Clinical trial NCT05650879: ELVN-002 in HER2 Mutant Non-Small Cell Lung Cancer
Official title: A Phase 1a/1b Study of ELVN-002 for the Treatment of Patients With HER2 Mutant Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: HER2 Mutant Non-small Cell Lung Cancer
HER2-positive Metastatic Breast Cancer
HER2 Gene Mutation
HER2 Amplification
Keywords: HER2 genetic alterations
HER2 mutation
ELVN-002
Non-small cell lung cancer
HER-2 positive metastatic breast cancer
Enhertu
trastuzumab emtansine
fam-trastuzumab deruxtecan-nxki
Kadcyla
Lead sponsor: Enliven Therapeutics
Sponsor class: INDUSTRY
First posted: 2022-12-14
Enrollment: 198
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Phase 1 will be a dose escalation monotherapy according to the Bayesian Optimal Interval Design model Phase 1b will be a dose expansion: up to 40 patients randomized between 2 dose levels
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Incidence of dose limiting toxicities in Phase 1a monotherapy
timeFrame: 21 days
measure: Incidence of adverse events in Phase 1a monotherapy
timeFrame: 24 months
measure: incidence of laboratory abnormalities in Phase 1a monotherapy
timeFrame: 24 months
measure: incidence of ECG abnormalities in Phase 1a monotherapy
timeFrame: 24 months
measure: incidence of dose limiting toxicities in Phase 1a combination with fam-trastuzumab deruxtecan (T-DXd)
timeFrame: 42 days
measure: Incidence of adverse events in Phase 1a combination with T-DXd
timeFrame: 24 months
measure: incidence of laboratory abnormalities in Phase 1a combination with T-DXd
timeFrame: 24 months
measure: incidence of ECG abnormalities in Phase 1a combination with T-DXd
timeFrame: 24 months
measure: incidence of dose limiting toxicities in Phase 1a combination with trastuzumab emantasine (T-DM1)
timeFrame: 42 days
measure: Incidence of adverse events in Phase 1a combination with T-DM1
timeFrame: 24 months
measure: incidence of laboratory abnormalities in Phase 1a combination with T-DM1
timeFrame: 24 months
measure: incidence of ECG abnormalities in Phase 1a combination with T-DM1
timeFrame: 24 months
measure: Incidence of adverse events in Phase 1b monotherapy
timeFrame: 24 months
measure: incidence of laboratory abnormalities in Phase 1b monotherapy
timeFrame: 24 months
measure: incidence of ECG abnormalities in Phase 1b monotherapy
timeFrame: 24 months
Secondary outcomes:
measure: Objective Response rate in Phase 1a monotherapy
timeFrame: 24 months
measure: Objective response rate in Phase 1b monotherapy
timeFrame: 24 months
measure: Duration of response in Phase 1b monotherapy
timeFrame: 24 months
measure: Brain metastases response in Phase 1b monotherapy
timeFrame: 24 months
measure: PK parameter of area under the curve of ELVN-002 in Phase 1a monotherapy
timeFrame: 21 days
measure: PK parameter of maximum concentration of ELVN-002 in Phase 1a monotherapy
timeFrame: 21 days
measure: PK parameter of terminal half life of ELVN-002 in Phase 1a monotherapy
timeFrame: 21 days
measure: PK parameter of area under the curve of ELVN-002 in Phase 1b monotherapy
timeFrame: 21 days
measure: PK parameter of maximum concentration of ELVN-002 in Phase 1b monotherapy
timeFrame: 21 days
measure: PK parameter of terminal half life of ELVN-002 in Phase 1b monotherapy
timeFrame: 21 days
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado - Anschutz Medical Campus - PPDS
state: Colorado
city: Orlando
country: United States
facility: Advent Health Orlando
state: Florida
city: Plantation
country: United States
facility: BRCR Medical Center Inc
state: Florida
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Fairfax
country: United States
facility: NEXT/Virginia Cancer Specialists
state: Virginia
city: Westmead
country: Australia
facility: Macquarie University Hospital
state: New South Wales
city: Nedlands
country: Australia
facility: Linear Clinical Research Limited
state: Western Australia
city: Darlinghurst
country: Australia
facility: Blacktown Hospital
city: Marseille
country: France
facility: Hôpital de la Timone Centre d'essais en cancérologie de Marseille (CEPCM-CLIPP)
state: Bouches-du-Rhône
city: Rennes
country: France
facility: Hôpital Pontchaillou
state: Brittany
city: Caen
country: France
facility: Centre Francois Baclesse
state: Calvados
city: Bordeaux
country: France
facility: EDOG - Institut Bergonie - PPDS
state: Gironde
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Lyon
country: France
facility: Centre Léon Berard
city: Villejuif Cedex
country: France
facility: Institut Gustave Roussy (IGR)
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori
state: Lombardia
city: Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria delle Marche
state: Marche
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia (IRCCS)
state: Piemonte
city: Aviano
country: Italy
facility: SOC Oncologia Medica e dei Tumori lmmunocorrelati, Centro Di Riferimento Oncologico Di Aviano (CRO) IRCCS
state: Pordenone
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli
city: Rozzano
country: Italy
facility: Unità Operativa Oncologia medica ed Ematologia
city: Suwon
country: Korea, Republic of
facility: The Catholic University of Korea, St. Vincent's Hospital
state: Gyeonggido
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Severence Hospital, Yonsei University
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Barcelona
country: Spain
facility: START Barcelona Hospital HM Nou Delfos
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: L'Hospitalet de Llobregat
country: Spain
facility: lnstitut Catala d'Oncologia (ICO) L'Hospitalet, Servicio de Oncologia Medica
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valencia
country: Spain
facility: Fundación Instituto Valenciano de Oncología
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
city: Taichung City
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Chen Kung University Hospital
city: Taipei City
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
References: