A Study to Investigate the Biological Effects of Saruparib (AZD5305), Darolutamide, and in Combination in Men With Newly Diagnosed Prostate Cancer.

Prostate Cancer Clinical Trial

— ASCERTAIN  

Official title:

An Open-label, Randomised, Phase-I, Multi-Centre Study to Investigate the Biological Effects of Saruparib (AZD5305) Alone, Darolutamide Alone, and in Combination Given Prior to Radical Prostatectomy in Men With Newly Diagnosed Prostate Cancer (ASCERTAIN)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05938270
• Other study ID #: D9721C00002
• Status: Recruiting
• Phase: Phase 1
• Start date: September 21, 2023
• Est. completion date: February 25, 2025

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

A Study to Investigate the Biological Effects of Saruparib (AZD5305) Alone, Darolutamide Alone, and in Combination Given Prior to Radical Prostatectomy in Men with Newly Diagnosed Prostate Cancer (ASCERTAIN)

Description:

An Open-label, Randomised, Phase-I, Multi-Centre Study to Investigate the Biological Effects of Saruparib (AZD5305) alone, Darolutamide alone, and in Combination Given Prior to Radical Prostatectomy in Men with Newly Diagnosed Prostate Cancer (ASCERTAIN)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: February 25, 2025
• Est. primary completion date: February 25, 2025
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• male participants >/= 18 years old
• participants deemed suitable for radical prostatectomy
• participants with localised prostate cancer with unfavourable intermediate/high/very high risk eligible for prostatectomy
• adequate organ and marrow function as per protocol
• capable of giving signed informed consent
• provision of signed and dated written Optional Genetic Research Information
• Available FFPE diagnostic tumour biopsy samples
• Participants must use a condom (with spermicide) from screening to 6 months after screening and refrain from fathering a child or donating sperm

Exclusion Criteria:

• As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including, active bleeding diatheses, or active infection including HepB, hepatitis C and HIV. Screening for chronic conditions is not required.

1. Active HBV is defined by a known positive HBsAg result. Participants with a past or resolved HBV infection (defined as the presence of HepB antibody and absence of HBsAg) are eligible.

2. Participants positive for HCV antibody are eligible only if PCR is negative for HCV RNA.

• Participants with any known predisposition to bleeding (eg, active peptic ulceration, recent [within 6 months] haemorrhagic stroke, proliferative diabetic retinopathy).
• Participants with history of MDS/AML or with features suggestive of MDS/AML (as determined by prior diagnostic investigation). Specific screening for MDS/AML not required.
• Prior malignancy within 3 years of screening whose natural history, in the Investigator's opinion, has the potential to interfere with safety and efficacy assessments of the investigational regimen.
• Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of TdP.
• Any of the following cardiac criteria:

1. Mean resting corrected QT interval (QTcF) > 450 milliseconds or QTcF < 340 milliseconds obtained from triplicate ECGs and averaged, recorded within 5 minutes.

2. Any factors that increase the risk of QT prolongation, shortening or risk of arrhythmic events such as hypokalaemia, congenital long or short QT syndrome, family history of long QT syndrome, familial short QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong or shorten the QT interval.

3. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, second or third degree atrioventricular block and clinically significant sinus node dysfunction not treated with pacemaker.

• Other CVS diseases as defined by any of the following:

1. Symptomatic heart failure (as defined by NYHA class = 2).

2. uncontrolled hypertension.

3. hypertensive heart disease with significant left ventricular hypertrophy.

4. History of acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention or coronary artery bypass grafting within 6 months prior to screening.

5. cardiomyopathy of any aetiology.

6. presence of clinically significant valvular heart disease.

7. history of atrial or ventricular arrhythmia requiring acute treatment; participants with atrial fibrillation and optimally controlled ventricular rate (heart rate < 100 bpm) are permitted.

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

9. participants with symptomatic hypotension at screening.

• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of Saruparib (AZD5305).
• History of prior malignancy, treated with chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, or other anticancer agent within 3 years of screening. Previously localised surgically treated malignancy is acceptable, if no evidence of recurrence.
• Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s).
• Prior treatment with any systemic or localised anti-cancer treatment for the localised prostate cancer.
• During the 4 weeks prior to the first dose, receiving immune modulatory agents including but not limited to, continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent.
• Concomitant use of medications or herbal supplements known to be:

1. Strong CYP3A4 inducers/inhibitors (applies for Saruparib (AZD5305) and Saruparib (AZD5305) + darolutamide arms)

2. Strong or moderate CYP3A4 and P-glycoprotein inducers (applies to darolutamide arm and Saruparib (AZD5305) + darolutamide arm) This is including, but not limited to, the prohibited medications listed in CSP Appendix G, or inability to stop the use thereof, at least 21 days or at least 5 half-lives (whichever is longer) before the first dose of study treatment until 30 days after the last dose of study treatment.

• Treatment with any investigational agents or study interventions from a previous clinical study within 5 half-lives or 3 weeks (whichever is longer) of the first dose of study treatment.
• Participants with contraindication to darolutamide for treatment arms
• Unable to comply with the visits and assessments.
• In the opinion of the Investigators should not be included in this study. No treatment arm only: if any participant meets exclusion 4, 9 or 11, they are not to be included in the study.

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Saruparib (AZD5305)
Saruparib (AZD5305) given orally once daily
• Darolutamide
Darolutamide tablet is 300mg, given BD orally, twice daily- total dose 1200mg

Other:
• No Treatment
No study treatment is to be taken by the participants in this arm. Radical prostatectomy should be performed as per local practice

Locations

Country	Name	City	State
Australia	Research Site	Melbourne
Australia	Research Site	South Brisbane
Canada	Research Site	Québec	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Vancouver	British Columbia
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Nijmegen
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Madrid
Spain	Research Site	Valencia
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Newcastle upon Tyne
United States	Research Site	Detroit	Michigan
United States	Research Site	Providence	Rhode Island
United States	Research Site	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Fold change in % ?H2AX positive cells from baseline value in tumour samples	To assess the effects of study treatment on ?H2AX change in participants with localised prostate cancer	Tumour biopsy taken at diagnosis within approx 2 months of Day 1 planned start of study treatment; post treatment tumour biopsy taken following 21 days (+ up to 7 days) of study treatment
Secondary	Severity of Treatment-Emergent AEs/SAEs per CTCAE v5.0	To assess the safety and tolerability of study treatment in participants with localised prostate cancer	Day 1 to 28 days post-surgery
Secondary	Incidence of Treatment-Emergent AEs/SAEs per CTCAE v5.0	To assess the safety and tolerability of study treatment in participants with localised prostate cancer	Day 1 to 28 days post-surgery
Secondary	Number of patients with abnormal laboratory values	To assess the safety and tolerability of study treatment in participants with localised prostate cancer	Day 1 to 28 days post-surgery
Secondary	Change from baseline in blood pressure reported as clinically significant	To assess the safety of study treatment in participants with localised prostate cancer	Day 1 to 28 days post-surgery
Secondary	Change from baseline in heart rate reported as clinically significant	To assess the safety of study treatment in participants with localised prostate cancer	Day 1 to 28 days post-surgery
Secondary	Change from baseline in QTc value	To assess the safety of study treatment in participants with localised prostate cancer	Day 1 to 28 days post-surgery
Secondary	Number of participants undergoing planned surgery	To assess the impact of study treatment on surgical feasibility in participants with localised prostate cancer	Measured based on Day 1 to Day 21 of treatment
Secondary	Reasons of participants requiring treatment-related and non-treatment related delays of surgery and delays > 7 days from scheduled day	To assess the impact of study treatment on surgical feasibility in participants with localised prostate cancer	Measured based on Day 1 to Day 21 of treatment
Secondary	Number of participants requiring treatment-related and non-treatment related delays of surgery and delays > 7 days from scheduled day	To assess the impact of study treatment on surgical feasibility in participants with localised prostate cancer	Measured based on Day 1 to Day 21 of treatment
Secondary	Change in Ki-67 % positive cells from baseline in tumour samples	To assess the effects of study treatment on Ki-67 change in participants with localised prostate cancer	Measured based on Day 1 to Day 21 of treatment