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

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.

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)