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

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Drug: ELVN-002
* Drug: Fam-Trastuzumab Deruxtecan-Nxki
* Drug: Trastuzumab emtansine


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a Monotherapy Dose Escalation<br>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<br>* capsule<br>|
| Experimental: Phase 1a Monotherapy Dose Exploration<br>ELVN-002 will be administered either once or twice daily. A maximum of 30 patients will enroll in this arm. A maximum of 10 patients may be enrolled at a single 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<br>* capsule<br>|
| Experimental: Phase 1b Monotherapy Dose Expansion<br>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<br>* capsule<br>|
| Experimental: Phase 1a Combination Dose Escalation with T-DXd<br>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<br>* capsule<br>Drug: Fam-Trastuzumab Deruxtecan-Nxki<br>* intravenous<br>* Other names: T-DXd;|
| Experimental: Phase 1a Combination Dose Escalation with T-DM1<br>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<br>* capsule<br>Drug: Trastuzumab emtansine<br>* intravenous<br>* Other names: T-DM1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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