Clinical trial NCT06521554: A Study of NVL-330 in Patients With Advanced or Metastatic HER2-altered NSCLC (HEROEX-1)
Official title: A Phase 1a/1b Study of the Selective Tyrosine Kinase Inhibitor NVL-330 in Patients With Advanced or Metastatic HER2-altered NSCLC (HEROEX-1)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Locally Advanced Solid Tumor
Metastatic Solid Tumor
Lead sponsor: Nuvalent Inc.
Sponsor class: INDUSTRY
First posted: 2024-07-26
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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. 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

Primary outcomes:
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: As determined by incidence of DLTs during the first 28 days of treatment (ie, Cycle 1)
measure: Maximum Tolerated Dose (MTD)
timeFrame: As determined by incidence of DLTs during the first 28 days of treatment (ie, Cycle 1)
measure: Incidence and severity of Treatment Emergent Adverse Events (TEAEs)
timeFrame: First dose of study drug through 30 days after the last dose of study drug
Secondary outcomes:
measure: Effect of Food on Maximum Plasma Concentration (Cmax) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Effect of Food on Area Under the Curve from Time 0 to 24 (AUC0-24) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Effect of Food on Area Under the Curve from Time 0 to Infinity (AUCinf) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Effect of Food on Time of Maximum Concentration (Tmax) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Maximum plasma concentration (Cmax) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Maximum plasma concentration (Cmax- dose normalized) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Plasma concentration at the end of the dosing interval (Ctau) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Plasma concentration 24 hours post-dose (C24) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Average plasma concentration (Cavg) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Time of maximum concentration (Tmax) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Area Under the Curve at the End of the Dosing Interval (AUCtau) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Area Under the Curve at the End of the Dosing Interval (AUCtau - dose normalized) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Area Under the Curve From Time 0 to 24 (AUC0-24) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Area Under the Curve From Time 0 to 24 (AUC0-24 - dose normalized) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Area Under the Curve From Time 0 to Infinity (AUCinf) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Area Under the Curve From Time 0 to Infinity (AUCinf - dose normalized) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Oral clearance (CL/F) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Volume of Distribution (Vz/F) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Accumulation Ratio of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Half-life (t1/2) of NVL-330
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Objective Response Rate (ORR)
timeFrame: 2 -3 years after first patient dosed
measure: Duration of Response (DOR)
timeFrame: 2 to 3 years after first patient dosed
measure: Intracranial Objective Response Rate (IC-ORR)
timeFrame: 2 to 3 years after first patient dosed
measure: Intracranial Duration of Response (IC-DOR)
timeFrame: 2 to 3 years after first patient dosed
measure: Time to Response (TTR)
timeFrame: Approximately 3 years
Other outcomes:
Locations:
city: Irvine
country: United States
facility: City of Hope - Lennar
state: California
city: Sacramento
country: United States
facility: University of California, Davis Comprehensive Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Denver
country: United States
facility: Sarah Cannon Research Institute at HealthONE
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Cancer Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Columbus
country: United States
facility: OSU Brain and Spine Hospital
state: Ohio
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: NEXT Virginia
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Saint Leonards
country: Australia
facility: North Shore Health Hub
state: New South Wales
Study officials:
affiliation: Nuvalent Inc.
name: Steve Margossian, MD PhD
role: STUDY_DIRECTOR
References: