HER2 Mutant Non-small Cell Lung Cancer, HER2-positive Metastatic Breast Cancer, HER2 Gene Mutation, HER2 Amplification
Conditions
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
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.
Interventions
Sponsors
Enliven Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| incidence of ECG abnormalities in Phase 1a combination with T-DXd | 24 months |
| Incidence of adverse events in Phase 1b monotherapy | 24 months |
| incidence of laboratory abnormalities in Phase 1b monotherapy | 24 months |
| 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 1b monotherapy | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Australia, France, Italy, South Korea, Spain, Taiwan, United States
Outcome results
None listed