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

Metastatic Solid Tumor Clinical Trial

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05118789
• Other study ID #: NVL-520-01
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 4, 2022
• Est. completion date: October 31, 2026

Study information

• Verified date: June 2024
• Source: Nuvalent Inc.
• Contact: Nuvalent
• Phone: 857-357-7000
• Email: clinicaltrials[@]nuvalent.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 359
• Est. completion date: October 31, 2026
• Est. primary completion date: October 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Locally Advanced Solid Tumor
• Metastatic Solid Tumor
• Neoplasms

Intervention

Drug:
• NVL-520
Oral tablet of NVL-520

Locations

Country	Name	City	State
Australia	Chris O'Brien Lifehouse	Camperdown	New South Wales
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Belgium	University Hospital Leuven	Leuven
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Princess Margaret Cancer Research	Toronto	Ontario
France	Centre Legon Berard	Lyon
France	CHU de Nantes	Nantes
France	Hospital Center University De Toulouse	Toulouse
France	Institute Gustave Roussy	Villejuif
Germany	Cologne University Hospital	Cologne
Italy	Università Politecnica Marche	Ancona
Italy	Istituto Europeo di Oncologia	Milan
Italy	Istituto Oncologico Veneto	Padova
Italy	Ospedale Santa Maria delle Croci	Ravenna
Japan	Kindai University	Osaka
Japan	Japanese Foundation for Cancer Research	Tokyo
Japan	National Cancer Center Hospital	Tokyo
Korea, Republic of	National Cancer Center	Gyeonggi-do
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Yonsei University Health System	Seoul
Netherlands	Netherlands Cancer Institute	Amsterdam
Netherlands	University Medical Centre Groningen	Groningen
Singapore	National Cancer Centre Singapore	Singapore
Singapore	National University Hospital Singapore	Singapore
Spain	UOMI Cancer Center - Clinica Tres Torres	Barcelona
Spain	Vall d'Hebron University Hospital	Barcelona
Spain	University Hospital of A Coruña	Coruna
Spain	Gregorio Marañón Hospital	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario HM Sanchinarro	Madrid
Taiwan	Chung Shan Medical University Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
United Kingdom	Royal Marsden Hospital	London
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Mass General Hospital	Boston	Massachusetts
United States	Atrium Health Levine Cancer Institute	Charlotte	North Carolina
United States	Ohio State University	Columbus	Ohio
United States	University of Miami	Coral Gables	Florida
United States	University of Colorado Cancer Center	Denver	Colorado
United States	Henry Ford Cancer Institute	Detroit	Michigan
United States	NEXT Oncology - Virginia Cancer Specialists	Fairfax	Virginia
United States	MD Anderson Cancer Center	Houston	Texas
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYU Langone Health	New York	New York
United States	UCI Medical Center	Orange	California
United States	Stanford Medicine	Palo Alto	California
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	UC Davis Comprehensive Cancer Center	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Washington / Fred Hutchinson Cancer Center	Seattle	Washington
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Nuvalent Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Singapore,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Recommended Phase 2 Dose (RP2D)	To determine the RP2D	Within 28 days of last patient dosed during dose escalation.
Primary	Objective Response Rate (ORR) (Phase 2)	To determine ORR as assessed by BICR	2-3 years after first patient dosed.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Objective response rate (ORR)	Determine ORR as assessed by BICR	2-3 years after first patient dosed
Secondary	Duration of response (DOR)	Determine DOR of NVL-520 until radiographic disease progression or death	2-3 years after first patient dosed
Secondary	Clinical benefit rate (CBR)	Determine CBR of NVL-520	2-3 years after first patient dosed
Secondary	Time to response	Determine time to response of NVL-520	2-3 years after first patient dosed
Secondary	Progression-free survival (PFS)	Determine PFS of NVL-520 until radiographic disease progression or death	Approximately 3 years
Secondary	Overall survival (OS)	Determine OS	Approximately 3 years
Secondary	Rate of CNS progression	The incidence of CNS as first site of progression, alone or with concurrent extra-CNS progression	Approximately 3 years
Secondary	Intracranial objective response rate (IC-ORR)	Determine the intracranial objective response rate	Approximately 3 years
Secondary	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
Secondary	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