ELVN-002 in HER2 Mutant Non-Small Cell Lung Cancer (HER2)

A Phase 1a/1b Study of ELVN-002 for the Treatment of Patients With HER2 Mutant Non-Small Cell Lung Cancer

The goal of this clinical trial is to test ELVN-002 in people with cancers that have an abnormal HER2 gene. The main question the trial aims to answer is if ELVN-002 is safe and tolerable at different doses. A second main question is to evaluate the concentration of ELVN-002 in the blood at different doses and to see how this correlates with safety and see how the concentration of drug changes over time. The third main question is to see if ELVN-002 works to shrink cancers that have HER2 genetic abnormalities, particularly non-small cell lung cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: HER2-positive Metastatic Breast Cancer; HER2 Gene Mutation; HER2 Mutant Non-small Cell Lung Cancer; HER2 Amplification
• Intervention / Treatment: Drug: ELVN-002; Drug: Fam-Trastuzumab Deruxtecan-Nxki; Drug: Trastuzumab emtansine

Detailed Description

There are 4 parts to the trial. Part 1 is a dose escalation with ELVN-002 monotherapy for people with advanced stage solid tumors that have a HER2 mutation, amplification or high HER2 over-expression. Part 2 is an ELVN-002 monotherapy dose exploration where additional people may be enrolled at dose levels that have cleared the dose escalation in Part 1 to further evaluate the safety, tolerability, pharmacokinetics and clinical activity. Part 3 is a dose expansion of ELVN-002 monotherapy which will enroll up to 40 patients people with advanced stage HER2 mutant non-small cell lung cancer. Patients in Part 3 will be randomized 1:1 to receive one of two dose levels.

Part 4 is a combination dose escalation where, based on the results of Part 1 and 2, a combination of ELVN-002 and either fam-trastuzumab deruxtecan-nxki (in HER2 mutant non-small cell lung cancer) or trastuzumab emtansine (in HER2 positive breast cancer) will be evaluated for safety and tolerability.

• Study Type: Interventional
• Enrollment (Estimated): 198
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Darlinghurst, Australia, 2010
    • Blacktown Hospital
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Macquarie University Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Linear Clinical Research Limited
• France
  • Dijon, France, 21079
    • Centre Georges François Leclerc
  • Lyon, France, 69373
    • Centre léon bérard
  • Villejuif Cedex, France, 94805
    • Institut Gustave Roussy (Igr)
  • Bouches-du-Rhône
    • Marseille, Bouches-du-Rhône, France, 13005
      • Hôpital de la Timone Centre d'essais en cancérologie de Marseille (CEPCM-CLIPP)
  • Brittany
    • Rennes, Brittany, France, 35033
      • Hôpital Pontchaillou
  • Calvados
    • Caen, Calvados, France, 14076
      • Centre François Baclesse
  • Gironde
    • Bordeaux, Gironde, France, 33000
      • EDOG - Institut Bergonie - PPDS
• Italy
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario A. Gemelli
  • Rozzano, Italy, 20089
    • Unità Operativa Oncologia medica ed Ematologia
  • Lombardia
    • Monza, Lombardia, Italy, 20900
      • Fondazione IRCCS San Gerardo dei Tintori
  • Marche
    • Ancona, Marche, Italy, 60126
      • Azienda Ospedaliero Universitaria delle Marche
  • Piemonte
    • Candiolo, Piemonte, Italy, 10060
      • Fondazione del Piemonte per l'Oncologia (IRCCS)
  • Pordenone
    • Aviano, Pordenone, Italy, 33081
      • SOC Oncologia Medica e dei Tumori lmmunocorrelati, Centro Di Riferimento Oncologico Di Aviano (CRO) IRCCS
• Korea, Republic of
  • Incheon, Korea, Republic of
    • Gachon University Gil Medical Center
  • Seoul, Korea, Republic of, 3080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 03722
    • Severence Hospital, Yonsei University
  • Gyeonggido
    • Suwon, Gyeonggido, Korea, Republic of, 16247
      • The Catholic University of Korea, St. Vincent'S Hospital
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08023
    • START Barcelona Hospital HM Nou Delfos
  • L'Hospitalet de Llobregat, Spain, 08908
    • lnstitut Catala d'Oncologia (ICO) L'Hospitalet, Servicio de Oncologia Medica
  • Lleida, Spain, 25198
    • Hospital Universitari Arnau de Vilanova
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Díaz
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de octubre
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Valencia, Spain, 46009
    • Fundacion Instituto Valenciano de Oncologia
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
• Taiwan
  • Taichung City, Taiwan, 40705
    • Taichung Veterans General Hospital
  • Tainan, Taiwan
    • National Chen Kung University Hospital
  • Taipei City, Taiwan
    • National Taiwan University Hospital
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado - Anschutz Medical Campus - PPDS
  • Florida
    • Orlando, Florida, United States, 32804
      • Advent Health Orlando
    • Plantation, Florida, United States, 33322
      • BRCR Medical Center Inc
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • NEXT/Virginia Cancer Specialists

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Phase 1a Monotherapy Dose Escalation and Exploration:

• Pathologically documented advanced stage solid tumor
• Progressed following all standard treatment or not appropriate for standard treatment
• HER2 mutation, HER2 amplification or HER2 positive based on local testing

Phase 1b Monotherapy

• Pathologically documented unresectable and/or metastatic non-squamous NSCLC
• HER2 mutation identified by tissue (fresh or archival) or ctDNA. Local testing for up to 20 patients the remainder centrally confirmed.
• Measurable disease
• No known epidermal growth factor receptor (EGFR), ROS1, anaplastic lymphoma kinase (ALK), or BRAF V600E mutation
• Progressed after receiving at least 1 prior systemic therapy including a platinum-based chemotherapy with or without immunotherapy, or not appropriate for standard treatment.
• No prior HER2 tyrosine kinase inhibitor. Prior HER2 directed antibodies or anti-body drug conjugates are allowed
• No limit on prior number of therapies

Phase 1a Combination with T-DXd

• Pathologically documented advanced stage NSCLC
• Progressed after receiving at least 1 prior systemic therapy.
• HER2 mutation based on local/historical testing of tissue or circulating tumor DNA
• No known EGFR, ROS1, ALK, or BRAF V600E mutation
• No prior T-DXd
• No clinically severe pulmonary compromise
• No limit on prior number of therapies

Phase 1a Combination Breast Cancer

• Documented HER2 positive (Immunohistochemical [IHC] 3+ or IHC2+/in situ hybridization (ISH+) breast cancer
• Must have previously received trastuzumab, a taxane, and T-DXd (if available and appropriate) in the metastatic setting.
• No limit on prior number of therapies
• No prior T-DM1

All Phases

• Eastern Cooperative Oncology Group performance status of 0-1
• Left ventricular ejection fraction ≥ 50%
• Platelet count ≥ 100 x 109/L
• Hemoglobin ≥ 8.5 g/dL
• Absolute neutrophil count ≥1.0 x 109/L
• Total bilirubin < 1.5 times upper limit of normal range (ULN), except for patients with Gilbert's syndrome
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 3 times ULN. In the setting of liver metastases < 5 times ULN.
• Creatinine clearance ≥ 60 mL/minute

Exclusion Criteria All Phases:

