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

Official title

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)

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. A drug-drug interaction (DDI) sub-study will determine the effect of neladalkib on the pharmacokinetics of midazolam and repaglinide, as well as the effect of itraconazole on the pharmacokinetics of neladalkib, in patients with advanced ALK-positive NSCLC

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.

In the DDI sub-study, study patients will be enrolled into 2 distinct cohorts:

* Cohort G (DDI sub-study with midazolam and repaglinide): Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received ≥1 prior ALK TKI. * Cohort H (DDI sub-study with itraconazole): Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received ≥1 prior ALK TKI.

Interventions

• Drug Neladalkib (NVL-655)
  Oral Tablet of Neladalkib (NVL-655)
• Drug Midazolam
  Oral Solution of Midazolam
• Drug Repaglinide
  Oral Tablet of Repaglinide
• Drug Itraconazole
  Oral Solution of Itraconazole

Primary outcome measures

• Dose limiting toxicities (DLTs) (Phase 1) [Time frame: Within the first 21 days of the first neladalkib (NVL-655) dose]
• Recommended Phase 2 Dose (RP2D) (Phase 1) [Time frame: Within 21 days of last patient dosed during escalation]
• Objective Response Rate (ORR) (Phase 2) [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) [Time frame: Approximately 3 years]
• Area under the curve of repaglinide (Phase 2 DDI sub-study) [Time frame: Pre-dose and up to 24 hours post-dose]
• Area under the curve of midazolam (Phase 2 DDI sub-study) [Time frame: Pre-dose and up to 24 hours post-dose]
• Area under the curve of neladalkib (NVL-655) (Phase 2 DDI sub-study) [Time frame: Pre-dose and up to 24 hours post-dose]

Secondary outcome measures (12)

• Maximum plasma concentration, (Cmax) of neladalkib (NVL-655) [Time frame: Pre-dose and up to 24 hours post-dose]
• Plasma concentration at the end of the dosing interval (Ctau) of neladalkib (NVL-655) [Time frame: Pre-dose and up to 24 hours post-dose]
• Average plasma concentration (Cavg) of neladalkib (NVL-655) [Time frame: Pre-dose and up to 24 hours post-dose]
• Time of maximum concentration (Tmax) of neladalkib (NVL-655) [Time frame: Pre-dose and up to 24 hours post-dose]
• Area under the curve at the end of the dosing interval (AUCtau) of neladalkib (NVL-655) [Time frame: Pre-dose and up to 24 hours post-dose]
• Area under the curve from time 0 to 24 (AUC0-24) of neladalkib (NVL-655) [Time frame: Pre-dose and up to 24 hours post-dose]
• Area under the curve from time 0 to infinity (AUCinf) of neladalkib (NVL-655) [Time frame: Pre-dose and up to 24 hours post-dose]
• Oral clearance (CL/F) of neladalkib (NVL-655) [Time frame: Pre-dose and up to 24 hours post-dose]
• Volume of distribution (Vz/F) of neladalkib (NVL-655) [Time frame: Pre-dose and up to 24 hours post-dose]
• Half-life (t1/2) of neladalkib (NVL-655) [Time frame: Pre-dose and up to 24 hours post-dose]
• Objective response rate (ORR) (Phase 1) [Time frame: 2-3 years after first patient dosed]
• Duration of response (DOR) [Time frame: 2-3 years after first patient dosed]

Eligibility criteria

Inclusion criteria

• Age ≥18 years, Phase 2 Cohort 2f only: Age ≥12 years and weighing >40 kg. DDI sub-study Cohorts G and H only: age 18-60 years, inclusive
• Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation.
• Phase 2

• Phase 2 Cohorts except 2f: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with a documented ALK rearrangement
• 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.
• DDI sub-study cohorts: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with a documented ALK rearrangement
• DDI sub-study cohorts: Must have previously received ≥1 ALK TKI; no prior investigational agents targeting ALK; any number of prior chemotherapy and/or immunotherapy
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 21 centers

• University of California Irvine Medical Center — Orange
• University of California, Davis Comprehensive Cancer Center — Sacramento
• Stanford Cancer Institute — Stanford
• University of Colorado Cancer Center — Aurora
• Georgetown University Medical Center — Washington D.C.
• University of Miami; Sylvester Cancer Center — Miami
• Winship Cancer Institute, Emory University — Atlanta
• University of Chicago Medical Center — Chicago
• … and 13 more centers

Italy · 7 centers

• Azienda Ospedaliera Universitaria Ospedali Riuniti Umberto — Ancona
• IRCCS Istituto Tumori "G. Paolo II" — Bari
• Fondazione IRCCS Istituto Nazionale dei Tumori — Milan
• Instituto Europeo di Oncologia — Milan
• Instituto Oncologico Veneto — Padova
• Ospedale Santa Maria delle Croci — Ravenna
• Regina Elena Institute for Cancer Research — Rome

Japan · 7 centers

• Kanagawa Cancer Center — Kanagawa
• Okayama University Hospital — Okayama
• Kindai University Hospital — Osaka
• Shizuoka Cancer Center — Shizuoka
• National Cancer Center Hospital — Tokyo
• Cancer Institute Hospital of JFCR — Tokyo
• Wakayama Medical University Hospital — Wakayama

Spain · 5 centers

• Complejo Hospitalario Universitario de A Coruna — A Coruña
• UOMI Cancer Center — Barcelona
• Vall d'Hebron — Barcelona
• Hospital General Universitario Gregorio Maranon — Madrid
• Hospital Universitario 12 de Octubre — Madrid

Canada · 4 centers

• Cross Cancer Institute — Edmonton
• BC Cancer Center — Vancouver
• The Ottawa Hospital Cancer Center — Ottawa
• Princess Margaret Cancer Centre — Toronto

France · 4 centers

• Centre Leon Berard — Lyon
• Chu De Nantes — Nantes
• Institut Claudius Regaud — Toulouse
• Institute Gustave Roussy — Villejuif

Germany · 4 centers

• Universitatsklinikum Koln - University Hospital Cologne — Cologne
• Universitätsklinikum Frankfurt — Frankfurt
• LungenClinic Grosshansdorf GmbH — Großhansdorf
• Universkitatsklinikum Heidelberg - University Hospital Heidelberg — Heidelberg

South Korea · 4 centers

• National Cancer Center — Goyang-si
• Seoul National University Hospital — Seoul
• Severance Hospital Yonsei University Health System — Seoul
• Samsung Medical Center — Seoul

United Kingdom · 4 centers

• Royal Marsden Hospital — Sutton
• Edinburgh Cancer Centre — Edinburgh
• The Royal Marsden - Chelsea — London
• The Christie NHS Foundation Trust — Manchester

Australia · 3 centers

• Royal North Shore Hospital — Sydney
• Princess Alexandra Hospital — Woolloongabba
• Peter MacCallum Cancer Centre — Melbourne

Taiwan · 3 centers

• Chung-Shan Medical University Hospital — Taichung
• National Cheng Kung University Hospital — Tainan
• National Taiwan University Hospital — Taipei

Belgium · 2 centers

• Universitair Ziekenhuis Antwerpen (UZA) — Antwerp
• Universitaire Ziekenhuizen Leuven Campus Gastthuisberg — Leuven

Netherlands · 2 centers

• The Netherlands Cancer Institute — Amsterdam
• University Medical Center Groningen (UMCG) — Groningen

Singapore · 2 centers

• National University Hospital — Singapore
• National Cancer Centre Singapore — Singapore

Switzerland · 2 centers

• Istituto Oncologico Svizzera Italiana — Bellinzona
• Luzerner Kantonsspital — Lucerne

Identifiers

NCT: NCT05384626 · NVL-655-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