A Study of Neladalkib (NVL-655) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1)

Phase 1

Recruiting

• Conditions: Locally Advanced Solid Tumor; Metastatic Solid Tumor
• Interventions: Drug: NVL-655; Drug: Neladalkib (NVL-655)

• Registration Number: NCT05384626
• Lead Sponsor: Nuvalent Inc.

Brief Summary

Phase 1/2, dose escalation and expansion study designed to evaluate the safety and tolerability of neladalkib (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 evaluate the overall safety and tolerability of neladalkib and will determine the RP2D and, if applicable, the maximum tolerated dose (MTD) of neladalkib 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 neladalkib 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 neladalkib in patients with advanced ALK-positive NSCLC and other solid tumors.

Detailed Description

In Phase 2, study patients will be enrolled into 6 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, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.

* Cohort 2b: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.

* Cohort 2c: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed.

* Cohort 2d: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.

* Cohort 2e: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.

* Cohort 2f: Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.

Study Timeline

• Study First Submitted: 2022-05-17
• Study First Submitted QC: 2022-05-17
• Study First Posted: 2022-05-20
• Study Start: 2022-06-09
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-21
• Last Update Posted: 2025-07-24
• Primary Completion: 2027-12
• Study Completion: 2028-01-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 840

Inclusion Criteria

1. Age ≥18 years, Phase 2 Cohort 2f only: Age ≥12 years and weighing >40 kg.

2. Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation.

3. Phase 2

   1. Phase 2 Cohorts except 2f: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with a documented ALK rearrangement
   2. Phase 2 Cohort 2f: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation detected by certified assay.

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 organ function and bone marrow reserve

Exclusion criteria:

1. Patient's cancer has a known oncogenic driver alteration other than ALK.
2. Known allergy/hypersensitivity to excipients of NVL-655.
3. Major surgery within 4 weeks of the study entry
4. Ongoing or anticancer therapy
5. Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 2d	NVL-655	Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.
Phase 1 dose escalation	NVL-655	NVL-655 oral daily dosing
Phase 1 dose escalation	Neladalkib (NVL-655)	Neladalkib (NVL-655) oral daily dosing
Cohort 2a	Neladalkib (NVL-655)	Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
Cohort 2b	Neladalkib (NVL-655)	Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
Cohort 2c	Neladalkib (NVL-655)	Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed.
Cohort 2d	Neladalkib (NVL-655)	Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.
Cohort 2e	Neladalkib (NVL-655)	Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.
Cohort 2f	Neladalkib (NVL-655)	Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.
Cohort 2c	NVL-655	Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed.
Cohort 2a	NVL-655	Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
Cohort 2b	NVL-655	Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
Cohort 2e	NVL-655	Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.
Cohort 2f	NVL-655	Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.

Primary Outcome Measures

Name	Time	Method
Dose limiting toxicities (DLTs) (Phase 1)	Within the first 21 days of the first neladalkib (NVL-655) dose	Define the dose limiting toxicities (DLTs)
Recommended Phase 2 Dose (RP2D) (Phase 1)	Within 21 days of last patient dosed during escalation	To determine the RP2D
Objective Response Rate (ORR) (Phase 2)	2-3 years after first patient dosed.	To determine ORR as assessed by BICR
Number of participants with treatment-emergent adverse events, as assessed by CTCAE, V5.0 (Phase 1)	Approximately 3 years	Incidence and severity of treatment-emergent adverse events (TEAEs)

Secondary Outcome Measures

Name	Time	Method
Maximum plasma concentration, (Cmax) of neladalkib (NVL-655)	Pre-dose and up to 24 hours post-dose	To determine the maximum plasma concentration (Cmax) of neladalkib (NVL-655)
Plasma concentration at the end of the dosing interval (Ctau) of neladalkib (NVL-655)	Pre-dose and up to 24 hours post-dose	To determine the plasma concentration at the end of the dosing interval (Ctau) of neladalkib (NVL-655)
Average plasma concentration (Cavg) of neladalkib (NVL-655)	Pre-dose and up to 24 hours post-dose	To determine the average plasma concentration (Cavg) of neladalkib (NVL-655)
Time of maximum concentration (Tmax) of neladalkib (NVL-655)	Pre-dose and up to 24 hours post-dose	To determine the time of maximum concentration (Tmax) of neladalkib (NVL-655)
Area under the curve at the end of the dosing interval (AUCtau) of neladalkib (NVL-655)	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 neladalkib (NVL-655)
Area under the curve from time 0 to 24 (AUC0-24) of neladalkib (NVL-655)	Pre-dose and up to 24 hours post-dose	To determine the area under the curve from time 0 to 24 (AUC0-24) of neladalkib (NVL-655)
Area under the curve from time 0 to infinity (AUCinf) of neladalkib (NVL-655)	Pre-dose and up to 24 hours post-dose	To determine the area under the curve from time 0 to infinity (AUCinf) of neladalkib (NVL-655)
Oral clearance (CL/F) of neladalkib (NVL-655)	Pre-dose and up to 24 hours post-dose	To determine the oral clearance (CL/F) of neladalkib (NVL-655)
Volume of distribution (Vz/F) of neladalkib (NVL-655)	Pre-dose and up to 24 hours post-dose	To determine the volume of distribution (Vz/F) of neladalkib (NVL-655)
Half-life (t1/2) of neladalkib (NVL-655)	Pre-dose and up to 24 hours post-dose	To determine the half-life (t1/2) of neladalkib (NVL-655)
Objective response rate (ORR) (Phase 1)	2-3 years after first patient dosed	Determine ORR as assessed by Investigator
Duration of response (DOR)	2-3 years after first patient dosed	Determine DOR of neladalkib (NVL-655) until radiographic disease progression or death
Clinical benefit rate (CBR)	2-3 years after first patient dosed	Determine CBR of neladalkib (NVL-655)
Time to response	Approximately 3 years	Determine time to response of neladalkib (NVL-655)
Progression-free survival (PFS)	2-3 years after first patient dosed	Determine PFS of neladalkib (NVL-655) until radiographic disease progression or death
Overall survival (OS) (Phase 2)	Approximately 3 years	Determine OS
Number of participants with treatment-emergent adverse events, as assessed by CTCAE, V5.0 (Phase 2)	Approximately 3 years	Incidence and severity of treatment-emergent adverse events (TEAEs)
Quality of life assessment	2-3 years after first patient dosed	Measure the quality of life in patients with cancer and/or lung cancer.

Trial Locations

Locations (74)

University of California Irvine Medical Center; 🇺🇸 Orange, California, United States

University of California, Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

Stanford Cancer Institute; 🇺🇸 Stanford, California, United States

University of Colorado Cancer Center; 🇺🇸 Aurora, Colorado, United States

Georgetown University Medical Center; 🇺🇸 Washington, District of Columbia, United States

University of Miami; Sylvester Cancer Center; 🇺🇸 Miami, Florida, United States

Winship Cancer Institute, Emory University; 🇺🇸 Atlanta, Georgia, United States

University of Chicago Medical Center; 🇺🇸 Chicago, Illinois, United States

John Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

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