AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies.
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.
Lymphoma
Non-Hodgkin
Hodgkin Lymphoma
Interventional
Description of intervention(s) / exposure
Treatment: Drugs – AZD3470
Experimental: Module 1: Part A (Dose Escalation) and Part B (Dose Expansion/Optimization) – In Part A, participants with Relapsed/Refractory classical Hodgkin Lymphoma (cHL) will take AZD3470 tablets orally until PD, unacceptable toxicity, or withdrawal of consent.
In Part B, adult and adolescent participants with r/r cHL will take AZD3470 tablets orally until PD, unacceptable toxicity, or withdrawal of consent.
Treatment: Drugs: AZD3470
AZD3470 is a novel, potent and selective, second-generation, Methylthioadenosine (MTA)-selective, small molecule inhibitor of PRMT5.
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.
Linear Clinical Research, Perth, Western Australia, 6009
Contact +61 08 6382 5100
cancertrialshaem4@linear.org.au
Professor Chan Cheah
AstraZeneca
Phase 1
D9971C00001
NCT06137144