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

• Sponsor: Nuvalent Inc. (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT05118789
• Collaborator: (none)
• Enrollment: 247
• Locations: 16
• Arms: 6
• Anticipated Duration (Months): 57.9
• Patients Per Site: 15.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• Anticipated 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: Jan 4, 2022
• Anticipated Primary Completion Date: Oct 31, 2025
• Anticipated Study Completion Date: Oct 31, 2026

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Dose limiting toxicities (DLTs) (Phase 1) [Within the first 28 days of the first NVL-520 dose]

   Define the dose limiting toxicities (DLTs)

2. Recommended Phase 2 Dose (RP2D) [Within 28 days of last patient dosed during dose escalation.]

   To determine the RP2D

3. Objective Response Rate (ORR) (Phase 2) [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 [Approximately 3 years.]

   Incidence and severity of treatment-emergent adverse events (TEAEs)

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. Objective response rate (ORR) [2-3 years after first patient dosed]

    Determine ORR as assessed by BICR

13. Duration of response (DOR) [2-3 years after first patient dosed]

    Determine DOR of NVL-520 until radiographic disease progression or death

14. Clinical benefit rate (CBR) [2-3 years after first patient dosed]

    Determine CBR of NVL-520

15. Time to response [Approximately 3 years]

    Determine time to response of NVL-520

16. Progression-free survival (PFS) [2-3 years after first patient dosed]

    Determine PFS of NVL-520 until radiographic disease progression or death

17. Overall survival (OS) [Approximately 3 years]

    Determine OS

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age ≥18 years (Cohort 2e only: Age ≥12 years and weighing>40 kg).

2. Phase 1:

3. Histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ROS1 rearrangement.

4. Cohorts 2a, 2b, 2c and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangement.

5. Cohort 2e: Histologically or cytologically confirmed locally advanced or metastatic solid tumor (other than NSCLC) with ROS1 rearrangement.

6. Prior anticancer treatment (except cohort 2a).

7. 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.

8. 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

Locations

	Site	City	State	Country	Postal Code
1	UCI Medical Center	Orange	California	United States	92868
2	University of Colorado Cancer Center	Denver	Colorado	United States	80045
3	University of Miami	Coral Gables	Florida	United States	33146
4	Mass General Hospital	Boston	Massachusetts	United States	02114
5	Henry Ford Cancer Institute	Detroit	Michigan	United States	48202
6	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
7	Atrium Health Levine Cancer Institute	Charlotte	North Carolina	United States	28204
8	Sarah Cannon	Nashville	Tennessee	United States	37203
9	MD Anderson Cancer Center	Houston	Texas	United States	77030
10	NEXT Oncology - Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
11	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
12	Institute Gustave Roussy	Villejuif		France	94805
13	University Medical Centre Groningen	Groningen		Netherlands
14	Vall d'Hebron University Hospital	Barcelona		Spain	08035
15	Gregorio Marañón Hospital	Madrid		Spain	28007
16	Hospital Universitario HM Sanchinarro	Madrid		Spain	28050

Sponsors and Collaborators

• Nuvalent Inc.

Investigators

• Study Director: Viola Zhu, MD, PhD, Nuvalent Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nuvalent Inc.
• ClinicalTrials.gov Identifier: NCT05118789
• Other Study ID Numbers: NVL-520-01
• First Posted: Nov 12, 2021
• Last Update Posted: Aug 24, 2022
• Last Verified: Aug 1, 2022

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

Study Results

No Results Posted as of Aug 24, 2022