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

Breast Cancer Clinical Trial

— PETRA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04644068
• Other study ID #: D9720C00001
• Secondary ID: 2020-002688-77
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 12, 2020
• Est. completion date: December 15, 2026

Study information

• Verified date: May 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 804
• Est. completion date: December 15, 2026
• Est. primary completion date: December 15, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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:

1. Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment

2. 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

3. Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks of the first dose of study treatment

4. 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:

1. Symptomatic heart failure,

2. uncontrolled hypertension,

3. hypertensive heart disease with significant left ventricular hypertrophy

4. 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.

5. cardiomyopathy of any etiology

6. presence of clinically significant valvular heart disease

7. history of atrial or ventricular arrhythmia requiring treatment; subjects with atrial fibrillation and optimally controlled ventricular rate (< 100 beats per minute) are permitted.

8. subjects with atrial fibrillation and optimally controlled ventricular rate are permitted

9. transient ischaemic attack, or stroke within 6 months prior to screening

10. 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

Related Conditions & MeSH terms

• Biliary Cancer
• Bladder Cancer
• Breast Cancer
• Cervical Cancer
• Colorectal Cancer
• Endometrial Cancer
• Endometrial Neoplasms
• Gastric Cancer
• Lung Neoplasms
• Non-small Cell Lung Cancer
• Ovarian Cancer
• Ovarian Neoplasms
• Pancreatic Cancer
• Pancreatic Neoplasms
• Prostate Cancer
• Prostatic Neoplasms
• Small Cell Lung Carcinoma

Intervention

Drug:
• AZD5305
Oral PARP inhibitor
• Paclitaxel
IV Anti-microtubule agent
• Carboplatin
IV Platinum chemotherapeutic
• T- Dxd
IV Antibody-drug conjugate
• Dato-DXd
IV Antibody-drug conjugate
• Camizestrant
Oral SERD Molecule

Locations

Country	Name	City	State
Australia	Research Site	Heidelberg
Australia	Research Site	Melbourne
Canada	Research Site	Kelowna	British Columbia
Canada	Research Site	London	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Vancouver	British Columbia
China	Research Site	Beijing
China	Research Site	Changchun
China	Research Site	Changsha
China	Research Site	Changsha
China	Research Site	Chengdu
China	Research Site	Chongqing
China	Research Site	Guangzhou
China	Research Site	Harbin
China	Research Site	Jining
China	Research Site	Shandong
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Taiyuan
China	Research Site	Wuhan
China	Research Site	Wuhan
China	Research Site	Xi'an
Czechia	Research Site	Brno
Czechia	Research Site	Olomouc
Czechia	Research Site	Praha
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Italy	Research Site	Milan
Italy	Research Site	Milano
Italy	Research Site	Modena
Italy	Research Site	Napoli
Italy	Research Site	Padova
Italy	Research Site	Roma
Japan	Research Site	Chuo-ku
Japan	Research Site	Koto-ku
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Poland	Research Site	Bydgoszcz
Poland	Research Site	Gdansk
Poland	Research Site	Gdynia
Poland	Research Site	Gliwice
Poland	Research Site	Grzepnica
Poland	Research Site	Kraków
Poland	Research Site	Lódz
Poland	Research Site	Lublin
Poland	Research Site	Torun
Poland	Research Site	Warszawa
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Spain	Research Site	Barcelona
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Málaga
Spain	Research Site	Pozuelo de Alarcon
Spain	Research Site	Sevilla
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Oxford
United Kingdom	Research Site	Sutton
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boston	Massachusetts
United States	Research Site	Houston	Texas
United States	Research Site	New York	New York
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Australia,  Canada,  China,  Czechia,  Hungary,  Italy,  Japan,  Korea, Republic of,  Poland,  Russian Federation,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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	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)
Secondary	Objective Response Rate	Best response until progression, as defined by RECIST 1.1.	From Screening to confirmed progressive disease (approximately 1 year)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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.
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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.
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

External Links

•   BreastCancerStudyLocator.com