A Study of NVL-655 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-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-655, determine the recommended phase 2 dose (RP2D), and evaluate the antitumor activity in patients with advanced ALK- positive (ALK+) NSCLC and other solid tumors. Phase 1 will determine the RP2D and, if applicable, the MTD of NVL-655 in patients with advanced ALK+ solid tumors. Phase 2 will determine the objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR) of NVL-655 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-655 in patients with advanced ALK-positive NSCLC and other solid tumors.

Detailed Description
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In Phase 2, study patients will be enrolled into 4 distinct cohorts: Cohort 2a: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, brigatinib) Cohort 2b: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior 1st or 2nd-generation ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib) Cohort 2c: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs, with lorlatinib in the 2nd or 3rd line Cohort 2d: Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, including patients with NSCLC not eligible for cohorts 2a-c, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists

Official Title
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A Phase 1/2 Study of the Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor NVL-655 in Patients With Advanced NSCLC and Other Solid Tumors (ALKOVE-1)

Conditions
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Locally Advanced Solid Tumor, Metastatic Solid Tumor

Intervention / Treatment
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* Drug: NVL-655


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Phase 2 Cohort 2d only: Age ≥12 years and weighing >40 kg. Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation. Phase 2 Cohorts 2a, 2b, and 2c: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with a documented ALK rearrangement Cohort 2d: histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation 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 organ function and bone marrow reserve Exclusion criteria: Patient's cancer has a known oncogenic driver alteration other than ALK. Known allergy/hypersensitivity to excipients of NVL-655. Major surgery within 4 weeks of the study entry Ongoing or 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-655 oral daily dosing | Drug: NVL-655<br>* Oral Tablet of NVL-655<br>|
| Experimental: Cohort 2a<br>ALK+ NSCLC treated with 1 prior 2nd-generation ALK TKI therapy | Drug: NVL-655<br>* Oral Tablet of NVL-655<br>|
| Experimental: Cohort 2b<br>ALK+ NSCLC treated with 2-3 prior 1st or 2nd-generation ALK TKIs | Drug: NVL-655<br>* Oral Tablet of NVL-655<br>|
| Experimental: Cohort 2c<br>ALK+ NSCLC treated with 2-3 prior ALK TKIs, with lorlatinib in the 2nd or 3rd line | Drug: NVL-655<br>* Oral Tablet of NVL-655<br>|
| Experimental: Cohort 2d<br>ALK+ solid tumors including patients with NSCLC not eligible for cohorts 2a-c, treated with ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists | Drug: NVL-655<br>* Oral Tablet of NVL-655<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities (DLTs) (Phase 1) | Define the dose limiting toxicities (DLTs) | Within the first 21 days of the first NVL-655 dose | 
| Recommended Phase 2 Dose (RP2D) | To determine the RP2D | Within 21 days of last patient dosed during 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-655 | To determine the maximum plasma concentration (Cmax) of NVL | Pre-dose and up to 24 hours post-dose | 
| Plasma concentration at the end of the dosing interval (Ctau) of NVL-655 | To determine the plasma concentration at the end of the dosing interval (Ctau) of NVL-655 | Pre-dose and up to 24 hours post-dose | 
| Average plasma concentration (Cavg) of NVL-655 | To determine the average plasma concentration (Cavg) of NVL-655 | Pre-dose and up to 24 hours post-dose | 
| Time of maximum concentration (Tmax) of NVL-655 | To determine the time of maximum concentration (Tmax) of NVL-655 | Pre-dose and up to 24 hours post-dose | 
| Area under the curve at the end of the dosing interval (AUCtau) of NVL-655 | To determine the area under the curve at the end of the dosing interval (AUCtau) of NVL-655 | Pre-dose and up to 24 hours post-dose | 
| Area under the curve from time 0 to 24 (AUC0-24) of NVL-655 | To determine the area under the curve from time 0 to 24 (AUC0-24) of NVL-655 | Pre-dose and up to 24 hours post-dose | 
| Area under the curve from time 0 to infinity (AUCinf) of NVL-655 | To determine the area under the curve from time 0 to infinity (AUCinf) of NVL-655 | Pre-dose and up to 24 hours post-dose | 
| Oral clearance (CL/F) of NVL-655 | To determine the oral clearance (CL/F) of NVL-655 | Pre-dose and up to 24 hours post-dose | 
| Volume of distribution (Vz/F) of NVL-655 | To determine the volume of distribution (Vz/F) of NVL-655 | Pre-dose and up to 24 hours post-dose | 
| Half-life (t1/2) of NVL-655 | To determine the half-life (t1/2) of NVL-655 | Pre-dose and up to 24 hours post-dose | 
| Objective response rate (ORR) (Phase 1) | Determine ORR as assessed by BICR | 2-3 years after first patient dosed | 
| Duration of response (DOR) | Determine DOR of NVL-655 until radiographic disease progression or death | 2-3 years after first patient dosed | 
| Clinical benefit rate (CBR) | Determine CBR of NVL-655 | 2-3 years after first patient dosed | 
| Time to response | Determine time to response of NVL-655 | Approximately 3 years | 
| Progression-free survival (PFS) | Determine PFS of NVL-520 until radiographic disease progression or death | 2-3 years after first patient dosed | 
| Overall survival (OS) | Determine OS | Approximately 3 years |