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

• ClinicalTrials.gov Identifier: NCT05650879
• Recruitment Status: Recruiting
• First Posted: December 14, 2022
• Last Update Posted: August 14, 2023
• Sponsor: Enliven Therapeutics
• Information provided by (Responsible Party): Enliven Therapeutics

Study Description

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.

Condition or disease	Intervention/treatment	Phase
HER2 Mutant Non-small Cell Lung Cancer; HER2-positive Metastatic Breast Cancer; HER2 Gene Mutation; HER2 Amplification	Drug: ELVN-002; Drug: Fam-Trastuzumab Deruxtecan-Nxki; Drug: Trastuzumab emtansine	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 178 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• 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
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1a/1b Study of ELVN-002 for the Treatment of Patients With HER2 Mutant Non-Small Cell Lung Cancer
• Actual Study Start Date: March 20, 2023
• Estimated Primary Completion Date: July 2026
• Estimated Study Completion Date: July 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1a Monotherapy Dose Escalation; 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; capsule
Experimental: Phase 1a Monotherapy Dose Exploration; 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; capsule
Experimental: Phase 1b Monotherapy Dose Expansion; 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; capsule
Experimental: Phase 1a Combination Dose Escalation with T-DXd; 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; capsule; Drug: Fam-Trastuzumab Deruxtecan-Nxki; intravenous; Other Names: Enhertu; T-DXd
Experimental: Phase 1a Combination Dose Escalation with T-DM1; 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; capsule; Drug: Trastuzumab emtansine; intravenous; Other Names: Kadcyla; T-DM1

Outcome Measures

Primary Outcome Measures :

1. Incidence of dose limiting toxicities in Phase 1a monotherapy [ Time Frame: 21 days ]
2. Incidence of adverse events in Phase 1a monotherapy [ Time Frame: 24 months ]
3. incidence of laboratory abnormalities in Phase 1a monotherapy [ Time Frame: 24 months ]
4. incidence of ECG abnormalities in Phase 1a monotherapy [ Time Frame: 24 months ]
5. incidence of dose limiting toxicities in Phase 1a combination with fam-trastuzumab deruxtecan (T-DXd) [ Time Frame: 42 days ]
6. Incidence of adverse events in Phase 1a combination with T-DXd [ Time Frame: 24 months ]
7. incidence of laboratory abnormalities in Phase 1a combination with T-DXd [ Time Frame: 24 months ]
8. incidence of ECG abnormalities in Phase 1a combination with T-DXd [ Time Frame: 24 months ]
9. incidence of dose limiting toxicities in Phase 1a combination with trastuzumab emantasine (T-DM1) [ Time Frame: 42 days ]
10. Incidence of adverse events in Phase 1a combination with T-DM1 [ Time Frame: 24 months ]
11. incidence of laboratory abnormalities in Phase 1a combination with T-DM1 [ Time Frame: 24 months ]
12. incidence of ECG abnormalities in Phase 1a combination with T-DM1 [ Time Frame: 24 months ]
13. Incidence of adverse events in Phase 1b monotherapy [ Time Frame: 24 months ]
14. incidence of laboratory abnormalities in Phase 1b monotherapy [ Time Frame: 24 months ]
15. incidence of ECG abnormalities in Phase 1b monotherapy [ Time Frame: 24 months ]

Secondary Outcome Measures :

