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

• ClinicalTrials.gov Identifier: NCT05118789
• Recruitment Status: Recruiting
• First Posted: November 12, 2021
• Last Update Posted: March 8, 2024
• Sponsor: Nuvalent Inc.
• Information provided by (Responsible Party): Nuvalent Inc.

Tracking Information

• First Submitted Date: October 19, 2021
• First Posted Date: November 12, 2021
• Last Update Posted Date: March 8, 2024
• Actual Study Start Date: January 4, 2022
• Estimated Primary Completion Date: October 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 6, 2023)

• 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%
• Recommended Phase 2 Dose (RP2D) [ Time Frame: Within 28 days of last patient dosed during dose escalation. ]
  To determine the RP2D
• Objective Response Rate (ORR) (Phase 2) [ Time Frame: 2-3 years after first patient dosed. ]
  To determine ORR as assessed by BICR

Original Primary Outcome Measures (submitted: November 3, 2021)

• 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)
• Recommended Phase 2 Dose (RP2D) [ Time Frame: Within 28 days of last patient dosed during dose escalation. ]
  To determine the RP2D
• Objective Response Rate (ORR) (Phase 2) [ Time Frame: 2-3 years after first patient dosed. ]
  To determine ORR as assessed by BICR

Current Secondary Outcome Measures (submitted: August 6, 2023)

• 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)
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Objective response rate (ORR) [ Time Frame: 2-3 years after first patient dosed ]
  Determine ORR as assessed by BICR
• Duration of response (DOR) [ Time Frame: 2-3 years after first patient dosed ]
  Determine DOR of NVL-520 until radiographic disease progression or death
• Clinical benefit rate (CBR) [ Time Frame: 2-3 years after first patient dosed ]
  Determine CBR of NVL-520
• Time to response [ Time Frame: 2-3 years after first patient dosed ]
  Determine time to response of NVL-520
• Progression-free survival (PFS) [ Time Frame: Approximately 3 years ]
  Determine PFS of NVL-520 until radiographic disease progression or death
• Overall survival (OS) [ Time Frame: Approximately 3 years ]
  Determine OS
• 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
• Intracranial objective response rate (IC-ORR) [ Time Frame: 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) [ 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.
• 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.

Original Secondary Outcome Measures (submitted: November 3, 2021)

• 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)
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Objective response rate (ORR) [ Time Frame: 2-3 years after first patient dosed ]
  Determine ORR as assessed by BICR
• Duration of response (DOR) [ Time Frame: 2-3 years after first patient dosed ]
  Determine DOR of NVL-520 until radiographic disease progression or death
• Clinical benefit rate (CBR) [ Time Frame: 2-3 years after first patient dosed ]
  Determine CBR of NVL-520
• Time to response [ Time Frame: Approximately 3 years ]
  Determine time to response of NVL-520
• Progression-free survival (PFS) [ Time Frame: 2-3 years after first patient dosed ]
  Determine PFS of NVL-520 until radiographic disease progression or death
• Overall survival (OS) [ Time Frame: Approximately 3 years ]
  Determine OS

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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.

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 Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Locally Advanced Solid Tumor
• Metastatic Solid Tumor

Intervention

Drug: NVL-520

Oral tablet of NVL-520

Study Arms

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 6, 2023): 359
• Original Estimated Enrollment (submitted: November 3, 2021): 246
• Estimated Study Completion Date: October 31, 2026
• Estimated Primary Completion Date: October 31, 2025 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Nuvalent; 857-357-7000; clinicaltrials@nuvalent.com

• Listed Location Countries: Australia, Belgium, Canada, France, Germany, Korea, Republic of, Netherlands, Singapore, Spain, Taiwan, United States

Administrative Information

• NCT Number: NCT05118789
• Other Study ID Numbers: NVL-520-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Nuvalent Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Nuvalent Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Vivek Upadhyay, MD, MBI; Nuvalent Inc.

• PRS Account: Nuvalent Inc.
• Verification Date: March 2024