A First-in-human Dose Escalation and Expansion Study to Evaluate the Safety, and Tolerability of AZD8421 Alone or in Combination in Participants With Selected Advanced or Metastatic Solid Tumors

Inclusion Criteria:

• Female participants only, aged 18 or above

• Participants with advanced solid tumors must have received prior adequate therapy inaccordance with local practice for their tumor type and stage of disease, or, in theopinion of the Investigator, a clinical study is the best option for their nexttreatment based on response to and/or tolerability of prior therapy.

• Metastatic or locoregionally recurrent disease and radiological or objectiveevidence of progression on or after the last systemic therapy prior to starting IMP.

• ECOG/WHO performance status 0 to 1, and a minimum life expectancy of 12 weeks.

• At least one lesion that is measurable and/or non-measurable, as per RECIST v1.1 andthat can be accurately assessed at baseline and is suitable for repeated assessment.

Exclusion Criteria:

• Intervention with any of the following:

• Any cytotoxic chemotherapy, investigational agents, or other anti-cancer drugs forthe treatment of advanced cancer from a previous treatment regimen or clinical studywithin 14 days or 5 half-lives (whichever is shorter) of the first dose of IMP (21days for myelosuppressive therapies) other than GnRHa (eg, goserelin) andbone-stabilizing agents (eg, zoledronic acid, denosumab).

• Any prescription or non-prescription drugs or other products, including herbalproducts, known to be moderate or strong inhibitors/inducers of CYP3A4/5 whichcannot be discontinued prior to first dose of IMP and withheld throughout the studyuntil 2 weeks after the last dose of study drug.

• Drugs that have a known risk of Torsades de Pointes.

• Radiotherapy with a limited field of radiation for palliation within 1 week of thefirst dose of IMP.

• Major surgical procedure or significant traumatic injury, within 4 weeks of thefirst dose of IMP, or an anticipated need for major surgery and/or any surgeryrequiring general anesthesia during the study.

• Any unresolved toxicities of Grade ≥ 2 from prior anti-cancer therapy (with theexception of alopecia). Participants with stable ≤ Grade 2 neuropathy are eligible.

• Presence of life-threatening metastatic visceral disease, as judged by theInvestigator, uncontrolled CNS metastatic disease. Participants with spinal cordcompression and/or brain metastases may be enrolled if definitively treated (eg,surgery or radiotherapy) and stable off steroids for at least 4 weeks prior to startof IMP.

• Any evidence of severe or uncontrolled systemic diseases, including uncontrolledhypertension and active bleeding diatheses, or eg, infection requiring IV antibiotictherapy, or active infection including hepatitis B, hepatitis C, and HIV (activeviral infection is defined as requiring antiviral therapy; screening for chronicconditions is not required).

• Any of the following cardiac criteria:

• Mean resting QTcF > 470 msec obtained from a triplicate ECG

• Any clinically important abnormalities in rhythm, conduction, or morphology ofresting ECG (eg, complete left bundle branch block, second- and third-degree heartblock), or clinically significant sinus pause. Participants with controlled atrialfibrillation can be enrolled.

• Any factors that increase the risk of QTc prolongation or risk of arrhythmic eventssuch as symptomatic heart failure, hypokalemia, congenital long QT syndrome,immediate family history of long QT syndrome or unexplained sudden death at < 40years of age. Hypertrophic cardiomyopathy and clinically significant stenotic valvedisease.

• LVEF < 50%, and/or experience of any of the following procedures or conditions inthe preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent,myocardial infarction, unstable angina pectoris, congestive heart failure NYHA Grade ≥ 2, cerebrovascular accident, or transient ischemic attack.

• Uncontrolled hypertension.

• Inadequate bone marrow reserve or organ function as demonstrated by relevantlaboratory values:

• Refractory nausea and vomiting, uncontrolled chronic gastrointestinal diseases, orprevious significant bowel resection that would preclude adequate absorption ofIMP(s).

• History of hypersensitivity to active or inactive excipients of AZD8421 or drugswith a similar chemical structure or class to AZD8421.

• Previous treatment with AZD8421 or with any CDK2-selective inhibitor, or proteinkinase membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase 1 (PKMYT1) inhibitor, or WEE1 inhibitor.

• Currently pregnant (confirmed with positive pregnancy test), breast feeding, orplanning to become pregnant. Participants of childbearing potential must agree touse one highly effective contraceptive measure.