U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer

NCT03260491 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: U31402-A-U1022024-511205-33-00194868
• Study Type: interventional
• Target: 312
• Locations: 6 countries
• Sites: 37

Brief Summary

This study was designed to evaluate safety and antitumor activity of HER3-DXd in two parts: Dose Escalation and Dose Expansion. In Dose Escalation, HER3-DXd was evaluated in participants with metastatic or unresectable NSCLC with epidermal growth factor receptor (EGFR) activating mutation after disease progression during/after EGFR tyrosine kinase inhibitor (TKI) therapy. In Dose Expansion, HER3-DXd will be evaluated in participants with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC (ie, without EGFR-activating mutations) with disease progression during/after systemic treatment for locally advanced or metastatic disease. In addition, HER3-DXd will be evaluated in participants with locally advanced or metastatic NSCLC whose tumors harbor a KRAS-G12C mutation after progression on the most recent line of therapy (Cohort 5).

Conditions

Non-Small Cell Lung Cancer (NSCLC)

Keywords

Oncology; Advanced Non-small Cell Lung Cancer; Metastatic; Unresectable; Epidermal growth factor receptor; EGFR; KRAS-G12C; Unresectable Non-small Cell Lung Cancer

Outcome Measures

Primary Outcomes (5)

• Dose-limiting toxicities (DLTs) during dose escalation

  21 days of Cycle 1

• Summary of adverse events during dose escalation

  By the global end of trial date, approximately within 36 months

• Overall response rate (ORR) assessed by Blinded Independent Central Review (BICR) Committee during dose expansion (Dose Expansion Cohorts 1, 2, 3a, 3b, and Cohort 5)

  ORR will be evaluated using RECIST v1.1.

  Approximately within 36 months

• Maximum serum concentration (Cmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Cohort 4)

  During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.

• Area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and up to last quantifiable time (AUC[last]) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Cohort 4)

  During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.

Secondary Outcomes (23)

• Maximum serum concentration (Cmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose escalation

  During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.

• Time of maximum concentration (Tmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose escalation

  During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.

• Area under the serum concentration-time curve from time 0 to 21 days (AUC[0-21]) and up to last quantifiable time (AUC[last]) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose escalation

  During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.

• Overall response rate (ORR) during dose escalation

  Approximately within 36 months

• Disease control rate (DCR) during dose escalation

  Approximately within 36 months

Study Arms (10)

Dose Escalation: Cohort 1, 3.2 mg/kg

EXPERIMENTAL

Participants in the Dose Escalation Cohort 1 will receive HER3-DXd intravenously (IV) once every three weeks at 3.2 mg/kg.

Drug: HER3-DXd (FL-DP)

Dose Escalation: Cohort 2, 4.8 mg/kg

EXPERIMENTAL

Participants in Dose Escalation Cohort 2 will receive HER3-DXd intravenously (IV) once every three weeks at 4.8 mg/kg.

Drug: HER3-DXd (FL-DP)

Dose Escalation: Cohort 3, 5.6 mg/kg

EXPERIMENTAL

Participants in Dose Escalation Cohort 3 will receive HER3-DXd intravenously (IV) once every three weeks at 5.6 mg/kg.

Drug: HER3-DXd (FL-DP)

Dose Escalation: Cohort 4, 6.4 mg/kg

EXPERIMENTAL

Participants in Dose Escalation Cohort 3 will receive HER3-DXd intravenously (IV) once every three weeks at 6.4 mg/kg.

Drug: HER3-DXd (FL-DP)

Dose Expansion: Cohort 1, EGFR mutant

EXPERIMENTAL

Participants with adenocarcinoma NSCLC with EGFR mutations in the Dose Expansion Cohort 1 will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE).

Drug: HER3-DXd (CTM-1 Lyo-DP)

Dose Expansion: Cohort 2, EGFR wild-type

EXPERIMENTAL

Participants with squamous or non-squamous NSCLC without EGFR-activating mutations in the Dose Expansion Cohort 2 will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE).

Drug: HER3-DXd (CTM-1 Lyo-DP)

Dose Expansion: Cohort 3a, EGFR mutant

EXPERIMENTAL

Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3a will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE) or, if applicable, adjusted RDE (aRDE).

Drug: HER3-DXd (CTM-1 Lyo-DP)

Dose Expansion: Cohort 3b, EGFR mutant

EXPERIMENTAL

Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3b will receive HER3-DXd IV once every three weeks following an up-titration regimen (Cycle 1, Day 1: 57% of RDE or aRDE; Cycle 2, Day 1: 86% of RDE or, if applicable aRDE; Cycle 3 and subsequent cycles, Day 1: 114% of RDE or aRDE).

Drug: HER3-DXd (CTM-1 Lyo-DP)

Dose Expansion: Cohort 4, EGFR mutant

EXPERIMENTAL

Participants with NSCLC (including any histology other than small-cell or combined small-cell and non-small cell) with an EGFR-activating mutation will receive HER3-DXd IV at 5.6 mg/kg every 3 weeks.

Drug: HER3-DXd (CTM-3 Lyo-DP)

Dose Expansion: Cohort 5, KRAS-G12C mutant NSCLC

EXPERIMENTAL

Participants with locally advanced or metastatic NSCLC whose tumors harbor a KRAS-G12C mutation and that have progressed on the most recent line of therapy will receive HER3-DXd IV at 5.6 mg/kg every 3 weeks.

Drug: HER3-DXd (CTM-3 Lyo-DP)

Interventions

HER3-DXd (FL-DP) DRUG

HER3-DXd (frozen liquid drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a).

Also known as: U3-1402

Dose Escalation: Cohort 1, 3.2 mg/kg; Dose Escalation: Cohort 2, 4.8 mg/kg; Dose Escalation: Cohort 3, 5.6 mg/kg; Dose Escalation: Cohort 4, 6.4 mg/kg

HER3-DXd (CTM-1 Lyo-DP) DRUG

HER3-DXd (lyophilized drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a) that was manufactured by the clinical manufacturing sites.

Also known as: U3-1402

Dose Expansion: Cohort 1, EGFR mutant; Dose Expansion: Cohort 2, EGFR wild-type; Dose Expansion: Cohort 3a, EGFR mutant; Dose Expansion: Cohort 3b, EGFR mutant

HER3-DXd (CTM-3 Lyo-DP) DRUG

HER3-DXd (lyophilized drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a) that was manufactured by the commercial manufacturing sites.

Also known as: U3-1402

Dose Expansion: Cohort 4, EGFR mutant; Dose Expansion: Cohort 5, KRAS-G12C mutant NSCLC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation
• Has at least one measurable lesion per RECIST version 1.1
• Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening
• Has histologically or cytologically documented adenocarcinoma NSCLC
• Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011)
• Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q)
• Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease \[Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1\] or World Health Organization (WHO)\] while on continuous treatment with an EGFR TKI
• Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib
• Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening
• Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib
• Is willing to provide archival tumor tissue from a biopsy performed within 6 months of progression during treatment with erlotinib, gefitinib, afatinib, or osimertinib OR has at least one lesion, not previously irradiated, amenable to core biopsy and is willing to undergo screening tumor biopsy
• Demonstrates absence of EGFR T790M mutation if treated with erlotinib, gefitinib, or afatinib. No EGFR mutation testing is required if treated with osimertinib.
• Has received systemic therapy for locally advanced or metastatic disease including at least 1 platinum-based chemotherapy regimen
• Has documented radiological disease progression during/after most recent treatment regimen for locally-advanced or metastatic disease
• For Cohorts 1, 2, 3a, and 3b: Is willing to provide archival tumor tissue from a biopsy performed within 6 months of consent and performed after progression during/after treatment with most recent cancer therapy regimen OR has at least 1 lesion, not previously irradiated, amenable to core biopsy and is willing to undergo tumor biopsy. Tumor tissue must be of sufficient quantity as defined in the laboratory manual and contain adequate tumor tissue content as confirmed by haematoxylin and eosin (H\&S) staining at central laboratory.

