A Modular Phase I/II, Open-label, Multicentre Study to Evaluate the Safety, Tolerability, and Efficacy of AZD3470, a PRMT5 Inhibitor, as Monotherapy and in Combination With Anticancer Agent(s) in Participants With Relapsed/Refractory Haematologic Malignancies

Description

This study is designed to evaluate the safety, tolerability, PK and preliminary efficacy following oral administration of AZD3470 as a monotherapy, and in combination with other anticancer agents in participants with haematologic malignancies.This is a FTiH modular, Phase I/II, open-label, multicentre, dose escalation and expansion study in participants with r/r haematologic malignancies. The study is designed to evaluate the safety, tolerability, PK and preliminary efficacy following oral administration of AZD3470 as a monotherapy, and in combination with other anticancer agents in participants with haematologic malignancies. This study will follow a modular protocol design evaluating AZD3470 as monotherapy and in combination with other anticancer agents. New cohorts (including further monotherapy expansion) and new modules for combination treatments may be added as protocol amendments in the future based on emerging supportive preclinical and/or clinical data. Module 1 Part A inclu

Trial Eligibility

Inclusion criteria * Adequate organ and bone marrow function. * In Part A (dose escalation), participants must be aged ≥ 18 years at the time of signing the informed consent. In Part B (dose optimization/expansion), participants must be at least 15 years of age. * Histologically confirmed documented diagnosis of r/r cHL based on criteria established by the World Health Organization * Must provide FFPE baseline tumour tissue to meet the minimum tissue requirement for central MTAP expression determination. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Module 1 (cHL): * At least 1 radiographically measurable, and/or FDG-avid lymphoma lesion \> 1.5 cm. * Participants must have documented r/r active disease, must have previously received at least 3 prior lines of therapy (including Brentuximab Vedotin and anti-PD-1 therapy) for the treatment of cHL, and must have exhausted all available therapies with demonstrated clinical benefit. Exclusion criteria * Any significant laboratory finding or any severe and uncontrolled medical condition. * Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord compression. * Serologic active HBV or HCV infection. * Known to have tested positive for HIV. * Active gastrointestinal disease or other condition that will interfere with oral therapy. * Any of the following cardiac criteria: * Mean resting QTcF \> 470 msec or clinically important abnormalities in rhythm (ventricular arrhythmias and uncontrolled atrial fibrillation) * Factors that increase the risk of QTc prolongation or risk of arrhythmic events * Cardiac procedures or conditions within the last 6 months: Coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI) or heart valve intervention vascular stent implantation, acute coronary syndrome / myocardial infarction, uncontrolled angina pectoris, use of therapeutic anti-coagulation for treatment of active thromboembolic events. * Severe valvular heart disease * Congestive heart failure Grade II to Grade IV * Prior or current cardiomyopathy * Uncontrolled hypertension * Brain perfusion problems such as haemorrhagic or thrombotic stroke (including transient ischemic attacks) * Unresolved non-haematological toxicities of Grade \> 1 from prior anticancer therapy (excluding peripheral neuropathy, vitiligo, alopecia, and endocrine disorders that are controlled with replacement hormone therapy, and asymptomatic laboratory abnormalities), unless immune-mediated. * History of another primary malignancy. * History of significant haemoptysis or haemorrhage within 4 weeks of the first dose of study treatment. * Requires ongoing immunosuppressive therapy, including systemic corticosteroids. * Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.

Study Info

Interventions

Locations Recruiting

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