RecruitingInterventionalPhase 1/Phase 2

A Phase 1/2 Study of the Highly Selective ROS1 Inhibitor Zidesamtinib (NVL-520) in Patients With Advanced NSCLC and Other Solid Tumors (ARROS-1)

NCT ID: NCT05118789Sponsor: Nuvalent Inc.Last updated: 2025-10-24

Summary

Phase 1/2, dose escalation and expansion study designed to evaluate the safety and tolerability of zidesamtinib (NVL-520), determine the recommended phase 2 dose (RP2D), and evaluate the antitumor activity in patients with advanced ROS1-positive (ROS1+) NSCLC and other advanced ROS1-positive solid tumors. Phase 1 will determine the RP2D and, if applicable, the maximum tolerated dose (MTD) of zidesamtinib in patients with advanced ROS1-positive solid tumors. Phase 2 will determine the objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR) of zidesamtinib at the RP2D. Secondary objectives will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and clinical benefit rate (CBR) of zidesamtinib in patients with advanced ROS1-positive NSCLC and other solid tumors.

Detailed description

In Phase 2, study patients will be enrolled into 5 distinct expansion cohorts: * Cohort 2a: ROS1-positive NSCLC naïve to Tyrosine Kinase Inhibitor (TKI) therapy and up to 1 prior chemotherapy and/or immunotherapy. * Cohort 2b: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy. * Cohort 2c: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy. * Cohort 2d: ROS1-positive NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy. * Cohort 2e: ROS1-positive solid tumor and progressed on any prior therapy.

Arms & interventions

DrugZidesamtinib (NVL-520)
Oral tablet of zidesamtinib (NVL-520)

Outcome measures

Primary

Maximum Tolerated Dose (MTD) (Phase 1)
Highest dose with dose-limiting toxicity (DLT) rate ≤ 25%
Time frame: Within 28 days of last patient dosed during dose escalation
Recommended Phase 2 Dose (RP2D)
To determine the RP2D
Time frame: Within 28 days of last patient dosed during dose escalation.
Objective Response Rate (ORR) (Phase 2)
To determine ORR as assessed by BICR
Time frame: 2-3 years after first patient dosed.

Secondary

Number of participants with treatment-emergent adverse events, as assessed by CTCAE, v5.0
Time frame: Approximately 3 years.
Maximum plasma concentration (Cmax) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Plasma concentration at the end of the dosing interval (Ctau) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Average plasma concentration (Cavg) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Time of maximum concentration (Tmax) of NVL-520
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-520
Time frame: Pre-dose and up to 24 hours post-dose
Area under the curve from time 0 to 24 (AUC0-24) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Area under the curve from time 0 to infinity (AUCinf) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Oral clearance (CL/F) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Volume of distribution (Vz/F) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Half-life (t1/2) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Objective response rate (ORR)
Time frame: 2-3 years after first patient dosed
Duration of response (DOR)
Time frame: 2-3 years after first patient dosed
Clinical benefit rate (CBR)
Time frame: 2-3 years after first patient dosed
Time to response
Time frame: 2-3 years after first patient dosed
Progression-free survival (PFS)
Time frame: Approximately 3 years
Overall survival (OS)
Time frame: Approximately 3 years
Rate of CNS progression
Time frame: Approximately 3 years
Intracranial objective response rate (IC-ORR)
Time frame: Approximately 3 years
Quality of life assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
Time frame: 2-3 years after first patient dosed
Quality of life assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 29 module (EORTC QLQ-LC29)
Time frame: 2-3 years after first patient dosed

Eligibility criteria

Sex: AllAge: 12 Years and olderHealthy volunteers: No

Inclusion Criteria: 1. Age ≥18 years (Cohort 2e only: Age ≥12 years). 2. Disease Criteria: 1. Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ROS1 rearrangement. 2. Phase 2: Cohorts 2a, 2b, 2c and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangement. 3. Phase 2: Cohort 2e: Histologically or cytologically confirmed locally advanced or metastatic solid tumor (other than NSCLC) with ROS1 rearrangement. 3. Prior anticancer treatment (except cohort 2a). 4. Phase 1: Must have evaluable disease (target or nontarget) according to RECIST 1.1. Phase 2: Must have measurable disease according to RECIST 1.1. 5. Adequate baseline organ function and bone marrow reserve. Exclusion Criteria: 1. Patient's cancer has a known oncogenic driver alteration other than ROS1. 2. Known allergy/hypersensitivity to excipients of NVL-520. 3. Major surgery within 4 weeks of first dose of study drug. 4. Ongoing anticancer therapy. 5. Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.

Study locations (20)

UCI Medical Center

Orange, California, 92868

Recruiting

Misako Nagasaka, MD, PhD · Principal Investigator

Stanford Medicine

Palo Alto, California, 94305

Recruiting

Joel Neal, MD, PhD · Principal Investigator

UC Davis Comprehensive Cancer Center

Sacramento, California, 95817

Recruiting

Jonathan Riess, MD · Principal Investigator

University of Colorado Cancer Center

Denver, Colorado, 80045

Recruiting

Ross Camidge, MD · Principal Investigator

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007

Recruiting

Stephen Liu, MD · Principal Investigator

University of Miami

Coral Gables, Florida, 33146

Recruiting

Gilberto de Lima Lopes, MD · Principal Investigator

University of Chicago

Chicago, Illinois, 60637

Recruiting

Marina Garassino, MD · Principal Investigator

Mass General Hospital

Boston, Massachusetts, 02114

Recruiting

Jessica Lin, MD · Principal Investigator

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215

Recruiting

Alice Shaw, MD, PhD · Principal Investigator

Henry Ford Cancer Institute

Detroit, Michigan, 48202

Recruiting

Shirish Gadgeel, MD · Principal Investigator

Washington University School of Medicine

St Louis, Missouri, 63110

Recruiting

Saiama Waqar, MD · Principal Investigator

NYU Langone Health

New York, New York, 10016

Recruiting

Elaine Shum, MD · Principal Investigator

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

Recruiting

Alexander Drilon, MD · Principal Investigator

Atrium Health Levine Cancer Institute

Charlotte, North Carolina, 28204

Recruiting

Daniel Haggstrom, MD · Principal Investigator

Ohio State University

Columbus, Ohio, 43210

Recruiting

Dwight Owen, MD, MS · Principal Investigator

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111

Recruiting

Jessica Bauman, MD · Principal Investigator

Sarah Cannon Research Institute

Nashville, Tennessee, 37203

Recruiting

Melissa Johnson, MD · Principal Investigator

MD Anderson Cancer Center

Houston, Texas, 77030

Active Not Recruiting

NEXT Oncology - Virginia Cancer Specialists

Fairfax, Virginia, 22031

Recruiting

Alexander Spira, MD, PhD · Principal Investigator

University of Washington / Fred Hutchinson Cancer Center

Seattle, Washington, 98109

Recruiting

Christina Baik, MD, MPH · Principal Investigator