A Study of Zidesamtinib (NVL-520) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1)

Official title

A Phase 1/2 Study of the Highly Selective ROS1 Inhibitor Zidesamtinib (NVL-520) in Patients With Advanced NSCLC and Other Solid Tumors (ARROS-1)

Overview

Phase 1/2, dose escalation and expansion study designed to evaluate the safety and tolerability of zidesamtinib (NVL-520), determine the recommended phase 2 dose (RP2D), and evaluate the antitumor activity in patients with advanced ROS1-positive (ROS1+) NSCLC and other advanced ROS1-positive solid tumors. Phase 1 will determine the RP2D and, if applicable, the maximum tolerated dose (MTD) of zidesamtinib in patients with advanced ROS1-positive solid tumors. Phase 2 will determine the objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR) of zidesamtinib 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 zidesamtinib in patients with advanced ROS1-positive NSCLC and other solid tumors.

Detailed description

In Phase 2, study patients will be enrolled into 5 distinct expansion cohorts:

* Cohort 2a: ROS1-positive NSCLC naïve to Tyrosine Kinase Inhibitor (TKI) therapy and up to 1 prior chemotherapy and/or immunotherapy. * Cohort 2b: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy. * Cohort 2c: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy. * Cohort 2d: ROS1-positive NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy. * Cohort 2e: ROS1-positive solid tumor and progressed on any prior therapy.

Interventions

• Drug Zidesamtinib (NVL-520)
  Oral tablet of zidesamtinib (NVL-520)

Primary outcome measures

• Maximum Tolerated Dose (MTD) (Phase 1) [Time frame: Within 28 days of last patient dosed during dose escalation]
• Recommended Phase 2 Dose (RP2D) [Time frame: Within 28 days of last patient dosed during dose escalation.]
• Objective Response Rate (ORR) (Phase 2) [Time frame: 2-3 years after first patient dosed.]

Secondary outcome measures (12)

• Number of participants with treatment-emergent adverse events, as assessed by CTCAE, v5.0 [Time frame: Approximately 3 years.]
• Maximum plasma concentration (Cmax) of NVL-520 [Time frame: Pre-dose and up to 24 hours post-dose]
• Plasma concentration at the end of the dosing interval (Ctau) of NVL-520 [Time frame: Pre-dose and up to 24 hours post-dose]
• Average plasma concentration (Cavg) of NVL-520 [Time frame: Pre-dose and up to 24 hours post-dose]
• Time of maximum concentration (Tmax) of NVL-520 [Time frame: Pre-dose and up to 24 hours post-dose]
• Area under the curve at the end of the dosing interval (AUCtau) of NVL-520 [Time frame: Pre-dose and up to 24 hours post-dose]
• Area under the curve from time 0 to 24 (AUC0-24) of NVL-520 [Time frame: Pre-dose and up to 24 hours post-dose]
• Area under the curve from time 0 to infinity (AUCinf) of NVL-520 [Time frame: Pre-dose and up to 24 hours post-dose]
• Oral clearance (CL/F) of NVL-520 [Time frame: Pre-dose and up to 24 hours post-dose]
• Volume of distribution (Vz/F) of NVL-520 [Time frame: Pre-dose and up to 24 hours post-dose]
• Half-life (t1/2) of NVL-520 [Time frame: Pre-dose and up to 24 hours post-dose]
• Objective response rate (ORR) [Time frame: 2-3 years after first patient dosed]

Eligibility criteria

Inclusion criteria

• Age ≥18 years (Cohort 2e only: Age ≥12 years).
• Disease Criteria:

• Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ROS1 rearrangement.
• Phase 2: Cohorts 2a, 2b, 2c and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangement.
• Phase 2: Cohort 2e: Histologically or cytologically confirmed locally advanced or metastatic solid tumor (other than NSCLC) with ROS1 rearrangement.
• Prior anticancer treatment (except cohort 2a).
• 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 baseline organ function and bone marrow reserve.

Exclusion criteria

• Patient's cancer has a known oncogenic driver alteration other than ROS1.
• Known allergy/hypersensitivity to excipients of NVL-520.
• Major surgery within 4 weeks of first dose of study drug.
• Ongoing 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 · 20 centers

• UCI Medical Center — Orange
• Stanford Medicine — Palo Alto
• UC Davis Comprehensive Cancer Center — Sacramento
• University of Colorado Cancer Center — Denver
• Georgetown University Medical Center — Washington D.C.
• University of Miami — Coral Gables
• University of Chicago — Chicago
• Mass General Hospital — Boston
• … and 12 more centers

Italy · 7 centers

• Università Politecnica Marche — Ancona
• IRCCS Istituto Tumori Giovanni Paolo II — Bari
• Istituto Europeo di Oncologia — Milan
• Fondazione IRCCS Istituto Nazionale dei Tumori — Milan
• Istituto Oncologico Veneto — Padova
• Ospedale Santa Maria delle Croci — Ravenna
• Istituto Nazionale Tumori Regina Elena — 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
• The Cancer Institute Hospital Of JFCR — Tokyo
• Wakayama Medical University Hospital — Wakayama

Spain · 6 centers

• University Hospital of A Coruña — A Coruña
• UOMI Cancer Center - Clinica Tres Torres — Barcelona
• Vall d'Hebron University Hospital — Barcelona
• Gregorio Marañón Hospital — Madrid
• Hospital Universitario 12 de Octubre — Madrid
• Hospital Universitario HM Sanchinarro — Madrid

France · 4 centers

• Centre Legon Berard — Lyon
• CHU de Nantes — Nantes
• Claudius Regaud Institute — Toulouse
• Institute Gustave Roussy — Villejuif

South Korea · 4 centers

• National Cancer Center — Gyeonggi-do
• Seoul National University Hospital — Seoul
• Yonsei University Health System — Seoul
• Samsung Medical Center — Seoul

Taiwan · 3 centers

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

Australia · 2 centers

• Chris O'Brien Lifehouse — Camperdown
• Peter MacCallum Cancer Centre — Melbourne

Canada · 2 centers

• Cross Cancer Institute — Edmonton
• Princess Margaret Cancer Research — Toronto

Netherlands · 2 centers

• Netherlands Cancer Institute — Amsterdam
• University Medical Centre Groningen — Groningen

Singapore · 2 centers

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

United Kingdom · 2 centers

• Royal Marsden Hospital — London
• Christie NHS Foundation Trust — Manchester

Belgium · 1 center

• University Hospital Leuven — Leuven

Germany · 1 center

• Cologne University Hospital — Cologne

Identifiers

NCT: NCT05118789 · NVL-520-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