You may not qualify if:

• Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in Screening biopsy performed after progression
• Treatment with any of the following:
• Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI in Cohorts 1, 3a, 3b, and 4 only), within 14 days of the first dose of study treatment
• Immune checkpoint inhibitor therapy within 21 days of the first dose of study treatment
• Prior treatment with an anti-HER3 antibody (dose escalation only)
• Prior treatment with a topoisomerase I inhibitor (dose escalation only)
• Prior treatment with an antibody-drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, DS-8201a) (dose escalation only)
• Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug treatment
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug treatment, or palliative radiation therapy within 2 weeks of the first dose of study drug treatment, or stereotactic radiotherapy within 1 week prior to the first dose of U3-1402
• Has history of other active malignancy within 3 years prior to enrollment, except:
• Adequately treated non-melanoma skin cancer OR
• Superficial bladder tumors (Ta, Tis, T1) OR
• Curatively treated in situ disease
• Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy)
• Has history of myocardial infarction within the past 6 months

Sponsors & Collaborators

• Daiichi Sankyo: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (37)

City of Hope

Duarte, California, 91010, United States

Location

University of California San Diego

La Jolla, California, 92093, United States

Location

Pacific Shores Medical Group

Long Beach, California, 90813, United States

Location

Winship Cancer Institute of Emory University

Atlanta, Georgia, 30322, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

NYU Langone Health - NYU Medical Oncology Associates

New York, New York, 10016-4744, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Gabrail Cancer Center (GCC) - Canton Facility

Canton, Ohio, 44718-2566, United States

Location

University of Pittsburgh Medical Center (UPMC) - Hillman Cancer Center (University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232-1301, United States

Location

Sarah Cannon Research Institute/Tennesse Oncology

Nashville, Tennessee, 37203, United States

Location

Oncology Consultants P.A.

Houston, Texas, 77030, United States

Location

Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

Location

Northwest Medical Specialties

Tacoma, Washington, 98405, United States

Location

National Cancer Center Hospital East (NCCHE) - Kashiwa Campus

Kashiwa-Shi, 277-8577, Japan

Location

Kurume University - Kurume University Hospital - Respiratory Diseases Center

Kurume-Shi, 830-0011, Japan

Location

Kindai University Hospital

Osaka, 5898511, Japan

Location

Shizuoka Cancer Center

Shizuoka, 4118777, Japan

Location

The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR)

Tokyo, 1358550, Japan

Location

Netherlands Cancer Institute

Amsterdam, 1066 CX, Netherlands

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

NEXT Oncology - Hospital Quironsalud Barcelona

Barcelona, 08023, Spain

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital General Universitario Gregorio Maranon (HGUGM)

Madrid, 28007, Spain

Location

Clinica Universidad Navarra(Madrid)

Madrid, 28027, Spain

Location

Hospital Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Universitario Madrid Sanchinarro - Centro Integral Oncologico Clara Campal (CIOCC)

Madrid, 28050, Spain

Location

Hospital Universitario Quirónsalud Madrid

Madrid, 28223, Spain

Location

Clínica Universidad de Navarra (Pamplona)

Pamplona, 31008, Spain

Location

Chung Shan Medical University Hospital

Taichung, 40705, Taiwan

Location

National Cheng Kung University Hospital

Tainan, 00704, Taiwan

Location

National Taiwan University Hospital

Taipei, 00100, Taiwan

Location

Related Publications (2)

• Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, Lynch T, Johnson BE, Miller VA. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2010 Jan 10;28(2):357-60. doi: 10.1200/JCO.2009.24.7049. Epub 2009 Nov 30.

  PMID: 19949011 BACKGROUND

• Steuer CE, Hayashi H, Su WC, Nishio M, Johnson ML, Kim DW, Massarelli E, Felip E, Gold KA, Murakami H, Baik CS, Kim SW, Smit EF, Fujimura M, Fan PD, Truchon K, Su X, Sternberg DW, Janne PA. Patritumab Deruxtecan (HER3-DXd; MK-1022) in Non-Small Cell Lung Cancer After Platinum-Based Chemotherapy and Immunotherapy. J Clin Oncol. 2025 Sep;43(25):2816-2826. doi: 10.1200/JCO-24-02744. Epub 2025 Jun 24.

  PMID: 40554742 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Neoplasms; Neoplasm Metastasis

Interventions

patritumab deruxtecan

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Global Clinical Lead

  Daiichi Sankyo

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 22, 2017
• First Posted: August 24, 2017
• Study Start: October 30, 2017
• Primary Completion: March 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: March 5, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• 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.

Locations

US (16); ES (9); NL (1); TW (3); JP (5); KR (3)