Phase I/IIa Study of AZD5335 as Monotherapy and Combination Therapy in Participants With Solid Tumors

Core Inclusion Criteria:

• Capable of giving signed informed consent, which includes compliance with therequirements and restrictions listed in the ICF and in this protocol.

• Provision of signed and dated written Optional Genetic Research Information informedconsent prior to collection of samples for optional genetic research that supportsGenomic Initiative. Participants who do not provide informed consent for OptionalGenetic Research may still be enrolled in the study.

• Participant must be ≥ 18 years at the time of signing the informed consent.

• Willing to provide adequate archival and/or baseline tumor sample as applicable permodule-specific criteria.

• For participants who have previously received targeted therapies such as ADCs, afresh baseline biopsy will be required unless the most recent archival tissue samplewas collected after receipt of such treatment.

• Eastern Cooperative Oncology Group Performance Status of 0 or 1.

• 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 trial is the best option for the nexttreatment based on response and/or tolerability to prior therapy. Participants withcontraindications or who refuse therapy in accordance with local practice may alsobe considered provided that it is documented that he/she was informed about alltherapeutic options.

• Participants must have measurable disease per RECIST v1.1,

1. A previously irradiated lesion can be considered a target lesion if the lesionis progressing and well defined.

2. For participants who undergo biopsies at screening and/or on treatment, it ispreferred though not required, that the biopsied lesion, be distinct from anytarget lesion used in the RECIST v1.1 evaluation.

• Life expectancy ≥ 12 weeks.

• Adequate organ and marrow function.

• Contraceptive use by men or women should be consistent with local regulationsregarding the methods of contraception for those participating in clinical studies.

(a) Male participants: (i) Male participants who are sexually active with a femalepartner of childbearing potential must use a male condom (plus an additionalcontraceptive method) post-screening through 5 months following the last dose ofstudy intervention. It is strongly recommended for the female partner of a maleparticipant to also use a highly effective method of contraception throughout thisperiod. In addition, male participants must refrain from freezing or donating spermwhile on study and for 5 months following the last dose of study intervention.

(b) Female participants: (i) Females of childbearing potential must have a negativeurine or serum pregnancy test within 72 hours prior to receiving the first dose ofstudy intervention and a negative urine or serum pregnancy test prior to startingtheir next cycle of treatment. If the urine test is positive or cannot be confirmedas negative, a serum pregnancy test will be required.

(ii) (ii) Sex and Contraceptive/Barrier Requirements: Highly effective birth control methods include: Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments) [(periodic abstinence e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to study intervention, and withdrawal are not acceptable methods of contraception], a vasectomized partner, Implanon®, bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, Depo Provera™ injections, oral contraceptive associated with inhibition of ovulation, and Evra Patch™, Xulane™, or NuvaRing®.

Female participants of childbearing potential who are sexually active with a non-sterilized male partner must agree to use one highly effective method of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly), from enrolment throughout the study and for 8 months following the last dose of study intervention. The male partner of a female participant of childbearing potential must also use a male condom (plus spermicide, if available) throughout this period. Cessation of contraception after this point should be discussed with a responsible physician. In addition, female participants must not donate or retrieve for their own use, ova while on study and for 8 months following the last dose of study intervention.

Core Exclusion Criteria:

• Patients with spinal cord compression or a history of leptomeningeal carcinomatosis.

• Patients with brain metastases unless, asymptomatic, stable, and not requiringcontinuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for atleast 4 weeks prior to first dose of study intervention.

• Treatment with any of the protocol defined medications, without adequate washoutperiods or time before the first dose of study intervention.

• Unresolved toxicities of Grade ≥ 2 (National Cancer Institute [NCI] CTCAE v5.0) fromprior therapy (excluding vitiligo, alopecia, and endocrine disorders that arecontrolled with replacement hormone therapy). Participants with stable ≤ Grade 2neuropathy are eligible.

• Active infection, including tuberculosis and infections with hepatitis B virus (HBV;verified by known positive hepatitis B surface antigen [HBsAg] result), hepatitis Cvirus (HCV) or known HIV infection that is not well controlled. All of the followingcriteria are required to define an HIV infection that is well controlled:undetectable viral RNA, CD4+ count ≥ 350/mm3, no history of acquired immunedeficiency syndrome-defining opportunistic infection within the past 12 months, andstable for at least 4 weeks on the same anti-HIV medications (meaning there are noexpected further changes in that time to the number or type of antiretroviral drugsin the regimen).

Patients with a past or resolved HBV/HCV infection are eligible if:

1. Negative for HBsAg and positive for anti-hepatitis B virus core protein (HBc) or

2. Are HBsAg + with chronic HBV infection (lasting 6 months or longer) and meetconditions i-iii below:

(i) HBV DNA viral load <100 IU/mL. (ii) Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) <3 x upper limit of normal (ULN), which are not attributable to HBV infection.

(iii) Start or maintain antiviral treatment if clinically indicated as per the Investigator or as per local guideline.

Note for Japan: Japanese patients with positive anti-HBs/anti-HBc and negative HBsAg will be assessed following local guidelines.

(c) Participants testing positive for HCV antibody are eligible only if the polymerase chain reaction test result is negative for HCV RNA.

• Patient has ILD/pneumonitis or has a history of (non-infectious) ILD/pneumonitisthat required oral or IV steroids or supplemental oxygen, or where suspectedILD/pneumonitis cannot be ruled out by imaging at screening.

• Patients with a history of radiation pneumonitis which has clinically andradiologically resolved and not requiring treatment with steroids may beeligible.

• History of another malignancy except for:

• Malignancy treated with curative intent and with no known active disease for atleast 2 years prior to screening of study intervention and with low potentialrisk for recurrence.

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.

• Adequately treated carcinoma in situ without evidence of disease.

• Localized non-invasive solid organ primary disease under surveillance.

• Patients with any of the following cardiac criteria:

• History of arrhythmia (such as multifocal premature ventricular contractions,bigeminy, trigeminy, and ventricular tachycardia), which is symptomatic orrequires treatment NCI CTCAE v5.0 Grade 3 except for: (i) Rate controlled asymptomatic atrial fibrillation.

• NOTE: significant abnormalities in serum electrolytes that can increasethe risk of arrhythmic events (ie, sodium, potassium, calcium, andmagnesium) should be corrected before starting the study intervention.

• Uncontrolled hypertension.

• Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris,coronary intervention procedure with percutaneous coronary intervention, orcoronary artery bypass grafting within 6 months of screening.

• History of brain perfusion problems (eg, carotid stenosis) or stroke, ortransient ischemic attack in the last 6 months prior to screening.

• Symptomatic heart failure (as defined by New York Heart Association class ≥ 2).

• Prior or current diagnosis of cardiomyopathy considered clinically relevant perinvestigator's judgement.

• Severe uncorrected valvular heart disease.

• Mean resting QTcF > 470 msec obtained from triplicate electrocardiograms (ECGs)and averaged, recorded within 5 minutes.

• Any factor that, in the opinion of the investigator, increases theproarrhythmic risk of QT prolongation, such as congenital long QT syndrome,family history of long QT syndrome, hypertrophic cardiomyopathy, or unexplainedsudden cardiac death under 40 years of age.

• Uncontrolled and/or unresolved intercurrent illness within 12 months prior toscreening, including but not limited to serious chronic gastrointestinal conditionsassociated with diarrhea, or illness (including psychiatric illness) and/or socialsituations, in the opinion of the investigator, that would limit compliance withstudy requirements and activities, substantially increase risk of incurring AEs orcompromise the ability of the participant to give written informed consent.

• Substance abuse or any other medical conditions that would increase the safety riskto the participant or interfere with participation of the participant or evaluationof the clinical study in the opinion of the Investigator.

• Receipt of live attenuated vaccine within 30 days prior to the first dose of studyintervention. Note: Participants, if enrolled, should not receive live vaccinewhilst receiving study intervention and up to 3 months after the last dose of studyintervention. Participants can receive Coronavirus (COVID)-19 vaccines, at thediscretion of the Investigator, following a benefit/risk evaluation for theindividual participant and in accordance with local rules and regulations andvaccination guidelines. Note: If a COVID-19 vaccine is administered it should bedone > 72 hours prior to study intervention initiation or after completion of theDLT period.

• For women only - currently pregnant (confirmed with positive pregnancy test orsuspected), lactating, breastfeeding, or intention to become pregnant during thestudy period.

• Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventionalstudy.

• Patients with a known hypersensitivity to study intervention or any of theexcipients of the product.

• Involvement in the planning and/or conduct of the study (applies to both AstraZenecastaff and/or staff at the study site).

• Judgment by the Investigator that the patient should not participate in the study ifthe patient is unlikely to comply with study procedures, restrictions andrequirements.

• Previous enrolment in the present study. **Other module specific criteria may apply