ≥4 months(see details on page 103)
Male subjects must not freeze or donate sperm starting at screening and throughout the study period and ≥4 months after the final study drug administration.
Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
Sub study: Participant is taking part in the Phase II open-label study.
Sub study: Participant provides consent to participate in the interview sub-study via the Study Informed Consent Form (ICF).
Sub study: Participant consents to be audio recorded.
Sub study: Participant resides in Belgium, Spain, Japan, Korea, Taiwan, continental US (Puerto Rico is excluded), UK, Australia, Canada, Czech Republic, Germany, Hungary, Italy, Norway, The Netherlands
Sub study: Participant can communicate and read fluently in country local language including Belgian-French, Spanish, Japanese, Korean, Taiwanese-Mandarin, Canadian-French, Czech, German, Hungarian, Italian, Norwegian, Dutch or English.
Sub study: Participant is physically able to participate in a one-on-one, approximately 45-minute interview (conducted in one sitting) using an internet-enabled computer or other device (such as a tablet) with screensharing / screen-viewing capabilities

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Exclusion Criteria

Has HER2-positive gastric cancer 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)
Has nasopharyngeal cancer
Has mucosal or uveal melanoma
Has a history of (non- infectious) ILD that required corticosteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging during screening.
Has clinically severe respiratory compromise (based on the investigator’s assessment) resulting from intercurrent pulmonary illnesses (see details on page 104)
Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone daily or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1 Day 1. Subjects who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study
Has any history of or evidence of current leptomeningeal disease
Has clinically significant corneal disease
Has evidence of clinically active spinal cord compression or brain metastases, defined as being symptomatic or untreated, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and not requiring treatment with corticosteroids or anticonvulsants) may be included in the study but must have a stable neurologic status for ≥4 weeks prior to Cycle 1 Day 1. Subjects with asymptomatic brain metastases and treated with anticonvulsants as prophylaxis are able to enroll.
Had inadequate washout period prior to Cycle 1 Day 1 (see details on page 105)
Had prior treatment with an anti-HER3 antibody and/or antibody-drug conjugate (ADC) that consists of a topoisomerase I inhibitor (eg, trastuzumab deruxtecan).
Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved by the National Cancer Institute – Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) to Grade ≤1 or baseline (see details on page 105).
Has history of other active malignancy within 3 years prior to Cycle 1 Day 1, except the following: a. Adequately treated nonmelanoma skin cancer and adequately treated thin primary melanoma <1 mm. b. Adequately treated intraepithelial carcinoma of the cervix c. Any other curatively treated in situ disease. d. Early prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) not requiring treatment
Has uncontrolled or significant cardiovascular disorder prior to Cycle 1 Day 1 (see details on page 106)
Has active or uncontrolled hepatitis C virus infection infection (see details on page 106).
Has uncontrolled HIV1/2 infection (see details on page 107).
Has active or uncontrolled HBV infection (see details on page 107).
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.
Has known hypersensitivity to either the drug substance or inactive ingredients in the drug product.
Is a female subject who is pregnant or breastfeeding or intends to become pregnant during the study
Has prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator’s opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism, or excretion of the study drug; or confound the assessment of study results
Has previously received topoisomerase-1 inhibitors (e.g., irinotecan treatment in the advanced or metastatic disease)
Sub study: Participant is unable to adhere to the requirements of the interview sub-study

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	29 May 2024	32
France	Recruiting	29 May 2024	167
Germany	Recruiting	29 May 2024	8
Hungary	Recruiting	29 May 2024	19
Italy	Recruiting	29 May 2024	23
The Netherlands	Recruiting	29 May 2024	—
Norway	Recruiting	29 May 2024	10
Spain	Recruiting	29 May 2024	97
Netherlands	—	—	17