Clinical trial NCT05938270: A Study to Investigate the Biological Effects of Saruparib (AZD5305), Darolutamide, and in Combination in Men With Newly Diagnosed Prostate Cancer.
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Prostate Cancer
Keywords: Prostate cancer, radical prostatectomy, Darolutamide, Saruparib (AZD5305)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-07-10
Enrollment: 120
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised, phase 1 multicentre study
Primary purpose: BASIC_SCIENCE

Brief 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).

Detailed 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).

Eligibility criteria: 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
* For participants participating in the Optional Genetic Research Only: 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). In case there is no Clinical MDS/AML suspicion, no specific screening for MDS/AML (by bone marrow/bone biopsy) is 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.

Primary outcomes:
measure: Fold change in % γH2AX positive cells from baseline value in tumour samples
timeFrame: 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 outcomes:
measure: Severity of Treatment-Emergent AEs/SAEs per CTCAE v5.0
timeFrame: Day 1 to 28 days post-surgery
measure: Incidence of Treatment-Emergent AEs/SAEs per CTCAE v5.0
timeFrame: Day 1 to 28 days post-surgery
measure: Number of patients with abnormal laboratory values
timeFrame: Day 1 to 28 days post-surgery
measure: Change from baseline in blood pressure reported as clinically significant
timeFrame: Day 1 to 28 days post-surgery
measure: Change from baseline in heart rate reported as clinically significant
timeFrame: Day 1 to 28 days post-surgery
measure: Change from baseline in QTc value
timeFrame: Day 1 to 28 days post-surgery
measure: Number of participants undergoing planned surgery
timeFrame: Measured based on Day 1 to Day 21 of treatment
measure: Reasons of participants requiring treatment-related and non-treatment related delays of surgery and delays > 7 days from scheduled day
timeFrame: Measured based on Day 1 to Day 21 of treatment
measure: Number of participants requiring treatment-related and non-treatment related delays of surgery and delays > 7 days from scheduled day
timeFrame: Measured based on Day 1 to Day 21 of treatment
measure: Change in Ki-67 % positive cells from baseline in tumour samples
timeFrame: Measured based on Day 1 to Day 21 of treatment
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Providence
country: United States
facility: Research Site
state: Rhode Island
city: Melbourne
country: Australia
facility: Research Site
city: South Brisbane
country: Australia
facility: Research Site
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Québec
country: Canada
facility: Research Site
state: Quebec
city: Amsterdam
country: Netherlands
facility: Research Site
city: Nijmegen
country: Netherlands
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Research Site
Study officials:
References: