A Study of NVL-520 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1)

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

Phase 1/2, dose escalation and expansion study designed to evaluate the safety and tolerability of 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 NVL-520 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 NVL-520 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 NVL-520 in patients with advanced ROS1-positive NSCLC and other solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Solid Tumor; Locally Advanced Solid Tumor
• Intervention / Treatment: Drug: NVL-520

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.

• Study Type: Interventional
• Enrollment (Estimated): 359
• Phase: Phase 2; Phase 1

Contacts and Locations

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

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Recruiting
      • Chris O'Brien Lifehouse
      • Principal Investigator: Steven Kao, PhD
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Recruiting
      • Peter Maccallum Cancer Centre
      • Principal Investigator: Ben Solomon, MD, PhD
• Belgium
  • Leuven, Belgium, 3000
    • Recruiting
    • University Hospital Leuven
    • Principal Investigator: Christophe Dooms, MD, PhD
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Recruiting
      • Cross Cancer Institute
      • Principal Investigator: Quincy Chu, MD
  • Ontario
    • Toronto, Ontario, Canada, M5GG 1L7
      • Recruiting
      • Princess Margaret Cancer Research
      • Principal Investigator: Geoffrey Liu, MD
• France
  • Lyon, France, 69008
    • Recruiting
    • Centre Legon Berard
    • Principal Investigator: Aurelie Swalduz, MD
  • Nantes, France, 44000
    • Recruiting
    • CHU de Nantes
    • Principal Investigator: Elvire Pons-Tostivint, MD, PhD
  • Toulouse, France, 31300
    • Recruiting
    • Hospital Center University De Toulouse
    • Principal Investigator: Julien Mazieres, MD, PhD
  • Villejuif, France, 94805
    • Recruiting
    • Institute Gustave Roussy
    • Principal Investigator: Benjamin Besse, MD, PhD
• Germany
  • Cologne, Germany
    • Recruiting
    • Cologne University Hospital
    • Principal Investigator: Juergen Wolf, MD
• Korea, Republic of
  • Gyeonggi-do, Korea, Republic of, 10408
    • Recruiting
    • National Cancer Center
    • Principal Investigator: Ji-Youn Han, MD
  • Seoul, Korea, Republic of, 03080
    • Recruiting
    • Seoul National University Hospital
    • Principal Investigator: Dong-Wan Kim, MD, PhD
  • Seoul, Korea, Republic of
    • Recruiting
    • Samsung Medical Center
    • Principal Investigator: Myung-Ju Ahn, MD, PhD
  • Seoul, Korea, Republic of, 03722
    • Recruiting
    • Yonsei University Health System
    • Principal Investigator: Byoung Chul Cho, MD, PhD
• Netherlands
  • Amsterdam, Netherlands, 1066
    • Recruiting
    • Netherlands Cancer Institute
    • Principal Investigator: Joop de Langen, MD, PhD
  • Groningen, Netherlands
    • Recruiting
    • University Medical Centre Groningen
    • Principal Investigator: Anthonie van der Wekken, MD, PhD
• Singapore
  • Singapore, Singapore, 119074
    • Recruiting
    • National University Hospital Singapore
    • Principal Investigator: Ross A Soo, MD
  • Singapore, Singapore, 168583
    • Recruiting
    • National Cancer Centre Singapore
    • Principal Investigator: Daniel Tan, PhD
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Vall D'Hebron University Hospital
    • Principal Investigator: Enriqueta Felip, Md, PhD
  • Barcelona, Spain, 08017
    • Recruiting
    • UOMI Cancer Center - Clinica Tres Torres
    • Principal Investigator: Santiago Viteri, MD
  • Coruna, Spain, 15006
    • Recruiting
    • University Hospital of A Coruña
    • Principal Investigator: Maria Campelo, MD
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital Universitario 12 de Octubre
    • Principal Investigator: Luis Paz-Ares, MD, PhD
  • Madrid, Spain, 28050
    • Recruiting
    • Hospital Universitario HM Sanchinarro
    • Principal Investigator: Maria Jose de Miguel, MD, PhD
  • Madrid, Spain, 28007
    • Recruiting
    • Gregorio Marañón Hospital
    • Principal Investigator: Antonio Calles, MD
• Taiwan
  • Taichung, Taiwan, 40201
    • Recruiting
    • Chung Shan Medical University Hospital
    • Principal Investigator: Gee Chen Chang, MD, PhD
  • Tainan, Taiwan, 704017
    • Recruiting
    • National Cheng Kung University Hospital
    • Principal Investigator: Chien-Chung Lin, MD, PhD
  • Taipei, Taiwan, 10002
    • Recruiting
    • National Taiwan University Hospital
    • Principal Investigator: Chia-Chi Lin, MD, PhD
• United States
  • California
    • Orange, California, United States, 92868
      • Recruiting
      • UCI Medical Center
      • Principal Investigator: Sai-Hong Ignatius Ou, MD
    • Palo Alto, California, United States, 94305
      • Recruiting
      • Stanford Medicine
      • Principal Investigator: Joel Neal, MD, PhD
    • Sacramento, California, United States, 95817
      • Recruiting
      • UC Davis Comprehensive Cancer Center
      • Principal Investigator: Jonathan Riess, MD
  • Colorado
    • Denver, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Cancer Center
      • Principal Investigator: Ross Camidge, MD
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Recruiting
      • Georgetown University Medical Center
      • Principal Investigator: Stephen Liu, MD
  • Florida
    • Coral Gables, Florida, United States, 33146
      • Recruiting
      • University of Miami
      • Principal Investigator: Gilberto de Lima Lopes, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Mass General Hospital
      • Principal Investigator: Jessica Lin, MD
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Recruiting
      • Henry Ford Cancer Institute
      • Principal Investigator: Shirish Gadgeel, MD
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Principal Investigator: Saiama Waqar, MD
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • NYU Langone Health
      • Principal Investigator: Vamsidhar Velchetti, MD
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Principal Investigator: Alexander Drilon, MD
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Recruiting
      • Atrium Health Levine Cancer Institute
      • Principal Investigator: Daniel Haggstrom, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Recruiting
      • Fox Chase Cancer Center
      • Principal Investigator: Jessica Bauman, MD
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Sarah Cannon Research Institute
      • Principal Investigator: Melissa Johnson, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Active, not recruiting
      • MD Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • NEXT Oncology - Virginia Cancer Specialists
      • Principal Investigator: Alexander Spira, MD, PhD
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • University of Washington / Fred Hutchinson Cancer Center
      • Principal Investigator: Christina Baik, MD, MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years (Cohort 2e only: Age ≥12 years and weighing>40 kg).

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 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

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 dose escalation; NVL-520 oral daily dosing	Drug: NVL-520; Oral tablet of NVL-520
Experimental: Cohort 2c; ROS1+ NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy	Drug: NVL-520; Oral tablet of NVL-520
Experimental: Cohort 2e; ROS1+ solid tumor and progressed on any prior therapy	Drug: NVL-520; Oral tablet of NVL-520
Experimental: Cohort 2a; ROS1+ NSCLC naïve to TKI therapy and up to 1 prior chemotherapy and/or immunotherapy	Drug: NVL-520; Oral tablet of NVL-520
Experimental: Cohort 2b; ROS1+ NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy	Drug: NVL-520; Oral tablet of NVL-520
Experimental: Cohort 2d; ROS1+ NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy	Drug: NVL-520; Oral tablet of NVL-520

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Determine OS	Approximately 3 years
Number of participants with treatment-emergent adverse events, as assessed by CTCAE, v5.0	Incidence and severity of treatment-emergent adverse events (TEAEs)	Approximately 3 years.
Maximum plasma concentration (Cmax) of NVL-520	To determine the maximum plasma concentration (Cmax) of NVL-520	Pre-dose and up to 24 hours post-dose
Plasma concentration at the end of the dosing interval (Ctau) of NVL-520	To determine the plasma concentration at the end of the dosing interval (Ctau) of NVL-520	Pre-dose and up to 24 hours post-dose
Average plasma concentration (Cavg) of NVL-520	To determine the average plasma concentration (Cavg) of NVL-520	Pre-dose and up to 24 hours post-dose
Time of maximum concentration (Tmax) of NVL-520	To determine the time of maximum concentration (Tmax) of NVL-520	Pre-dose and up to 24 hours post-dose
Area under the curve at the end of the dosing interval (AUCtau) of NVL-520	To determine the area under the curve at the end of the dosing interval (AUCtau) of NVL-520	Pre-dose and up to 24 hours post-dose
Area under the curve from time 0 to 24 (AUC0-24) of NVL-520	To determine the area under the curve from time 0 to 24 (AUC0-24) of NVL-520	Pre-dose and up to 24 hours post-dose
Area under the curve from time 0 to infinity (AUCinf) of NVL-520	To determine the area under the curve from time 0 to infinity (AUCinf) of NVL-520	Pre-dose and up to 24 hours post-dose
Oral clearance (CL/F) of NVL-520	To determine the oral clearance (CL/F) of NVL-520	Pre-dose and up to 24 hours post-dose
Volume of distribution (Vz/F) of NVL-520	To determine the volume of distribution (Vz/F) of NVL-520	Pre-dose and up to 24 hours post-dose
Half-life (t1/2) of NVL-520	To determine the half-life (t1/2) of NVL-520	Pre-dose and up to 24 hours post-dose
Objective response rate (ORR)	Determine ORR as assessed by BICR	2-3 years after first patient dosed
Duration of response (DOR)	Determine DOR of NVL-520 until radiographic disease progression or death	2-3 years after first patient dosed
Clinical benefit rate (CBR)	Determine CBR of NVL-520	2-3 years after first patient dosed
Time to response	Determine time to response of NVL-520	2-3 years after first patient dosed
Progression-free survival (PFS)	Determine PFS of NVL-520 until radiographic disease progression or death	Approximately 3 years
Rate of CNS progression	The incidence of CNS as first site of progression, alone or with concurrent extra-CNS progression	Approximately 3 years
Intracranial objective response rate (IC-ORR)	Determine the intracranial objective response rate	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)	EORTC QLQ-C30 measures cancer patients' physical, psychological, and social functions. Scale ranges from: 1, "Not at all"; 2, "A little"; 3, "Quite a bit"; to 4, "Very much." Higher score for the functioning scales and global health status denotes a better level of functioning, while higher scores on the symptom and single-item scales indicate a higher level of symptoms.	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)	EORTC-QLQ-LC29 measures the quality of life in patients with lung cancer. Symptom scale ranges from: 1, "Not at all"; 2, "A little"; 3, "Quite a bit"; to 4, "Very much." For symptoms scales, higher scores indicated greater symptom burden.	2-3 years after first patient dosed

Collaborators and Investigators

• Sponsor: Nuvalent Inc.
• Investigators: Study Director: Vivek Upadhyay, MD, MBI, Nuvalent Inc.

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2022
• Primary Completion (Estimated): October 31, 2025
• Study Completion (Estimated): October 31, 2026

Study Registration Dates

• First Submitted: October 19, 2021
• First Submitted That Met QC Criteria: November 3, 2021
• First Posted (Actual): November 12, 2021

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: NVL-520-01

Drug and device information, study documents

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