A Study of AZD3470, a PRMT5 Inhibitor, Given as Monotherapy and in Combination in Patients With MTAP Deficient Advanced/Metastatic Solid Tumors

Exclusion Criteria

• •NSCLC of mixed histology is allowed if not predominantly squamous; no small cell or large cell neuroendocrine components.
• •Participants meet one of the following:
• •Tumor has a documented EGFR alteration eligible for EGFR-directed therapy (per protocol-defined criteria) and the participant has received prior systemic therapy appropriate for EGFR-altered advanced/metastatic NSCLC (per protocol), OR Tumor is negative for EGFR alterations eligible for EGFR-directed therapy, has no other known actionable genomic alterations for which locally approved/available targeted therapies exist (per protocol-defined criteria), meets any additional protocol-required biomarker criteria for this cohort (as applicable), and the participant has received prior systemic therapy appropriate for non-actionable-alteration advanced/metastatic NSCLC (per protocol).
• •Participants have a history of allogeneic organ transplantation. Participants have any clinically significant abnormal laboratory finding or severe and uncontrolled medical condition that, in the Investigator's opinion, makes participation unsafe, including active infection requiring systemic treatment.
• •Participants have clinically significant cardiovascular disease or risk factors (including reduced LVEF, cardiomyopathy, clinically active cardiovascular disease, recent major ischemic events or revascularization procedures, uncontrolled angina, severe valvular disease, uncontrolled hypertension, clinically significant heart failure, or recent stroke/TA clinically significant ECG abnormalities, prolonged QTc, or conditions/medications that increase risk of QTc prolongation or arrhythmic events)..
• •Participants require therapeutic anticoagulation for treatment of acute thromboembolic events, per protocol.
• •Participants have active hepatitis B or hepatitis C infection (including detectable viral load, per protocol-defined testing).
• •Participants have known HIV infection. Participants have current ILD/pneumonitis, or a history of (non-infectious) ILD/pneumonitis requiring systemic steroids or supplemental oxygen, or suspected ILD/pneumonitis that cannot be ruled out by screening imaging.
• •Participants have active gastrointestinal disease, malabsorption, or other GI condition/surgery that would significantly interfere with oral drug absorption or tolerability.
• •Participants have a history of another primary malignancy. Participants have unresolved clinically significant toxicity from prior anticancer therapy (typically Grade ≥ 2).
• •Participants have had prior treatment with a PRMT5 inhibitor Participants are pregnant, breastfeeding, or intend to become pregnant during study participation.
• •Participants have contraindication to required CNS imaging (brain MRI preferred or CT with contrast).
• •Participants have clinically significant corneal disease. Participants have known active tuberculosis infection, per clinical evaluation and local practice.
• •Participants have significant third-space fluid (e.g., pleural effusion/ascites) not amenable to required repeated drainage, per Investigator judgment.
• •Participants have severe pulmonary function compromise due to intercurrent pulmonary illness (e.g., severe COPD/asthma/restrictive lung disease, recent pulmonary embolism), per protocol.
• •Participants have recent radiotherapy that does not meet protocol-defined washout requirements and/or ongoing radiation-related toxicities requiring corticosteroids.
• •Participants have had prior treatment with protocol-prohibited anticancer therapies.