A Study of NVL-330 in Patients With Advanced or Metastatic HER2-altered NSCLC (HEROEX-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)

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Solid Tumor; Locally Advanced Solid Tumor
• Intervention / Treatment: Drug: NVL-330

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).

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Lisa Morelli; Phone Number: 857-357-7000; Email: clinicaltrials@nuvalent.com

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, NSW 2050
      • Recruiting
      • Chris O'Brien Lifehouse
      • Principal Investigator: Steven Kao, MD
    • Saint Leonards, New South Wales, Australia, 2065
      • Recruiting
      • North Shore Health Hub
      • Principal Investigator: Nick Pavlakis, MD
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Recruiting
      • Cross Cancer Institute
      • Contact: Clinical Trial Unit
  • Ontario
    • Toronto, Ontario, Canada, M5G 1L7
      • Recruiting
      • Princess Margaret Cancer Center - University Health Network
      • Principal Investigator: Geoffrey Liu, MD
• United States
  • California
    • Irvine, California, United States, 92618
      • Recruiting
      • City of Hope - Lennar
      • Principal Investigator: Danny Nguyen, MD
    • Sacramento, California, United States, 95817
      • Recruiting
      • University of California, Davis Comprehensive Cancer Center
      • Principal Investigator: Jonathan Riess, MD
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford Cancer Institute
      • Principal Investigator: Joel Neal, MD PhD
  • Colorado
    • Denver, Colorado, United States, 80218
      • Recruiting
      • Sarah Cannon Research Institute at HealthONE
      • Principal Investigator: Gerald Falchook, MD MS
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20016
      • Recruiting
      • Sibley Memorial Hospital
      • Principal Investigator: Susan Scott, MD
    • Washington D.C., District of Columbia, United States, 20007
      • Recruiting
      • Georgetown University Medical Center
      • Principal Investigator: Joshua Reuss, MD
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • Sylvester Comprehensive Cancer Center
      • Principal Investigator: Gilberto de Lima Lopes, Jr., MD
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Recruiting
      • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Bayview Medical Center
      • Principal Investigator: Susan Scott, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Principal Investigator: Zofia Piotrowska, MD MHS
  • Michigan
    • Detroit, Michigan, United States, 48242
      • Recruiting
      • Henry Ford Cancer Center
      • Principal Investigator: Shirish Gadgeel, MD
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University
      • Principal Investigator: Maria Baggstrom, MD
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Principal Investigator: Fernando Santini, MD
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • OSU Brain and Spine Hospital
      • Principal Investigator: Dwight Owen, MD
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • SCRI Oncology Partners
      • Principal Investigator: Melissa Johnson, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University of Texas MD Anderson Cancer Center
      • Principal Investigator: Haniel Araujo, MD
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • NEXT Virginia
      • Principal Investigator: Alexander Spira, MD PhD FACP
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutchinson Cancer Center
      • Principal Investigator: Christina Baik, MD
      • Contact: Rebecca Wood; Phone Number: 206-606-6970

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1a dose escalation; NVL-330 oral daily dosing	Drug: NVL-330; Oral Tablet of NVL-330
Experimental: Phase 1b dose expansion; NVL-330 oral daily dosing	Drug: NVL-330; Oral Tablet of NVL-330

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase 2 Dose (RP2D)	To determine up to 2 RP2D Candidates	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	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	First dose of study drug through 30 days after the last dose of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Food on Maximum Plasma Concentration (Cmax) of NVL-330	To determine the effect of food on maximum plasma concentration (Cmax) of NVL-330	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	To determine the effect of food on area under the curve from time 0 to 24 of NVL-330	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	To determine the effect of food on area under the curve from time 0 to infinity of NVL-330	Pre-dose and up to 24 hours post-dose
Effect of Food on Time of Maximum Concentration (Tmax) of NVL-330	To determine the effect of food on time of maximum concentration of NVL-330	Pre-dose and up to 24 hours post-dose
Maximum plasma concentration (Cmax) of NVL-330	To determine the maximum plasma concentration (Cmax) of NVL-330	Pre-dose and up to 24 hours post-dose
Maximum plasma concentration (Cmax- dose normalized) of NVL-330	To determine the maximum plasma concentration (Cmax-dose normalized) of NVL-330	Pre-dose and up to 24 hours post-dose
Plasma concentration at the end of the dosing interval (Ctau) of NVL-330	To determine the plasma concentration at the end of the dosing interval (Ctau) of NVL-330	Pre-dose and up to 24 hours post-dose
Plasma concentration 24 hours post-dose (C24) of NVL-330	To determine the plasma concentration 24 hours post-dose (C24) of NVL-330	Pre-dose and up to 24 hours post-dose
Average plasma concentration (Cavg) of NVL-330	To determine the average plasma concentration (Cavg) of NVL-330	Pre-dose and up to 24 hours post-dose
Time of maximum concentration (Tmax) of NVL-330	To determine the time of maximum concentration (Tmax) of NVL-330	Pre-dose and up to 24 hours post-dose
Area Under the Curve at the End of the Dosing Interval (AUCtau) of NVL-330	To determine the area under the curve at the end of the dosing interval (AUCtau) of NVL-330	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	To determine the area under the curve at the end of the dosing interval (AUCtau - dose normalized) of NVL-330	Pre-dose and up to 24 hours post-dose
Area Under the Curve From Time 0 to 24 (AUC0-24) of NVL-330	To determine the area under the curve from time 0 to 24 (AUC0-24) of NVL-330	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	To determine the area under the curve from time 0 to 24 (AUC0-24 - dose normalized) of NVL-330	Pre-dose and up to 24 hours post-dose
Area Under the Curve From Time 0 to Infinity (AUCinf) of NVL-330	To determine the area under the curve from time 0 to infinity (AUCinf) of NVL-330	Pre-dose and up to 24 hours post-dose
Area Under the Curve From Time 0 to Infinity (AUCinf - dose normalized) of NVL-330	To determine the area under the curve from time 0 to infinity (AUCinf - dose normalized) of NVL-330	Pre-dose and up to 24 hours post-dose
Oral clearance (CL/F) of NVL-330	To determine the oral clearance (CL/F) of NVL-330	Pre-dose and up to 24 hours post-dose
Volume of Distribution (Vz/F) of NVL-330	To determine the volume of distribution (Vz/F) of NVL-330	Pre-dose and up to 24 hours post-dose
Accumulation Ratio of NVL-330	To determine the ratio of accumulation of NVL-330	Pre-dose and up to 24 hours post-dose
Half-life (t1/2) of NVL-330	To determine the half-life (t1/2) of NVL-330	Pre-dose and up to 24 hours post-dose
Time to Response (TTR)	The time from first dose to first confirmed radiographic response	Approximately 3 years
Objective Response Rate (ORR)	Objective Response Rate (ORR) as determined by RECIST 1.1 criteria	2 -3 years after first participant dosed
Duration of Response (DOR)	Time from first investigator-assessed response to radiographic disease progression or death	2 to 3 years after first participant dosed
Intracranial Objective Response Rate (IC-ORR)	The proportion of participants with a confirmed intracranial response (IC-CR or IC-PR)	2 to 3 years after first participant dosed
Intracranial Duration of Response (IC-DOR)	The time from first investigator-assessed intracranial response to radiographic intracranial disease progression or death	2 to 3 years after first participant dosed

Collaborators and Investigators

• Sponsor: Nuvalent Inc.
• Investigators: Study Director: Steve Margossian, MD PhD, Nuvalent Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 18, 2024
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: July 22, 2024
• First Submitted That Met QC Criteria: July 25, 2024
• First Posted (Actual): July 26, 2024

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis
• Other Study ID Numbers: NVL-330-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No