Phase I/IIa Study of AZD5335 as monotherapy and combination therapy in participants with solid tumors - FONTANA

Exclusion Criteria

• - Patients with spinal cord compression or a history of leptomeningeal carcinomatosis.
• - Patients with brain metastases unless, asymptomatic, stable, and not requiring continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for at least 4 weeks prior to first dose of study intervention.
• - Treatment with any of the protocol defined medications, without adequate washout periods or time before the first dose of study intervention.
• - Unresolved toxicities of Grade ≥ 2 (National Cancer Institute [NCI] CTCAE v5.0) from prior therapy (excluding vitiligo, alopecia, and endocrine disorders that are controlled with replacement hormone therapy). Participants with stable ≤ Grade 2 neuropathy are eligible.
• - Active infection, including tuberculosis and infections with hepatitis B virus (HBV; verified by known positive hepatitis B surface antigen [HBsAg] result), hepatitis C virus (HCV) or known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count ≥ 350/mm3, no history of acquired immune deficiency syndrome-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen).
• Patients with a past or resolved HBV/HCV infection are eligible if:
• (a) Negative for HBsAg and positive for anti-hepatitis B virus core protein (HBc) or
• (b) Are HBsAg + with chronic HBV infection (lasting 6 months or longer) and meet conditions 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 AST/ALT <3 × 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/pneumonitis that required oral or IV steroids or supplemental oxygen, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• • Patients with a history of radiation pneumonitis which has clinically and radiologically resolved and not requiring treatment with steroids may be eligible.
• - History of another primary malignancy except for:
• • Malignancy treated with curative intent and with no known active disease for at least 2 years prior to screening of study intervention and with low potential risk for recurrence.
• • Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease.
• • Adequately treated carcinoma in situ without evidence of disease.
• • Localized non-invasive 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 or requires treatment (NCI CTCAE v5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.
• o NOTE: significant abnormalities in serum electrolytes that can increase the risk of arrhythmic events (ie, sodium, potassium, calcium, and magnesium) 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, or coronary artery bypass grafting within 6 months of screening.
• • History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient 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 cardiomyopathy.
• • Severe valvular heart disease.
• • Mean resting QTcF > 470 msec obtained from triplicate electrocardiograms (ECGs) and averaged, recorded within 5 minutes.
• • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
• - Uncontrolled intercurrent illness within 12 months prior to screening, including but not limited to serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements and activities, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent.
• - Substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the Investigator.
• - Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live vaccine whilst receiving study intervention and up to 3 months after the last dose of study intervention. Participants can receive Coronavirus (COVID)-19 vaccines, at the discretion of the Investigator, following a benefit/risk evaluation for the individual participant and in accordance with local rules and regulations and vaccination guidelines. Note: If a COVID-19 vaccine is administered it should be done > 72 hours prior to study intervention initiation or after completion of the DLT period.
• - For women only – currently pregnant (confirmed with positive pregnancy test), lactating, breastfeeding, or intend to become pregnant during the study period.
• - Concurrent enrolment in another clinical study, unless it is an observational (non interventional) clinical study or during the follow-up period of an interventional study.
• - Patients with a known hypersensitivity to study intervention or any of the excipients of the product.
• - Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• - Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• - Previous enrolment in the present study.
• **Other module specific criteria may apply