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Trial record 1 of 1 for:    NVL-520-01
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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 : March 8, 2024
Sponsor:
Information provided by (Responsible Party):
Nuvalent Inc.

Study Description
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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 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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 359 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
Arms and Interventions
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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 and up to 1 prior chemotherapy and/or immunotherapy
 Drug: NVL-520
Oral tablet of NVL-520
Experimental: Cohort 2b
ROS1+ NSCLC treated with 1 prior ROS1 TKI and no prior 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 chemotherapy and/or 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


Outcome Measures
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Primary Outcome Measures :
  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 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: 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.


Eligibility Criteria
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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. 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.
Contacts and Locations
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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: Nuvalent 857-357-7000 clinicaltrials@nuvalent.com

Locations
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Sponsors and Collaborators
Nuvalent Inc.
Investigators
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Study Director: Vivek Upadhyay, MD, MBI Nuvalent Inc.
More Information
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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: March 8, 2024
Last Verified: March 2024

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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