• Severe cardiac arrhythmias, requiring treatment, symptomatic congestive heart failure, myocardial infarction within 28 days prior to first dose, or unstable angina.
• Another active malignancy within 2 years except basal cell skin cancer and carcinoma in situ treated curatively
• Active or chronic liver disease
• Active infection requiring systemic therapy within 14 days before the first dose
• Brain lesion requiring immediate local therapy
• Leptomeningeal disease
• Uncontrolled seizures
• Corrected QT interval (QTc) of >470 milliseconds (ms) females or >450 ms for males by Fridericia (QTcF)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1a Monotherapy Dose Escalation; ELVN-002 will be administered either once or twice daily. Each cohort of patients will receive a higher dose. ELVN-002 is an oral capsule. Duration of treatment will be until disease progression or patient discontinues ELVN-002 for another reason.	Drug: ELVN-002; capsule
Experimental: Phase 1b Monotherapy Dose Expansion; ELVN-002 will be administered either once or twice daily. A maximum of 40 patients will enroll in this arm. Patients will be randomized 1:1 to one of two dose levels. ELVN-002 is an oral capsule. Duration of treatment will be until disease progression or patient discontinues ELVN-002 for another reason.	Drug: ELVN-002; capsule
Experimental: Phase 1a Combination Dose Escalation with T-DXd; ELVN-002 will be administered either once or twice daily starting on Day 1. ELVN-002 is an oral capsule. Each cohort will receive a higher dose of ELVN-002. All patients in all cohorts will initiate with 5.4mg/kg of intravenous T-DXd once every 3 weeks starting on day 22 of the study. Duration of treatment will be until disease progression or patient discontinues ELVN-002 for another reason.	Drug: ELVN-002; capsule; Drug: Fam-Trastuzumab Deruxtecan-Nxki; intravenous; Other Names: Enhertu; T-DXd
Experimental: Phase 1a Combination Dose Escalation with T-DM1; ELVN-002 will be administered either once or twice daily starting on Day 1. ELVN-002 is an oral capsule. Each cohort will receive a higher dose of ELVN-002. All patients in all cohorts will initiate with 3.6 mg/kg of intravenous T-DM1 once every 3 weeks starting on day 22 of the study. Duration of treatment will be until disease progression or patient discontinues ELVN-002 for another reason.	Drug: ELVN-002; capsule; Drug: Trastuzumab emtansine; intravenous; Other Names: Kadcyla; T-DM1
Experimental: Phase 1a Monotherapy Dose Exploration; ELVN-002 will be administered either once or twice daily. A maximum of 80 patients will enroll in this arm. A maximum of 10 patients may be enrolled at a single dose or tumor type. ELVN-002 is an oral capsule. Duration of treatment will be until disease progression or patient discontinues ELVN-002 for another reason.	Drug: ELVN-002; capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of dose limiting toxicities in Phase 1a monotherapy	21 days
Incidence of adverse events in Phase 1a monotherapy	24 months
incidence of laboratory abnormalities in Phase 1a monotherapy	24 months
incidence of ECG abnormalities in Phase 1a monotherapy	24 months
incidence of dose limiting toxicities in Phase 1a combination with fam-trastuzumab deruxtecan (T-DXd)	42 days
Incidence of adverse events in Phase 1a combination with T-DXd	24 months
incidence of laboratory abnormalities in Phase 1a combination with T-DXd	24 months
incidence of ECG abnormalities in Phase 1a combination with T-DXd	24 months
incidence of dose limiting toxicities in Phase 1a combination with trastuzumab emantasine (T-DM1)	42 days
Incidence of adverse events in Phase 1a combination with T-DM1	24 months
incidence of laboratory abnormalities in Phase 1a combination with T-DM1	24 months
incidence of ECG abnormalities in Phase 1a combination with T-DM1	24 months
Incidence of adverse events in Phase 1b monotherapy	24 months
incidence of laboratory abnormalities in Phase 1b monotherapy	24 months
incidence of ECG abnormalities in Phase 1b monotherapy	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response rate in Phase 1a monotherapy	For patients with measurable disease at baseline, confirmed response per RECIST 1.1	24 months
Objective response rate in Phase 1b monotherapy	Confirmed response per RECIST 1.1	24 months
Duration of response in Phase 1b monotherapy	The time from the first response to progression or death per RECIST 1.1	24 months
Brain metastases response in Phase 1b monotherapy	for patients with measurable brain metastases at baseline, the percent of patients who have a confirmed response per RECIST 1.1	24 months
PK parameter of area under the curve of ELVN-002 in Phase 1a monotherapy	the concentration of ELVN-002 measured in the blood over 24 hours at steady state	21 days
PK parameter of maximum concentration of ELVN-002 in Phase 1a monotherapy	the maximum concentration of ELVN-002 measured in the blood at any time point at steady state	21 days
PK parameter of terminal half life of ELVN-002 in Phase 1a monotherapy	the half life of ELVN-002 calculated from the concentration of ELVN-002 in blood	21 days
PK parameter of area under the curve of ELVN-002 in Phase 1b monotherapy	the concentration of ELVN-002 measured in the blood over 24 hours at steady state	21 days
PK parameter of maximum concentration of ELVN-002 in Phase 1b monotherapy	the maximum concentration of ELVN-002 measured in the blood at any time point at steady state	21 days
PK parameter of terminal half life of ELVN-002 in Phase 1b monotherapy	the half life of ELVN-002 calculated from the concentration of ELVN-002 in blood	21 days

Collaborators and Investigators

• Sponsor: Enliven Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2023
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: November 28, 2022
• First Submitted That Met QC Criteria: December 6, 2022
• First Posted (Actual): December 14, 2022

Study Record Updates

• Last Update Posted (Actual): July 15, 2025
• Last Update Submitted That Met QC Criteria: July 10, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Non-small cell lung cancer; HER2 mutation; Enhertu; HER2 genetic alterations; ELVN-002; HER-2 positive metastatic breast cancer; trastuzumab emtansine; fam-trastuzumab deruxtecan-nxki; Kadcyla
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Immunoconjugates; Immunotoxins; Trastuzumab; Ado-Trastuzumab Emtansine; Trastuzumab deruxtecan; Maytansine
• Other Study ID Numbers: ELVN-002-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No