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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Locally Advanced Solid Tumor, Metastatic Solid Tumor

Intervention / Treatment
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* Drug: NVL-520


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years (Cohort 2e only: Age ≥12 years and weighing>40 kg). 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.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 dose escalation<br>NVL-520 oral daily dosing | Drug: NVL-520<br>* Oral tablet of NVL-520<br>|
| Experimental: Cohort 2a<br>ROS1+ NSCLC naïve to TKI therapy and up to 1 prior chemotherapy and/or immunotherapy | Drug: NVL-520<br>* Oral tablet of NVL-520<br>|
| Experimental: Cohort 2b<br>ROS1+ NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy | Drug: NVL-520<br>* Oral tablet of NVL-520<br>|
| Experimental: Cohort 2c<br>ROS1+ NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy | Drug: NVL-520<br>* Oral tablet of NVL-520<br>|
| Experimental: Cohort 2d<br>ROS1+ NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy | Drug: NVL-520<br>* Oral tablet of NVL-520<br>|
| Experimental: Cohort 2e<br>ROS1+ solid tumor and progressed on any prior therapy | Drug: NVL-520<br>* Oral tablet of NVL-520<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) (Phase 1) | Highest dose with dose-limiting toxicity (DLT) rate ≤ 25% | Within 28 days of last patient dosed during dose escalation | 
| Recommended Phase 2 Dose (RP2D) | To determine the RP2D | Within 28 days of last patient dosed during dose escalation. | 
| Objective Response Rate (ORR) (Phase 2) | To determine ORR as assessed by BICR | 2-3 years after first patient dosed. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent adverse events, as assessed by CTCAE, v5.0 | Incidence and severity of treatment-emergent adverse events (TEAEs) | Approximately 3 years. | 
| Maximum plasma concentration (Cmax) of NVL-520 | To determine the maximum plasma concentration (Cmax) of NVL-520 | Pre-dose and up to 24 hours post-dose | 
| Plasma concentration at the end of the dosing interval (Ctau) of NVL-520 | To determine the plasma concentration at the end of the dosing interval (Ctau) of NVL-520 | Pre-dose and up to 24 hours post-dose | 
| Average plasma concentration (Cavg) of NVL-520 | To determine the average plasma concentration (Cavg) of NVL-520 | Pre-dose and up to 24 hours post-dose | 
| Time of maximum concentration (Tmax) of NVL-520 | To determine the time of maximum concentration (Tmax) of NVL-520 | Pre-dose and up to 24 hours post-dose | 
| Area under the curve at the end of the dosing interval (AUCtau) of NVL-520 | To determine the area under the curve at the end of the dosing interval (AUCtau) of NVL-520 | Pre-dose and up to 24 hours post-dose | 
| Area under the curve from time 0 to 24 (AUC0-24) of NVL-520 | To determine the area under the curve from time 0 to 24 (AUC0-24) of NVL-520 | Pre-dose and up to 24 hours post-dose | 
| Area under the curve from time 0 to infinity (AUCinf) of NVL-520 | To determine the area under the curve from time 0 to infinity (AUCinf) of NVL-520 | Pre-dose and up to 24 hours post-dose | 
| Oral clearance (CL/F) of NVL-520 | To determine the oral clearance (CL/F) of NVL-520 | Pre-dose and up to 24 hours post-dose | 
| Volume of distribution (Vz/F) of NVL-520 | To determine the volume of distribution (Vz/F) of NVL-520 | Pre-dose and up to 24 hours post-dose | 
| Half-life (t1/2) of NVL-520 | To determine the half-life (t1/2) of NVL-520 | Pre-dose and up to 24 hours post-dose | 
| Objective response rate (ORR) | Determine ORR as assessed by BICR | 2-3 years after first patient dosed | 
| Duration of response (DOR) | Determine DOR of NVL-520 until radiographic disease progression or death | 2-3 years after first patient dosed | 
| Clinical benefit rate (CBR) | Determine CBR of NVL-520 | 2-3 years after first patient dosed | 
| Time to response | Determine time to response of NVL-520 | 2-3 years after first patient dosed | 
| Progression-free survival (PFS) | Determine PFS of NVL-520 until radiographic disease progression or death | Approximately 3 years | 
| Overall survival (OS) | Determine OS | Approximately 3 years | 
| Rate of CNS progression | The incidence of CNS as first site of progression, alone or with concurrent extra-CNS progression | Approximately 3 years | 
| Intracranial objective response rate (IC-ORR) | Determine the intracranial objective response rate | Approximately 3 years | 
| Quality of life assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) | 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. | 2-3 years after first patient dosed | 
| 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) | 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. | 2-3 years after first patient dosed |