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

Enliven Therapeutics

Status and phase: Enrolling; Phase 1

Conditions: HER2 Mutant Non-small Cell Lung Cancer; HER2 Amplification; HER2-positive Metastatic Breast Cancer; HER2 Gene Mutation

Treatments: Drug: ELVN-002; Drug: Trastuzumab emtansine; Drug: Fam-Trastuzumab Deruxtecan-Nxki

Study type: Interventional

Funder types: Industry

Identifiers

NCT05650879

ELVN-002-001

Details and patient eligibility

About

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.

Full 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.

Enrollment: 198 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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)

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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198 participants in 5 patient groups

Phase 1a Monotherapy Dose Escalation

Experimental group

Description:

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.

Treatment:

Drug: ELVN-002

Phase 1a Monotherapy Dose Exploration

Experimental group

Description:

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.

Treatment:

Drug: ELVN-002

Phase 1b Monotherapy Dose Expansion

Experimental group

Description:

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.

Treatment:

Drug: ELVN-002

Phase 1a Combination Dose Escalation with T-DXd

Experimental group

Description:

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.

Treatment:

Drug: Fam-Trastuzumab Deruxtecan-Nxki

Drug: ELVN-002

Phase 1a Combination Dose Escalation with T-DM1

Experimental group

Description:

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.

Treatment:

Drug: Trastuzumab emtansine

Drug: ELVN-002