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 2RecruitingNCT05384626

Nuvalent Inc.840 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

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.

Locations (74)

University of California Irvine Medical Center

Orange, California, United States

RECRUITING

University of California, Davis Comprehensive Cancer Center

Sacramento, California, United States

RECRUITING

Stanford Cancer Institute

Stanford, California, United States

RECRUITING

University of Colorado Cancer Center

Aurora, Colorado, United States

Outcomes

Primary Outcomes

Dose limiting toxicities (DLTs) (Phase 1)

Define the dose limiting toxicities (DLTs)

Time frame: Within the first 21 days of the first neladalkib (NVL-655) dose

Recommended Phase 2 Dose (RP2D) (Phase 1)

To determine the RP2D

Time frame: Within 21 days of last patient dosed during escalation

Objective Response Rate (ORR) (Phase 2)

To determine ORR as assessed by BICR

Time frame: 2-3 years after first patient dosed.

Number of participants with treatment-emergent adverse events, as assessed by CTCAE, V5.0 (Phase 1)

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

Time frame: Approximately 3 years