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NCT Number: NCT05118789

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

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.

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Key information

Conditions

Locally Advanced Solid Tumor Metastatic Solid Tumor Neoplasm Metastasis Neoplasms Neoplastic Processes Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

12 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia

Loading trial locations.

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age ≥18 years (Cohort 2e only: Age ≥12 years).
  • Disease Criteria:
  • Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ROS1 rearrangement.
  • Phase 2: Cohorts 2a, 2b, 2c and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangement.
  • Phase 2: Cohort 2e: Histologically or cytologically confirmed locally advanced or metastatic solid tumor (other than NSCLC) with ROS1 rearrangement.
  • Prior anticancer treatment (except cohort 2a).
  • 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.
  • Adequate baseline organ function and bone marrow reserve.

Exclusion criteria

  • Patient's cancer has a known oncogenic driver alteration other than ROS1.
  • Known allergy/hypersensitivity to excipients of NVL-520.
  • Major surgery within 4 weeks of first dose of study drug.
  • Ongoing anticancer therapy.
  • Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.

Treatment and study plan

Zidesamtinib (NVL-520)

Drug

Oral tablet of zidesamtinib (NVL-520)

Primary outcomes

  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 outcomes

  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.

Study contacts

Contact information is provided by the study sponsor or research team.

Nuvalent

CONTACT

[email protected]

857-357-7000

Sponsors and collaborators

Lead sponsor

Nuvalent Inc.

Industry

Registry information

Official study title

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

Important dates

Study start
2022
Primary completion
2027
Study completion
2028
First posted
Nov 12, 2021
Registry last updated
Oct 24, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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