A Study of NVL-330 in Patients With Advanced or Metastatic HER2-altered NSCLC (HEROEX-1)

Phase 1

Recruiting

• Conditions: Locally Advanced Solid Tumor; Metastatic Solid Tumor
• Interventions: Drug: NVL-330

• Registration Number: NCT06521554
• Lead Sponsor: Nuvalent Inc.

Brief 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 patients with advanced or metastatic HER2-altered 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 patients 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 patients with advanced or metastatic HER2-altered NSCLC. The dose escalation phase of the trial is designed to enroll a set number of patients per cohort at protocol defined dose levels. After the initial patients 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).

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2024-07-18
• Study First Submitted: 2024-07-22
• Study First Submitted QC: 2024-07-25
• Study First Posted: 2024-07-26
• Status Verified: 2024-10
• Last Update Submitted: 2025-01-03
• Last Update Posted: 2025-01-07
• Primary Completion: 2026-03
• Study Completion: 2026-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 120

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

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Exclusion Criteria

1. Patient'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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1a dose escalation	NVL-330	NVL-330 oral daily dosing
Phase 1b dose expansion	NVL-330	NVL-330 oral daily dosing

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (11)

Sylvester Comprehensive Cancer Center; 🇺🇸 Miami, Florida, United States

Stanford Cancer Institute; 🇺🇸 Stanford, California, United States

Sarah Cannon Research Institute at HealthONE; 🇺🇸 Denver, Colorado, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Henry Ford Cancer Center; 🇺🇸 Detroit, Michigan, United States

Washington University; 🇺🇸 Saint Louis, Missouri, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

SCRI Oncology Partners; 🇺🇸 Nashville, Tennessee, United States

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

NEXT Virginia; 🇺🇸 Fairfax, Virginia, United States

Fred Hutchinson Cancer Center; 🇺🇸 Seattle, Washington, United States