PRIMROSE: A Modular Phase I/IIa, Multi-centre, Dose Escalation, and Expansion Study of AZD3470, a MTA Cooperative PRMT5 Inhibitor, as Monotherapy and in Combination With Anticancer Agents in Patients With Advanced/Metastatic Solid Tumours That Are MTAP Deficient

This first time in human, open-label, multi-centre study of AZD3470 in participants with advanced or metastatic solid tumours with MTAP deficiency follows a modular design. Module 1 will include dose escalation and DDI (Part A) and dose optimisation and expansion (Part B). New modules for combination treatments may be added in the future based on emerging data.

Principal Inclusion Criteria:

• Participant must be at least 18 years of age or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the ICF.
• Willing to provide archival and/or baseline tumour sample to meet the minimum tissue requirement for central MTAP deficiency testing.
• Participants must have received and progressed, are refractory or are intolerant to standard therapy for the specific tumour type. All participants are required to have had at least one prior line of treatment in the recurrent or metastatic setting.
• MTAP deficient tumours defined as evidence of homozygous deletion of one or more exons of the MTAP gene in tumour tissue AND/OR loss of MTAP expression in the tumour tissue.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• A minimum life expectance of 12 weeks in the opinion of the Investigator.
• Participants must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1
• Adequate organ and bone marrow reserve function.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Principal Exclusion Criteria:

• Spinal cord compression or symptomatic and unstable brain metastases or leptomeningeal disease.
• Allogenic organ transplantation.
• Any significant laboratory finding or any severe and uncontrolled medical condition.
• Any of the following cardiac criteria:
• LVEF ≤ 50%
• prior or current cardiomyopathy
• clinically active cardiovascular disease, or a history of myocardial infarction within the last 6 months
• uncontrolled angina or acute coronary syndrome within 6 months
• severe valvular heart disease
• uncontrolled hypertension
• risk of brain perfusion problems. Stroke or transient ischemic attack in the last 6 months, undergone coronary artery bypass graft, angioplasty or vascular stent
• chronic heart failure
• factors that increase the risk of QTc prolongation or risk of arrhythmic events
• Mean resting QTcF > 470 msec or any clinically important abnormalities in rhythm
• Use of therapeutic anti-coagulation for treatment of active thromboembolic events.
• Serologic active hepatitis B or C infection.
• Known to have tested positive for Human immunodeficiency virus (HIV).
• Confirmed or suspected ILD/pneumonitis or history of (non-infectious) ILD/pneumonitis that required oral or IV steroids or supplemental oxygen
• Active gastrointestinal disease or other condition that would interfere with oral therapy.
• History of another primary malignancy.
• Unresolved toxicities from prior anti-cancer therapy, except alopecia and neuropathy.
• Prior treatment with a protein arginine methyltransferase 5 (PRMT5) inhibitor.