Study to Determine the Safety and Pharmacokinetics of DO-2 in Patients With Advanced or Refractory Solid Tumours

Official title

A Phase 1 Study to Determine the Safety, and Pharmacokinetics of the Selective MET Kinase Inhibitor, DO-2 in Patients With Advanced or Refractory Solid Tumours

Overview

This study is a first-in-human, open-label, 2-part, Phase 1 dose escalation study of DO-2, administered orally to patients with advanced or refractory solid tumours, with MET aberrations, and no available, approved therapeutic alternative. The dose escalation is completed, Part 2 of the study is ongoing.

Detailed description

In Part 1, a Simon Design 3 accelerated titration design will be followed. One patient will be enrolled per cohort, until grade 2 toxicity is observed. Three sequential patients per cohort will be enrolled thereafter, with a minimum of 1 week between first dose administration in the first patient and the subsequent ones, in those latter cohorts.

In part 2, up to 30 evaluable patients with locally advanced, unresectable or metastatic non-small-cell cancer (NSCLC), no longer eligible for approved, available standard therapies and having tumour harbouring MET exon14 skipping mutation from an assessment not older than 3 months, will received DO-2 at the selected dose.

Interventions

• Drug DO-2
  Deuterated MET kinase inhibitor

Primary outcome measures

• Number of subjects who experience specific treatment-related adverse events (TRAEs) [Time frame: Baseline through study completion, an average of 12 months]

Secondary outcome measures (5)

• Objective responses rate (ORR) [Time frame: Baseline through study completion, an average of 12 months]
• Duration of response (DoR) [Time frame: Baseline through study completion, an average of 12 months]
• Disease Control Rate (DCR) [Time frame: Baseline through study completion, an average of 12 months]
• Progression-free survival (PFS) [Time frame: Baseline through study completion, an average of 12 months]
• Overall survival (OS) [Time frame: Baseline through study completion, an average of 12 months]

Eligibility criteria

Inclusion criteria

• 18 years or older
• histologically or cytologically confirmed locally advanced, unresectable or metastatic NSCLC, no longer eligible for approved, available standard therapies. To be entered patients must have proven MET exon 14 skipping mutation, determined by local next generation sequencing (NGS), whole exome sequencing (WES), whole transcriptome sequencing (WTS) or other genomic analysis methods, from an assessment not older than 3 months
• measurable disease in accordance with RECIST 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• adequate bone marrow function, without the support of cytokines
• adequate liver function
• adequate renal function with serum creatinine <1 x institutional UNL and GFR within normal range
• agree to follow the contraception requirements of the trial
• signed informed consent, indicating study patients understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion criteria

• tumour harbouring other known oncogenic mutations promoting tumour growth
• major surgery within 3 weeks before enrolment
• chemotherapy (in the case of nitrosoureas and mitomycin C within 6 weeks), radiotherapy, immunotherapy, or any other study drug within 3 weeks before study drug administration
• antibody based cancer therapy within 4 weeks before administration of the first dose of DO-2
• patients who became progressive on previous treatment with a MET-kinase inhibitor
• patients with brain metastases are excluded unless all of the following criteria are met:

• CNS lesions are asymptomatic and previously treated
• No ongoing requirement for corticosteroids as therapy for CNS metastases
• Imaging demonstrates stability of disease > 28 days from last treatment for CNS metastases
• leptomeningeal involvement (leptomeningeal carcinomatosis)
• history of uncontrolled heart disease including unstable angina, congestive heart failure, myocardial infarction within preceding 12 months, clinically significant rhythm or conduction abnormality, congenital long QT syndrome, obligate use of a cardiac pacemaker, QTc at screening greater than 450 milliseconds in males and greater than 470 milliseconds in females
• uncontrolled arterial hypertension despite appropriate therapy
• positive pregnancy test (urinary beta-hCG) at screening (applicable to women of child-bearing potential who are sexually active)
• mental status alteration or history of major psychiatric illness, which may potentially impair patient's compliance with study procedures
• signs and symptoms of active infection requiring systemic therapy
• other medical condition (e.g. pre-existing kidney dysfunction) that in the opinion of the investigator makes it undesirable for a patient to participate
• inability or unwillingness to swallow capsules and malabsorption syndrome or other condition that would interfere with enteral absorption

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

France · 7 centers

• Institut Bergonie — Bordeaux
• Institut Cœur Poumon - CHU Lille — Lille
• Centre Léon Bérard — Lyon
• Hôpitaux Universitaires de Marseille Timone — Marseille
• Centre Antoine Lacassagne — Nice
• Centre Hospitalier Universitaire De Rennes — Rennes
• Institut Gustave Roussy — Villejuif

Belgium · 4 centers

• Institut Roi Albert II - UC Louvain — Brussels
• UZA — Edegem
• Universitair Ziekenhuis Gent — Ghent
• UZ Leuven — Leuven

Netherlands · 2 centers

• Radboud UMC — Nijmegen
• Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC) — Rotterdam

Identifiers

NCT: NCT05752552 · DO2.22.01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