Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies (PETRA)

Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies

A Modular Phase I/IIa, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of Ascending Doses of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies

This research is designed to determine if experimental treatment with PARP inhibitor, AZD5305, alone, or in combination with anti-cancer agents is safe, tolerable, and has anti-cancer activity in patients with advanced solid tumors.

This study is a Phase I/IIa modular, open-label, multi-center study of AZD5305 administered orally, either as monotherapy or in combination with other anti-cancer agents in patients with advanced solid malignancies.

Ovarian Cancer, Breast Cancer, Pancreatic Cancer, Prostate Cancer, Additional Indications Below for Module 4 and 5, Non-small Cell Lung Cancer, Small Cell Lung Cancer, Colorectal Cancer, Bladder Cancer, Gastric Cancer, Biliary Cancer, Cervical Cancer, Endometrial Cancer

PARP inhibitor, Breast Cancer, Pancreatic Cancer, Prostate Cancer, Ovarian Cancer, AZD5305, T-DXd, Enhertu, Trastuzumab Deruxtecan, Dato-DXd, Datopotamab Deruxtecan, Camizestrant

The study consists of individual modules each evaluating the safety and tolerability of AZD5305 dosed as monotherapy, or with a specific combination partner: Module 1 (AZD5305 monotherapy) Module 2 (AZD5305 in combination with paclitaxel) Module 3 (AZD5305 in combination with carboplatin, with or without paclitaxel) Module 4 (AZD5305 in combination with T DXd) Module 5 (AZD5305 in combination with Dato-DXd). Module 6 (AZD5305 in combination with Camizestrant) Modules 1 and 2 has 2 study parts: Part A consisting of dose-escalation cohorts and Part B, consisting of expansion cohorts. Module 3, Module 4, Module 5 and Module 6 have only PART A.

Number of patients with adverse events and with serious adverse events including abnormal clinical observations, abnormal ECG parameters, abnormal laboratory assessments and abnormal vital signs that changed from baseline

From time of Informed Consent to 28 days post last dose (approximately 1 year). 40 days post last dose for Module 4

A DLT is defined as any toxicity that occurs from the first dose of study treatment (either AZD5305 or combination anti-cancer agent) up to and including the planned end of Cycle 1 (the DLT assessment period) that is assessed as unrelated to the disease or disease-related processes under investigation. DLTs occurring outside the DLT window (ie, late onset toxicities) may be defined as a DLT after consultation with the sponsor and investigators, based on the emerging safety profile.

The concentration of AZD5305 in plasma will be determined. Area under the curve is the integral of the concentration-time curve. The AUC reflects the actual body exposure to drug after administration. The AUC is dependent on the rate of elimination of the drug from the body and the dose administered.

PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment

The concentration of AZD5305 in plasma will be determined. Area under the curve is the integral of the concentration-time curve. The AUC reflects the actual body exposure to drug after administration. The AUC is dependent on the rate of elimination of the drug from the body and the dose administered.

The concentration of AZD5305 in plasma will be determined. Area under the curve is the integral of the concentration-time curve. The AUC reflects the actual body exposure to drug after administration. The AUC is dependent on the rate of elimination of the drug from the body and the dose administered.

The concentration of AZD5305 in plasma will be determined. Area under the curve is the integral of the concentration-time curve. The AUC reflects the actual body exposure to drug after administration. The AUC is dependent on the rate of elimination of the drug from the body and the dose administered.

Samples will be collected within 1 hour before dose administration on Day 1 of Cycle 1, 2, and 4, then every 4 Cycles (each cycle is 21 days), EoT, and at safety follow-up (40 days after last dose) as per Schedule of Assessments

The concentration of AZD5305 in plasma will be determined. Area under the curve is the integral of the concentration-time curve. The AUC reflects the actual body exposure to drug after administration. The AUC is dependent on the rate of elimination of the drug from the body and the dose administered.

Whole blood samples for determination of ADA for Dato-DXd in plasma will be collected in patients receiving Dato-DXd per the schedule specified in the SoA : Day 1 of Cycle 1, 2, 4, and 8 (each cycle is 21 days) , EoT, and then 28 day follow up visit.

Effect on High fat meal on PK parameters of AZD5305.PK parameters, including but not limited to AUC and/or AUC(0-t), Cmax, Tmax, AUC(0-t) and Cmax ratio, with and without food

Cycle 0, Day 1 (C0D1), in either the "fasted" or "fed" state, followed by a single oral dose of AZD5305 in the other state for Cycle 1, Day 1 (C1D1) at least 72 hours later; 1 cycle is 28 days.

Module 6: To characterise the PK of AZD5305 and camizestrant following a single dose and at steady state after multiple dosing, when given in combination.

Plasma concentrations and PK parameters of AZD5305 and camizestrant after single dose and multiple dose administration, including, but not limited to: AUC, Cmax, Tmax, as data allow

PK parameters, including but not limited to AUC and/or AUC(0-t), Cmax, Tmax, AUC(0-t) and Cmax ratio, with and without camizestrant.

PK parameters, including but not limited to AUC and/or AUC(0-t), Cmax, Tmax, AUC(0-t) and Cmax ratio, with and without AZD5305.

Key Inclusion Criteria: Age ≥ 18 at the time of screening Histological or cytological confirmation of advanced malignancy considered to be suitable for study treatment and meeting module specific eligibility criteria.. Eastern Cooperative Oncology Group Performance status (ECOG PS: 0-2) Life expectancy ≥ 12 weeks Progressive cancer at the time of study entry Patients must have evaluable disease as defined in module-specific criteria for Part A and Part B Adequate organ and marrow function as defined by the protocol. For Part B expansion cohorts: Provision of formalin-fixed and paraffin embedded (FFPE) tumour specimen is mandatory, where available, except if stated that it is optional in a specific Module. For Part A: - Patients may have received up to one prior line of therapy with a PARPi-based regimen (either as a treatment or as maintenance) For Part B: - Patients must not have received prior therapy with a PARPi-based regimen (either as a treatment or as maintenance). Key Exclusion Criteria: Treatment with any of the following: Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment Any investigational agents or study drugs from a previous clinical study within 5 half-lives or 3 weeks (whichever is shorter) of the first dose of study treatment Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks of the first dose of study treatment Any live virus or bacterial vaccine within 28 days of the first dose of study treatment Concomitant use of medications or herbal supplements known to be cytochrome P450 3A4 (CYP3A4) strong and moderate inhibitors or inducers. Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of Torsades de Pointes. Receiving continuous corticosteroids at a dose of >10 mg prednisone/day or equivalent for any reason. Major surgery within 4 weeks of the first dose of study treatment. Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study treatment. Any history of persisting (> 2 weeks) severe pancytopenia due to any cause Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring continuous corticosteroids at a dose of >10mg prednisone/day or equivalent for at least 4 weeks prior to start of study treatment. Patients with leptomeningeal carcinomatosis are excluded. patient with known predisposition to bleeding (e.g., active peptic ulceration, recent [within 6 months] haemorrhagic stroke, proliferative diabetic retinopathy). Cardiac conditions as defined by the clinical study protocol Other cardiovascular diseases as defined by any of the following: Symptomatic heart failure, uncontrolled hypertension, hypertensive heart disease with significant left ventricular hypertrophy acute coronary syndrome (ACS)/acute myocardial infarction (AMI), unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 6 months. cardiomyopathy of any etiology presence of clinically significant valvular heart disease history of atrial or ventricular arrhythmia requiring treatment; subjects with atrial fibrillation and optimally controlled ventricular rate (< 100 beats per minute) are permitted. subjects with atrial fibrillation and optimally controlled ventricular rate are permitted transient ischaemic attack, or stroke within 6 months prior to screening patients with symptomatic hypotension at screening Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML). Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5305 Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s). Prior malignancy whose natural history, in the Investigator's opinion, has the potential to interfere with safety and efficacy assessments of the investigational regimen. other module-specific criteria may apply

Illuzzi G, Staniszewska AD, Gill SJ, Pike A, McWilliams L, Critchlow SE, Cronin A, Fawell S, Hawthorne G, Jamal K, Johannes J, Leonard E, Macdonald R, Maglennon G, Nikkila J, O'Connor MJ, Smith A, Southgate H, Wilson J, Yates J, Cosulich S, Leo E. Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper. Clin Cancer Res. 2022 Nov 1;28(21):4724-4736. doi: 10.1158/1078-0432.CCR-22-0301.