Locally Advanced Solid Tumor, Metastatic Solid Tumor
Conditions
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 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).
Interventions
DRUGNVL-330
Oral Tablet of NVL-330
Sponsors
Nuvalent Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 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 |
| 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 |
| 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 |
| 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 |
| 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) 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Objective Response Rate (ORR) | 2 -3 years after first participant dosed | Objective Response Rate (ORR) as determined by RECIST 1.1 criteria |
| Duration of Response (DOR) | 2 to 3 years after first participant dosed | Time from first investigator-assessed response to radiographic disease progression or death |
| Intracranial Objective Response Rate (IC-ORR) | 2 to 3 years after first participant dosed | The proportion of participants with a confirmed intracranial response (IC-CR or IC-PR) |
| Intracranial Duration of Response (IC-DOR) | 2 to 3 years after first participant 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 |
Countries
Australia, Canada, United States
Contacts
CONTACTLisa Morelli
STUDY_DIRECTORSteve Margossian, MD PhD
Nuvalent Inc.
Outcome results
None listed