1. Objective Response rate in Phase 1a monotherapy [ Time Frame: 24 months ]
   For patients with measurable disease at baseline, confirmed response per RECIST 1.1
2. Objective response rate in Phase 1b monotherapy [ Time Frame: 24 months ]
   Confirmed response per RECIST 1.1
3. Duration of response in Phase 1b monotherapy [ Time Frame: 24 months ]
   The time from the first response to progression or death per RECIST 1.1
4. Brain metastases response in Phase 1b monotherapy [ Time Frame: 24 months ]
   for patients with measurable brain metastases at baseline, the percent of patients who have a confirmed response per RECIST 1.1
5. PK parameter of area under the curve of ELVN-002 in Phase 1a monotherapy [ Time Frame: 21 days ]
   the concentration of ELVN-002 measured in the blood over 24 hours at steady state
6. PK parameter of maximum concentration of ELVN-002 in Phase 1a monotherapy [ Time Frame: 21 days ]
   the maximum concentration of ELVN-002 measured in the blood at any time point at steady state
7. PK parameter of terminal half life of ELVN-002 in Phase 1a monotherapy [ Time Frame: 21 days ]
   the half life of ELVN-002 calculated from the concentration of ELVN-002 in blood
8. PK parameter of area under the curve of ELVN-002 in Phase 1b monotherapy [ Time Frame: 21 days ]
   the concentration of ELVN-002 measured in the blood over 24 hours at steady state
9. PK parameter of maximum concentration of ELVN-002 in Phase 1b monotherapy [ Time Frame: 21 days ]
   the maximum concentration of ELVN-002 measured in the blood at any time point at steady state
10. PK parameter of terminal half life of ELVN-002 in Phase 1b monotherapy [ Time Frame: 21 days ]
    the half life of ELVN-002 calculated from the concentration of ELVN-002 in blood

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Contacts

Contact: Helen L Collins, MD; 707 799-3272; helen.collins@enliventherapeutics.com

Contact: Sabine Tricon; sabine.tricon@enliventherapeutics.com

Locations

United States, Colorado

University of Colorado - Anschutz Medical Campus - PPDS; Recruiting

Aurora, Colorado, United States, 80045

Contact: Tejas Patil, MD 720-848-0170

United States, Florida

BRCR Medical Center Inc; Recruiting

Plantation, Florida, United States, 33322

Contact: Harsad Amin, MD

United States, Massachusetts

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Julia Rotow, MD 617-632-4764

Contact: Rebecca Rivenburgh (617) 632-4764

United States, Virginia

NEXT/Virginia Cancer Specialists; Recruiting

Fairfax, Virginia, United States, 22031

Contact: Alexander Spira, MD

Australia, New South Wales

Macquarie University Hospital; Recruiting

Westmead, New South Wales, Australia, 2145

Contact: Dhanusha Sabanathan, BSc, MBBS +61298458238

Australia, Western Australia

Linear Clinical Research Limited; Recruiting

Nedlands, Western Australia, Australia, 6009

Contact: Samantha Bowyer, MD

Australia

Blacktown Hospital; Recruiting

Darlinghurst, Australia, 2010

Contact: Adnan Nagrial, BS, MB, MBBS +61292958100

Korea, Republic of

The Catholic University of Korea, St. Vincent's Hospital; Recruiting

Suwon, Gyeonggido, Korea, Republic of, 16247

Contact: Byoung Yong Shim, MD +82312497120

Gachon University Gil Medical Center; Recruiting

Incheon, Korea, Republic of

Contact: Young Saing Kim, MDPhD +82324603213

Severence Hospital, Yonsei University; Recruiting

Seoul, Korea, Republic of, 03722

Contact: Byoung Chul Cho, MD +82222288216

Samsung Medical Center; Recruiting

Seoul, Korea, Republic of, 06351

Contact: Myung-Ju Ahn, MDPhD +82234103438

Seoul National University Hospital; Recruiting

Seoul, Korea, Republic of, 3080

Contact: Tae Min Kim, MD, PhD +82220723559

Korea University Anam Hospital; Recruiting

Seoul, Korea, Republic of

Contact: Sang Won Shin, MD +8229205350

Taiwan

National Chen Kung University Hospital; Recruiting

Tainan, Taiwan

Contact: Chun-Hui Lee, MD +88662353535

National Taiwan University Hospital; Recruiting

Taipei City, Taiwan

Contact: Chia-Chi Lin, MDPhD +886223123456

Sponsors and Collaborators

Enliven Therapeutics

More Information

• Responsible Party: Enliven Therapeutics
• ClinicalTrials.gov Identifier: NCT05650879
• Other Study ID Numbers: ELVN-002-001
• First Posted: December 14, 2022
• Last Update Posted: August 14, 2023
• Last Verified: August 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Enliven Therapeutics:

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

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasms by Site; Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Trastuzumab; Ado-Trastuzumab Emtansine; Maytansine; Trastuzumab deruxtecan; Antineoplastic Agents, Immunological; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Immunotoxins; Immunoconjugates; Immunologic Factors; Physiological Effects of Drugs