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

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ClinicalTrials.gov Identifier: NCT05118789
Recruitment Status : Recruiting
First Posted : November 12, 2021
Last Update Posted : September 21, 2022
Sponsor:
Information provided by (Responsible Party):
Nuvalent Inc.

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.
  • Cohort 2b: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and no prior platinum-based chemotherapy with or without 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 platinum-based chemotherapy with or without immunotherapy.
  • Cohort 2e: ROS1-positive solid tumor and progressed on any prior therapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 247 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

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
Drug: NVL-520
Oral tablet of NVL-520

Experimental: Cohort 2b
ROS1+ NSCLC treated with 1 prior ROS1 TKI and no prior platinum-based 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 platinum-based chemotherapy with or without 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




Primary Outcome Measures :
  1. Dose limiting toxicities (DLTs) (Phase 1) [ Time Frame: Within the first 28 days of the first NVL-520 dose ]
    Define the dose limiting toxicities (DLTs)

  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: Approximately 3 years ]
    Determine time to response of NVL-520

  16. Progression-free survival (PFS) [ Time Frame: 2-3 years after first patient dosed ]
    Determine PFS of NVL-520 until radiographic disease progression or death

  17. Overall survival (OS) [ Time Frame: Approximately 3 years ]
    Determine OS



Information from the National Library of Medicine

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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. Phase 1:

    1. Histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ROS1 rearrangement.
    2. Cohorts 2a, 2b, 2c and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangement.
    3. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05118789


Contacts
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Contact: Gosia Riley 857-357-7000 medical@nuvalent.com

Locations
Show Show 19 study locations
Sponsors and Collaborators
Nuvalent Inc.
Investigators
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Study Director: Viola Zhu, MD, PhD Nuvalent Inc.
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Responsible Party: Nuvalent Inc.
ClinicalTrials.gov Identifier: NCT05118789    
Other Study ID Numbers: NVL-520-01
First Posted: November 12, 2021    Key Record Dates
Last Update Posted: September 21, 2022
Last Verified: September 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms