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

Официальное название

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)

Обзор

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

Подробное описание

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.

Вмешательства

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

Первичные конечные точки

• Dose limiting toxicities (DLTs) (Phase 1) [Срок оценки: Within the first 21 days of the first neladalkib (NVL-655) dose]
• Recommended Phase 2 Dose (RP2D) (Phase 1) [Срок оценки: Within 21 days of last patient dosed during escalation]
• Objective Response Rate (ORR) (Phase 2) [Срок оценки: 2-3 years after first patient dosed.]
• Number of participants with treatment-emergent adverse events, as assessed by CTCAE, V5.0 (Phase 1) [Срок оценки: Approximately 3 years]
• Area under the curve of repaglinide (Phase 2 DDI sub-study) [Срок оценки: Pre-dose and up to 24 hours post-dose]
• Area under the curve of midazolam (Phase 2 DDI sub-study) [Срок оценки: Pre-dose and up to 24 hours post-dose]
• Area under the curve of neladalkib (NVL-655) (Phase 2 DDI sub-study) [Срок оценки: Pre-dose and up to 24 hours post-dose]

Вторичные конечные точки (12)

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

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 21 центр

• 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
• … и ещё 13 центров

Италия · 7 центров

• 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

Япония · 7 центров

• 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

Испания · 5 центров

• 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

Канада · 4 центра

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

Франция · 4 центра

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

Германия · 4 центра

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

South Korea · 4 центра

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

Великобритания · 4 центра

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

Австралия · 3 центра

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

Тайвань · 3 центра

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

Бельгия · 2 центра

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

Нидерланды · 2 центра

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

Сингапур · 2 центра

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

Швейцария · 2 центра

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

Идентификаторы

NCT: NCT05384626 · NVL-655-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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