RecruitingInterventionalPhase 1

A Phase 1a/1b Study of the Selective Tyrosine Kinase Inhibitor NVL-330 in Patients With Advanced or Metastatic HER2-altered NSCLC (HEROEX-1)

NCT ID: NCT06521554Sponsor: Nuvalent Inc.Last updated: 2026-02-25

Summary

Phase 1a/1b dose escalation and expansion study designed to evaluate the safety and tolerability of NVL-330, determine the recommended Phase 2 dose (RP2D), and evaluate the antitumor activity in participants with advanced or metastatic human epidermal growth factor receptor 2 (HER2) -altered non-small lung cancer (NSCLC). Phase 1a dose escalation is designed to assess the safety and tolerability of NVL-330 and to select the candidate RP2D(s) and, if applicable, the MTD. Phase 1b expansion is designed to further evaluate the overall safety and tolerability of the candidate RP2D(s) of NVL-330 and to determine the RP2D of NVL-330 in participants with advanced or metastatic HER2 mutant NSCLC.

Detailed description

The planned Phase 1a/1b first-in-human study is designed as a two-part clinical trial to investigate NVL-330 in pre-treated participants with advanced or metastatic HER2-altered NSCLC. The dose escalation phase of the trial is designed to enroll a set number of participants per cohort at protocol defined dose levels. After the initial participants are treated at a given dose level and monitored for at least 28 days, available data will be reviewed, and initiation of the next dosing group will proceed with consideration given to the overall safety profile. The expansion phase of the trial is designed to further evaluate safety and activity and to confirm the RP2D(s).

Arms & interventions

DrugNVL-330
Oral Tablet of NVL-330

Outcome measures

Primary

Recommended Phase 2 Dose (RP2D)
To determine up to 2 RP2D Candidates
Time frame: As determined by incidence of DLTs during the first 28 days of treatment (ie, Cycle 1)
Maximum Tolerated Dose (MTD)
If applicable, to determine the MTD
Time frame: As determined by incidence of DLTs during the first 28 days of treatment (ie, Cycle 1)
Incidence and severity of Treatment Emergent Adverse Events (TEAEs)
Number of participants with TEAEs as assessed by CTCAE, v5.0
Time frame: First dose of study drug through 30 days after the last dose of study drug

Secondary

Effect of Food on Maximum Plasma Concentration (Cmax) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Effect of Food on Area Under the Curve from Time 0 to 24 (AUC0-24) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Effect of Food on Area Under the Curve from Time 0 to Infinity (AUCinf) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Effect of Food on Time of Maximum Concentration (Tmax) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Maximum plasma concentration (Cmax) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Maximum plasma concentration (Cmax- dose normalized) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Plasma concentration at the end of the dosing interval (Ctau) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Plasma concentration 24 hours post-dose (C24) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Average plasma concentration (Cavg) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Time of maximum concentration (Tmax) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Area Under the Curve at the End of the Dosing Interval (AUCtau) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Area Under the Curve at the End of the Dosing Interval (AUCtau - dose normalized) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Area Under the Curve From Time 0 to 24 (AUC0-24) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Area Under the Curve From Time 0 to 24 (AUC0-24 - dose normalized) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Area Under the Curve From Time 0 to Infinity (AUCinf) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Area Under the Curve From Time 0 to Infinity (AUCinf - dose normalized) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Oral clearance (CL/F) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Volume of Distribution (Vz/F) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Accumulation Ratio of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Half-life (t1/2) of NVL-330
Time frame: Pre-dose and up to 24 hours post-dose
Objective Response Rate (ORR)
Time frame: 2 -3 years after first participant dosed
Duration of Response (DOR)
Time frame: 2 to 3 years after first participant dosed
Intracranial Objective Response Rate (IC-ORR)
Time frame: 2 to 3 years after first participant dosed
Intracranial Duration of Response (IC-DOR)
Time frame: 2 to 3 years after first participant dosed
Time to Response (TTR)
Time frame: Approximately 3 years

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No

Inclusion Criteria: 1. Age ≥ 18 years 2. Histologically or cytologically confirmed locally advanced or metastatic NSCLC 3. Documented HER2 status as follows: 1. Phase 1a: Documented oncogenic HER2 mutation such as HER2 exon20 insertion mutations or single nucleotide variants or HER2 amplification. 2. Phase 1b: Documented oncogenic HER2 mutation. 4. Identification of lesions as follows: 1. Phase 1a: Must have evaluable disease (target or nontarget) according to RECIST 1.1. 2. Phase 1b: Must have measurable disease, defined as ≥ 1 radiologically measurable target lesion according to RECIST 1.1. 5. Adequate organ function and bone marrow reserve Exclusion Criteria: 1. Participant's cancer has known oncogenic driver alteration other than HER2 2. Known allergy/hypersensitivity to excipients of NVL-330 3. Major surgery within 4 weeks of the first dose of study drug 4. Ongoing or recent anticancer therapy 5. Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study

Study locations (17)

City of Hope - Lennar

Irvine, California, 92618

Recruiting

Danny Nguyen, MD · Principal Investigator

University of California, Davis Comprehensive Cancer Center

Sacramento, California, 95817

Recruiting

Jonathan Riess, MD · Principal Investigator

Stanford Cancer Institute

Stanford, California, 94305

Recruiting

Joel Neal, MD PhD · Principal Investigator

Sarah Cannon Research Institute at HealthONE

Denver, Colorado, 80218

Recruiting

Gerald Falchook, MD MS · Principal Investigator

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007

Recruiting

Joshua Reuss, MD · Principal Investigator

Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016

Recruiting

Susan Scott, MD · Principal Investigator

Sylvester Comprehensive Cancer Center

Miami, Florida, 33136

Recruiting

Gilberto de Lima Lopes, Jr., MD · Principal Investigator

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Bayview Medical Center

Baltimore, Maryland, 21224

Recruiting

Susan Scott, MD · Principal Investigator

Massachusetts General Hospital

Boston, Massachusetts, 02114

Recruiting

Zofia Piotrowska, MD MHS · Principal Investigator

Henry Ford Cancer Center

Detroit, Michigan, 48242

Recruiting

Shirish Gadgeel, MD · Principal Investigator

Washington University

St Louis, Missouri, 63110

Recruiting

Maria Baggstrom, MD · Principal Investigator

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

Recruiting

Fernando Santini, MD · Principal Investigator

OSU Brain and Spine Hospital

Columbus, Ohio, 43210

Recruiting

Dwight Owen, MD · Principal Investigator

SCRI Oncology Partners

Nashville, Tennessee, 37203

Recruiting

Melissa Johnson, MD · Principal Investigator

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030

Recruiting

Haniel Araujo, MD · Principal Investigator

NEXT Virginia

Fairfax, Virginia, 22031

Recruiting

Alexander Spira, MD PhD FACP · Principal Investigator

Fred Hutchinson Cancer Center

Seattle, Washington, 98109

Recruiting

Rebecca Wood · Contact

206-606-6970

Christina Baik, MD · Principal Investigator