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

• ClinicalTrials.gov Identifier: NCT05118789
• Recruitment Status: Recruiting
• First Posted: November 12, 2021
• Last Update Posted: August 9, 2023
• Sponsor: Nuvalent Inc.
• Information provided by (Responsible Party): Nuvalent Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Locally Advanced Solid Tumor; Metastatic Solid Tumor	Drug: NVL-520	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 359 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Study of the Highly Selective ROS1 Inhibitor NVL-520 in Patients With Advanced NSCLC and Other Solid Tumors (ARROS-1)
• Actual Study Start Date: January 4, 2022
• Estimated Primary Completion Date: October 31, 2025
• Estimated Study Completion Date: October 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1 dose escalation; NVL-520 oral daily dosing	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 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 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
Experimental: Cohort 2e; ROS1+ solid tumor and progressed on any prior therapy	Drug: NVL-520; Oral tablet of NVL-520

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Number of participants with treatment-emergent adverse events, as assessed by CTCAE, v5.0 [ Time Frame: Approximately 3 years. ]
   Incidence and severity of treatment-emergent adverse events (TEAEs)
2. Maximum plasma concentration (Cmax) of NVL-520 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the maximum plasma concentration (Cmax) of NVL-520
3. Plasma concentration at the end of the dosing interval (Ctau) of NVL-520 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the plasma concentration at the end of the dosing interval (Ctau) of NVL-520
4. Average plasma concentration (Cavg) of NVL-520 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the average plasma concentration (Cavg) of NVL-520
5. Time of maximum concentration (Tmax) of NVL-520 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the time of maximum concentration (Tmax) of NVL-520
6. 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 ]
   To determine the area under the curve at the end of the dosing interval (AUCtau) of NVL-520
7. 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 ]
   To determine the area under the curve from time 0 to 24 (AUC0-24) of NVL-520
8. Area under the curve from time 0 to infinity (AUCinf) of NVL-520 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the area under the curve from time 0 to infinity (AUCinf) of NVL-520
9. Oral clearance (CL/F) of NVL-520 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
   To determine the oral clearance (CL/F) of NVL-520
10. Volume of distribution (Vz/F) of NVL-520 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
    To determine the volume of distribution (Vz/F) of NVL-520
11. Half-life (t1/2) of NVL-520 [ Time Frame: Pre-dose and up to 24 hours post-dose ]
    To determine the half-life (t1/2) of NVL-520
12. Objective response rate (ORR) [ Time Frame: 2-3 years after first patient dosed ]
    Determine ORR as assessed by BICR
13. Duration of response (DOR) [ Time Frame: 2-3 years after first patient dosed ]
    Determine DOR of NVL-520 until radiographic disease progression or death
14. Clinical benefit rate (CBR) [ Time Frame: 2-3 years after first patient dosed ]
    Determine CBR of NVL-520
15. Time to response [ Time Frame: 2-3 years after first patient dosed ]
    Determine time to response of NVL-520
16. Progression-free survival (PFS) [ Time Frame: Approximately 3 years ]
    Determine PFS of NVL-520 until radiographic disease progression or death
17. Overall survival (OS) [ Time Frame: Approximately 3 years ]
    Determine OS
18. Rate of CNS progression [ Time Frame: Approximately 3 years ]
    The incidence of CNS as first site of progression, alone or with concurrent extra-CNS progression
19. Intracranial objective response rate (IC-ORR) [ Time Frame: Approximately 3 years ]
    Determine the intracranial objective response rate
20. 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 ]
    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.
21. 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 ]
    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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Nuvalent; 857-357-7000; clinicaltrials@nuvalent.com

Locations

United States, California

UCI Medical Center; Recruiting

Orange, California, United States, 92868

Principal Investigator: Sai-Hong Ignatius Ou, MD

United States, Colorado

University of Colorado Cancer Center; Recruiting

Denver, Colorado, United States, 80045

Principal Investigator: Ross Camidge, MD

United States, District of Columbia

Georgetown University Medical Center; Recruiting

Washington, District of Columbia, United States, 20007

Principal Investigator: Stephen Liu, MD

United States, Florida

University of Miami; Recruiting

Coral Gables, Florida, United States, 33146

Principal Investigator: Gilberto de Lima Lopes, MD

United States, Massachusetts

Mass General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Principal Investigator: Jessica Lin, MD

United States, Michigan

Henry Ford Cancer Institute; Recruiting

Detroit, Michigan, United States, 48202

Principal Investigator: Shirish Gadgeel, MD

United States, New York

NYU Langone Health; Recruiting

New York, New York, United States, 10016

Principal Investigator: Vamsidhar Velchetti, MD

Memorial Sloan Kettering Cancer Center; Recruiting

New York, New York, United States, 10065

Principal Investigator: Alexander Drilon, MD

United States, North Carolina

Atrium Health Levine Cancer Institute; Recruiting

Charlotte, North Carolina, United States, 28204

Principal Investigator: Daniel Haggstrom, MD

United States, Pennsylvania

Fox Chase Cancer Center; Recruiting

Philadelphia, Pennsylvania, United States, 19111

Principal Investigator: Jessica Bauman, MD

United States, Tennessee

Sarah Cannon Research Institute; Recruiting

Nashville, Tennessee, United States, 37203

Principal Investigator: Melissa Johnson, MD

United States, Texas

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Principal Investigator: George Blumenschein, MD

United States, Virginia

NEXT Oncology - Virginia Cancer Specialists; Recruiting

Fairfax, Virginia, United States, 22031

Principal Investigator: Alexander Spira, MD, PhD

United States, Washington

University of Washington / Fred Hutchinson Cancer Center; Recruiting

Seattle, Washington, United States, 98109

Principal Investigator: Christina Baik, MD, MPH

Australia, New South Wales

Chris O'Brien Lifehouse; Recruiting

Camperdown, New South Wales, Australia, 2050

Principal Investigator: Steven Kao, PhD

Australia, Victoria

Peter MacCallum Cancer Centre; Recruiting

Melbourne, Victoria, Australia, 3000

Principal Investigator: Ben Solomon, MD, PhD

Belgium

University Hospital Leuven; Recruiting

Leuven, Belgium, 3000

Principal Investigator: Christophe Dooms, MD, PhD

Canada, Ontario

Princess Margaret Cancer Research; Recruiting

Toronto, Ontario, Canada, M5GG 1L7

Principal Investigator: Geoffrey Liu, MD

France

Hospital Center University De Toulouse; Recruiting

Toulouse, France, 31300

Principal Investigator: Julien Mazieres, MD, PhD

Institute Gustave Roussy; Recruiting

Villejuif, France, 94805

Principal Investigator: Benjamin Besse, MD, PhD

Netherlands

University Medical Centre Groningen; Recruiting

Groningen, Netherlands

Principal Investigator: Anthonie van der Wekken, MD, PhD

Spain

UOMI Cancer Center - Clinica Tres Torres; Recruiting

Barcelona, Spain, 08017

Principal Investigator: Santiago Viteri, MD

Vall d'Hebron University Hospital; Recruiting

Barcelona, Spain, 08035

Principal Investigator: Enriqueta Felip, MD, PhD

Gregorio Marañón Hospital; Recruiting

Madrid, Spain, 28007

Principal Investigator: Antonio Calles, MD

Hospital Universitario HM Sanchinarro; Recruiting

Madrid, Spain, 28050

Principal Investigator: Maria Jose de Miguel, MD, PhD

Taiwan

National Cheng Kung University Hospital; Active, not recruiting

Tainan, Taiwan, 704017

Sponsors and Collaborators

Nuvalent Inc.

Investigators

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

More Information

• Responsible Party: Nuvalent Inc.
• ClinicalTrials.gov Identifier: NCT05118789
• Other Study ID Numbers: NVL-520-01
• First Posted: November 12, 2021
• Last Update Posted: August 9, 2023
• Last Verified: August 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasms