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

Phase 1

Recruiting

• Conditions: Metastatic Solid Tumor; Locally Advanced Solid Tumor
• Interventions: Drug: Zidesamtinib (NVL-520)

• Registration Number: NCT05118789
• Lead Sponsor: Nuvalent Inc.

Brief 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.

Study Timeline

• Study First Submitted: 2021-10-19
• Study First Submitted QC: 2021-11-03
• Study First Posted: 2021-11-12
• Study Start: 2022-01-04
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-30
• Last Update Posted: 2025-08-03
• Primary Completion: 2025-10-31
• Study Completion: 2026-10-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 359

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1 dose escalation	Zidesamtinib (NVL-520)	Zidesamtinib (NVL-520) oral daily dosing
Cohort 2b	Zidesamtinib (NVL-520)	ROS1+ NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy
Cohort 2a	Zidesamtinib (NVL-520)	ROS1+ NSCLC naïve to TKI therapy and up to 1 prior chemotherapy and/or immunotherapy
Cohort 2c	Zidesamtinib (NVL-520)	ROS1+ NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy
Cohort 2d	Zidesamtinib (NVL-520)	ROS1+ NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy
Cohort 2e	Zidesamtinib (NVL-520)	ROS1+ solid tumor and progressed on any prior therapy

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Number of participants with treatment-emergent adverse events, as assessed by CTCAE, v5.0	Approximately 3 years.	Incidence and severity of treatment-emergent adverse events (TEAEs)
Time of maximum concentration (Tmax) of NVL-520	Pre-dose and up to 24 hours post-dose	To determine the time of maximum concentration (Tmax) of NVL-520
Area under the curve at the end of the dosing interval (AUCtau) of NVL-520	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
Plasma concentration at the end of the dosing interval (Ctau) of NVL-520	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
Average plasma concentration (Cavg) of NVL-520	Pre-dose and up to 24 hours post-dose	To determine the average plasma concentration (Cavg) of NVL-520
Area under the curve from time 0 to infinity (AUCinf) of NVL-520	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
Volume of distribution (Vz/F) of NVL-520	Pre-dose and up to 24 hours post-dose	To determine the volume of distribution (Vz/F) of NVL-520
Half-life (t1/2) of NVL-520	Pre-dose and up to 24 hours post-dose	To determine the half-life (t1/2) of NVL-520
Objective response rate (ORR)	2-3 years after first patient dosed	Determine ORR as assessed by BICR
Maximum plasma concentration (Cmax) of NVL-520	Pre-dose and up to 24 hours post-dose	To determine the maximum plasma concentration (Cmax) of NVL-520
Area under the curve from time 0 to 24 (AUC0-24) of NVL-520	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
Oral clearance (CL/F) of NVL-520	Pre-dose and up to 24 hours post-dose	To determine the oral clearance (CL/F) of NVL-520
Time to response	2-3 years after first patient dosed	Determine time to response of NVL-520
Duration of response (DOR)	2-3 years after first patient dosed	Determine DOR of NVL-520 until radiographic disease progression or death
Progression-free survival (PFS)	Approximately 3 years	Determine PFS of NVL-520 until radiographic disease progression or death
Overall survival (OS)	Approximately 3 years	Determine OS
Rate of CNS progression	Approximately 3 years	The incidence of CNS as first site of progression, alone or with concurrent extra-CNS progression
Intracranial objective response rate (IC-ORR)	Approximately 3 years	Determine the intracranial objective response rate
Quality of life assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)	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.
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)	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.
Clinical benefit rate (CBR)	2-3 years after first patient dosed	Determine CBR of NVL-520

Trial Locations

Locations (63)

UCI Medical Center; 🇺🇸 Orange, California, United States

Stanford Medicine; 🇺🇸 Palo Alto, California, United States

UC Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

University of Colorado Cancer Center; 🇺🇸 Denver, Colorado, United States

Georgetown University Medical Center; 🇺🇸 Washington, District of Columbia, United States

University of Miami; 🇺🇸 Coral Gables, Florida, United States

University of Chicago; 🇺🇸 Chicago, Illinois, United States

Mass General Hospital; 🇺🇸 Boston, Massachusetts, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Henry Ford Cancer Institute; 🇺🇸 Detroit, Michigan, United States

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