Clinical trial NCT05118789: A Study of NVL-520 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1)
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Locally Advanced Solid Tumor
Metastatic Solid Tumor
Lead sponsor: Nuvalent Inc.
Sponsor class: INDUSTRY
First posted: 2021-11-12
Enrollment: 359
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) (Phase 1)
timeFrame: Within 28 days of last patient dosed during dose escalation
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: Within 28 days of last patient dosed during dose escalation.
measure: Objective Response Rate (ORR) (Phase 2)
timeFrame: 2-3 years after first patient dosed.
Secondary outcomes:
measure: Number of participants with treatment-emergent adverse events, as assessed by CTCAE, v5.0
timeFrame: Approximately 3 years.
measure: Maximum plasma concentration (Cmax) of NVL-520
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Plasma concentration at the end of the dosing interval (Ctau) of NVL-520
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Average plasma concentration (Cavg) of NVL-520
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Time of maximum concentration (Tmax) of NVL-520
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-520
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Area under the curve from time 0 to 24 (AUC0-24) of NVL-520
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Area under the curve from time 0 to infinity (AUCinf) of NVL-520
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Oral clearance (CL/F) of NVL-520
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Volume of distribution (Vz/F) of NVL-520
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Half-life (t1/2) of NVL-520
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: 2-3 years after first patient dosed
measure: Clinical benefit rate (CBR)
timeFrame: 2-3 years after first patient dosed
measure: Time to response
timeFrame: 2-3 years after first patient dosed
measure: Progression-free survival (PFS)
timeFrame: Approximately 3 years
measure: Overall survival (OS)
timeFrame: Approximately 3 years
measure: Rate of CNS progression
timeFrame: Approximately 3 years
measure: Intracranial objective response rate (IC-ORR)
timeFrame: Approximately 3 years
measure: Quality of life assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
timeFrame: 2-3 years after first patient dosed
measure: 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)
timeFrame: 2-3 years after first patient dosed
Other outcomes:
Locations:
city: Orange
country: United States
facility: UCI Medical Center
state: California
city: Palo Alto
country: United States
facility: Stanford Medicine
state: California
city: Sacramento
country: United States
facility: UC Davis Comprehensive Cancer Center
state: California
city: Denver
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Coral Gables
country: United States
facility: University of Miami
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Mass General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Cancer Institute
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Atrium Health Levine Cancer Institute
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: NEXT Oncology - Virginia Cancer Specialists
state: Virginia
city: Seattle
country: United States
facility: University of Washington / Fred Hutchinson Cancer Center
state: Washington
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Cancer Research
state: Ontario
city: Lyon
country: France
facility: Centre Legon Berard
city: Nantes
country: France
facility: CHU de Nantes
city: Toulouse
country: France
facility: Claudius Regaud Institute
city: Villejuif
country: France
facility: Institute Gustave Roussy
city: Cologne
country: Germany
facility: Cologne University Hospital
city: Ancona
country: Italy
facility: Università Politecnica Marche
city: Bari
country: Italy
facility: IRCCS Istituto Tumori Giovanni Paolo II
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Milan
country: Italy
facility: Istituto Europeo di Oncologia
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci
city: Rome
country: Italy
facility: Istituto Nazionale Tumori Regina Elena
city: Nagaizumi
country: Japan
facility: Shizuoka Cancer Center
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Kindai University
city: Tokyo
country: Japan
facility: National Cancer Center Hospital
city: Tokyo
country: Japan
facility: Japanese Foundation for Cancer Research
city: Wakayama
country: Japan
facility: Wakayama Medical University Hospital
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Singapore
country: Singapore
facility: National University Hospital Singapore
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore
city: Barcelona
country: Spain
facility: UOMI Cancer Center - Clinica Tres Torres
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Coruna
country: Spain
facility: University Hospital of A Coruña
city: Madrid
country: Spain
facility: Gregorio Marañón Hospital
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Taichung
country: Taiwan
facility: Chung Shan Medical University Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: Manchester
country: United Kingdom
facility: Christie NHS Foundation Trust
Study officials:
affiliation: Nuvalent Inc.
name: Vivek Upadhyay, MD, MBI
role: STUDY_DIRECTOR
References: