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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: AZD5305
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: T- Dxd
* Drug: Dato-DXd
* Drug: Camizestrant


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 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 4 has 2 study parts: Part A consisting of dose-escalation cohorts and Part B, consisting of expansion cohorts. Modules 2, 3, 5 and 6 have only PART A.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module 1: AZD5305 Monotherapy<br>AZD5305 Monotherapy | Drug: AZD5305<br>* Oral PARP inhibitor<br>|
| Experimental: Module 2: AZD5305 + Paclitaxel<br>AZD5305 + Paclitaxel | Drug: AZD5305<br>* Oral PARP inhibitor<br>Drug: Paclitaxel<br>* IV Anti-microtubule agent<br>|
| Experimental: Module 3: AZD5305 + Carboplatin with or without Paclitaxel<br>AZD5305 + Carboplatin with or without Paclitaxel | Drug: AZD5305<br>* Oral PARP inhibitor<br>Drug: Paclitaxel<br>* IV Anti-microtubule agent<br>Drug: Carboplatin<br>* IV Platinum chemotherapeutic<br>|
| Experimental: Module 4: AZD5305 + Trastuzumab Deruxtecan<br>AZD5305 + T- DXd | Drug: AZD5305<br>* Oral PARP inhibitor<br>Drug: T- Dxd<br>* IV Antibody-drug conjugate<br>|
| Experimental: Module 5 AZD5305 + Datopotamab Deruxtecan<br>AZD5305 + Dato-DXd | Drug: AZD5305<br>* Oral PARP inhibitor<br>Drug: Dato-DXd<br>* IV Antibody-drug conjugate<br>|
| Experimental: Module 6 AZD5305 + Camizestrant<br>AZD5305 + Camizestrant | Drug: AZD5305<br>* Oral PARP inhibitor<br>Drug: Camizestrant<br>* Oral SERD Molecule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of subjects with adverse events/serious adverse events | 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 + 7 days post last dose ( modules 1,2,3,5 and 6). 40+7 days post last dose for Module 4. | 
| The number of subjects with dose-limiting toxicity (DLT), as defined in the protocol. | 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. | From first dose of study treatment until the end of Cycle 1. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best percentage change in target lesion | Change in target lesion size from baseline, as defined by RECIST 1.1. | From Screening to confirmed progressive disease (approximately 1 year) | 
| Objective Response Rate | Best response until progression, as defined by RECIST 1.1. | From Screening to confirmed progressive disease (approximately 1 year) | 
| Duration of Response | Time from first response to progression or death , as defined by RECIST 1.1. | From Screening to confirmed progressive disease (approximately 1 year) | 
| Progression Free Survival | Time from C1D1 to progression or death, as defined by RECIST 1.1. | From Screening to confirmed progressive disease (approximately 1 year) | 
| Time To Response | Time from C1D1 to complete or partial response, as defined by RECIST 1.1. | From Screening to confirmed progressive disease (approximately 1 year) | 
| Effects of AZD5305 on pH2AX (Ser139) PD biomarker | Measure change from baseline in pH2AX | From Cycle 0 Day 1 to Cycle 1 Day 15 (approximately 21 days) | 
| CA125 response (ovarian cancer) | at least a 50% reduction in CA125 levels from a pre-treatment sample as defined by GCIG criteria. | From Screening to confirmed progressive disease (approximately 1 year) | 
| Module 1: Area Under Curve (AUC) | 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. | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 1: Maximum plasma concentration of the drug (Cmax) | The concentration of AZD5305 in plasma will be determined (Cmax will be derived). | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 1: The time taken to reach the maximum concentration (Tmax) | The concentration of AZD5305 in plasma will be determined (Tmax will be derived). | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 1 and Module 5: Objective Response Rate (prostate cancer) | Best response until progression, as defined by RECIST 1.1 or PCWG3 (bone) | From Screening to confirmed progressive disease (approximately 1 year) | 
| Module 1: Radiographic progression free survival (prostate cancer) | Time from C1D1 to progression or death, as defined by RECIST 1.1 and PCWG3(bone). | From Screening to confirmed progressive disease (approximately 1 year) | 
| Module 1: Proportion of subjects with ≥ 50% PSA decrease (prostate cancer) | PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment | From Screening to confirmed progressive disease (approximately 1 year) | 
| Module 1 : To investigate the effect of a high-fat meal on the PK of AZD5305 | 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 2: Area Under Curve (AUC) | 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. | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 2: Maximum plasma concentration of the drug (Cmax) | The concentration of AZD5305 in plasma will be determined (Cmax will be derived). | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 2: The time taken to reach the maximum concentration (Tmax) | The concentration of AZD5305 in plasma will be determined (Tmax will be derived). | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 3: Area Under Curve (AUC) | 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. | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 3: Maximum plasma concentration of the drug (Cmax) | The concentration of AZD5305 in plasma will be determined (Cmax will be derived). | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 3: The time taken to reach the maximum concentration (Tmax) | The concentration of AZD5305 in plasma will be determined (Tmax will be derived). | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 4 : Area Under Curve | 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. | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 4: Maximum plasma concentration of the drug (Cmax) | The concentration of AZD5305 in plasma will be determined (Cmax will be derived). | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 4: The time taken to reach the maximum concentration (Tmax) | The concentration of AZD5305 in plasma will be determined (Tmax will be derived). | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 4: Anti-Drug Antibody (ADA) | To investigate the presence of ADAs for T-DXd | 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 | 
| Module 4: To assess the preliminary anti-tumour activity of AZD5305 as monotherapy and in combination with T-DXd. | Time from C1D1 to progression or death, as defined by RECIST v 1.1 summarised at the 6 month landmark (PFS6) | From screening to approximately 6 months | 
| Module 5: Area Under Curve | 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. | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 5: Maximum plasma concentration of the drug (Cmax) | The concentration of AZD5305 in plasma will be determined (Cmax will be derived). | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 5: The time taken to reach the maximum concentration (Tmax) | The concentration of AZD5305 in plasma will be determined (Tmax will be derived). | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 5: Anti-Drug Antibody (ADA) | Presence of ADAs for Dato-DXd | 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. | 
| Module 5: Premilinary anti tumour activity AZD5305 in combination with | objective response rate and radiographic progression-free survival using RECIST v1.1. Proportion of patients achieving a ≥ 50% decrease in PSA from baseline to the post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later (PSA50 response). | From screening to confirmed progresive disease ( approximately 12 weeks) | 
| 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 | At predefined interval throughout the treatment (approximately 12 weeks) | 
| Module 6: To evaluate the effect of camizestrant on the PK 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 camizestrant. | At predefined intervals throughout the treatment period (approximately 12 weeks) | 
| Module 6: To evaluate the effect of AZD5305 on the PK of 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. | At predefined intervals throughout the treatment period (approximately 12 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PARP inhibitor, Breast Cancer, Pancreatic Cancer, Prostate Cancer, Ovarian Cancer, AZD5305, T-DXd, Enhertu, Trastuzumab Deruxtecan, Dato-DXd, Datopotamab Deruxtecan, Camizestrant