ELVN-002 in HER2 Mutant Non-Small Cell Lung Cancer
- Conditions
- HER2 Mutant Non-small Cell Lung CancerHER2-positive Metastatic Breast CancerHER2 Gene MutationHER2 Amplification
- Interventions
- Registration Number
- NCT05650879
- Lead Sponsor
- Enliven Therapeutics
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 198
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)
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase 1a Monotherapy Dose Escalation ELVN-002 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. Phase 1a Combination Dose Escalation with T-DXd Fam-Trastuzumab Deruxtecan-Nxki 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. Phase 1a Combination Dose Escalation with T-DM1 Trastuzumab emtansine 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. Phase 1a Monotherapy Dose Exploration ELVN-002 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. Phase 1b Monotherapy Dose Expansion ELVN-002 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. Phase 1a Combination Dose Escalation with T-DXd ELVN-002 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. Phase 1a Combination Dose Escalation with T-DM1 ELVN-002 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.
- Primary Outcome Measures
Name Time Method 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
Name Time Method Objective Response rate in Phase 1a monotherapy 24 months For patients with measurable disease at baseline, confirmed response per RECIST 1.1
Objective response rate in Phase 1b monotherapy 24 months Confirmed response per RECIST 1.1
Duration of response in Phase 1b monotherapy 24 months The time from the first response to progression or death per RECIST 1.1
Brain metastases response in Phase 1b monotherapy 24 months for patients with measurable brain metastases at baseline, the percent of patients who have a confirmed response per RECIST 1.1
PK parameter of area under the curve of ELVN-002 in Phase 1a monotherapy 21 days the concentration of ELVN-002 measured in the blood over 24 hours at steady state
PK parameter of maximum concentration of ELVN-002 in Phase 1a monotherapy 21 days the maximum concentration of ELVN-002 measured in the blood at any time point at steady state
PK parameter of terminal half life of ELVN-002 in Phase 1a monotherapy 21 days the half life of ELVN-002 calculated from the concentration of ELVN-002 in blood
PK parameter of area under the curve of ELVN-002 in Phase 1b monotherapy 21 days the concentration of ELVN-002 measured in the blood over 24 hours at steady state
PK parameter of maximum concentration of ELVN-002 in Phase 1b monotherapy 21 days the maximum concentration of ELVN-002 measured in the blood at any time point at steady state
PK parameter of terminal half life of ELVN-002 in Phase 1b monotherapy 21 days the half life of ELVN-002 calculated from the concentration of ELVN-002 in blood
Trial Locations
- Locations (39)
University of Colorado - Anschutz Medical Campus - PPDS
🇺🇸Aurora, Colorado, United States
Advent Health Orlando
🇺🇸Orlando, Florida, United States
BRCR Medical Center Inc
🇺🇸Plantation, Florida, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
NEXT/Virginia Cancer Specialists
🇺🇸Fairfax, Virginia, United States
Macquarie University Hospital
🇦🇺Westmead, New South Wales, Australia
Linear Clinical Research Limited
🇦🇺Nedlands, Western Australia, Australia
Blacktown Hospital
🇦🇺Darlinghurst, Australia
Hôpital de la Timone Centre d'essais en cancérologie de Marseille (CEPCM-CLIPP)
🇫🇷Marseille, Bouches-du-Rhône, France
Hôpital Pontchaillou
🇫🇷Rennes, Brittany, France
Centre Francois Baclesse
🇫🇷Caen, Calvados, France
EDOG - Institut Bergonie - PPDS
🇫🇷Bordeaux, Gironde, France
Centre Georges François Leclerc
🇫🇷Dijon, France
Centre Léon Berard
🇫🇷Lyon, France
Institut Gustave Roussy (IGR)
🇫🇷Villejuif Cedex, France
Fondazione IRCCS San Gerardo dei Tintori
🇮🇹Monza, Lombardia, Italy
Azienda Ospedaliero Universitaria delle Marche
🇮🇹Ancona, Marche, Italy
Fondazione del Piemonte per l'Oncologia (IRCCS)
🇮🇹Candiolo, Piemonte, Italy
SOC Oncologia Medica e dei Tumori lmmunocorrelati, Centro Di Riferimento Oncologico Di Aviano (CRO) IRCCS
🇮🇹Aviano, Pordenone, Italy
Fondazione Policlinico Universitario A. Gemelli
🇮🇹Roma, Italy
Unità Operativa Oncologia medica ed Ematologia
🇮🇹Rozzano, Italy
The Catholic University of Korea, St. Vincent's Hospital
🇰🇷Suwon, Gyeonggido, Korea, Republic of
Gachon University Gil Medical Center
🇰🇷Incheon, Korea, Republic of
Severence Hospital, Yonsei University
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Korea University Anam Hospital
🇰🇷Seoul, Korea, Republic of
START Barcelona Hospital HM Nou Delfos
🇪🇸Barcelona, Spain
Hospital Universitari Vall d'Hebrón
🇪🇸Barcelona, Spain
lnstitut Catala d'Oncologia (ICO) L'Hospitalet, Servicio de Oncologia Medica
🇪🇸L'Hospitalet de Llobregat, Spain
Hospital Universitari Arnau de Vilanova
🇪🇸Lleida, Spain
Hospital Universitario Fundación Jiménez Díaz
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario Virgen Macarena
🇪🇸Sevilla, Spain
Fundación Instituto Valenciano de Oncología
🇪🇸Valencia, Spain
Hospital Universitari i Politècnic La Fe
🇪🇸Valencia, Spain
Taichung Veterans General Hospital
🇨🇳Taichung City, Taiwan
National Chen Kung University Hospital
🇨🇳Tainan, Taiwan
National Taiwan University Hospital
🇨🇳Taipei City, Taiwan