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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05425862




Registration number
NCT05425862
Ethics application status
Date submitted
10/06/2022
Date registered
21/06/2022
Date last updated
11/12/2023

Titles & IDs
Public title
Pidnarulex and Talazoparib in Patients With Metastatic Castration Resistant Prostate Cancer
Scientific title
Phase 1 Trial of Pidnarulex and Talazoparib in Patients With Metastatic Castration Resistant Prostate Cancer
Secondary ID [1] 0 0
20/019
Universal Trial Number (UTN)
Trial acronym
REPAIR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Castration Resistant Prostate Cancer (mCRPC) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Pidnarulex
Treatment: Drugs - Talazoparib

Experimental: Treatment with both talazoparib and pidnarulex - At the time of registration, patients will be assigned to the specific dose-schedule of talazoparib and pidnarulex depending on where the study is at in terms of dose-escalation or dose-expansion


Treatment: Drugs: Pidnarulex
Pidnarulex is a treatment that is designed to stop the action of a particular protein in the body called Polymerase I, that cancer cells rely on. Laboratory studies show that pidnarulex targets a process involving Polymerase I within cells, which can lead to a decrease in cancer growth. Pidnarulex has been shown to have some anticancer activity in ovarian cancer and haematological cancers.

Treatment: Drugs: Talazoparib
Talazoparib belongs to a class of drugs called PARP inhibitors, which is currently being used to treat various types of cancer. Talazoparib blocks the function of PARP, a protein that is involved in repairing DNA in cells. By stopping damaged DNA in cells from being repaired, this will lead to accumulation of DNA damage in the cancer cell and ultimately cancer cell death. Talazoparib has established anticancer activity in breast, ovarian and prostate cancers with underlying DNA repair defects. This class of drug have also been used in combination with other treatments such as radiation or chemotherapy to further increase cell death within the cancer.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
The MTD is defined as the highest tolerable dose of pidnarulex when talazoparib is given at the highest tolerable dose and the highest dose of pidnarulex when talazoparib is given at the lowest dose (two MTDs will be estimated).
Timepoint [1] 0 0
From study start to end of 2 years of recruitment period.
Secondary outcome [1] 0 0
Safety will be measured by serious adverse events (SAEs) and adverse events (AEs) assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Timepoint [1] 0 0
From the time of signing consent until 28 days after the last dose of protocol treatment.
Secondary outcome [2] 0 0
Prostate Surface Antigen (PSA) response will be defined as a 50% or greater decrease in PSA from baseline to the lowest post-baseline PSA result. A second consecutive value obtained 4 or more weeks later confirms the PSA response.
Timepoint [2] 0 0
From Cycle 1 Day 1 of treatment until the date of first documented progression, assessed up to 36 months.
Secondary outcome [3] 0 0
Radiographic Progression Free Survival (rPFS)
Timepoint [3] 0 0
From Cycle 1 Day 1 of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
Secondary outcome [4] 0 0
Prostate Surface Antigen Progression Free Survival (PSA-PFS).
Timepoint [4] 0 0
From Cycle 1 Day 1 of treatment until the date of first documented PSA progression or date of death from any cause, whichever came first, assessed up to 36 months.
Secondary outcome [5] 0 0
Overall response (OR) is only applicable for the subset of patients with measurable disease by RECIST1.1.
Timepoint [5] 0 0
From Cycle 1 Day 1 of treatment to the time of subsequent systemic anti-cancer treatment, assessed up to 36 months.
Secondary outcome [6] 0 0
Overall survival (OS)
Timepoint [6] 0 0
From Cycle 1 Day 1 of treatment to the date of death due to any cause, assessed up to 36 months.
Secondary outcome [7] 0 0
Duration of Response Prostate Cancer Working Group 3 (DOR-PCWG3)
Timepoint [7] 0 0
12 weeks from Cycle 1 Day 1 of treatment to date of first documented radiographic progression. Assessed up to 36 months.
Secondary outcome [8] 0 0
Treatment discontinuation at any time due to treatment related toxicity for each patient.
Timepoint [8] 0 0
From study start to the end of study treatment. An average of 18 months

Eligibility
Key inclusion criteria
1. Patient must be =18 years of age and must have provided written informed consent.

2. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or
small cell differentiation.

3. Eastern Cooperative Oncology Group (ECOG) performance status of = 1.

4. Patients must have had at least one prior treatment line of taxane (docetaxel)
chemotherapy either in the hormone sensitive or castrate resistant setting unless the
patient is deemed medically unsuitable for chemotherapy. If a patient has had
docetaxel chemotherapy twice, this will be considered one line.

5. Patients must have progressed on a second-generation androgen receptor (AR) targeted
agent (e.g. enzalutamide, abiraterone and/or apalutamide). Determination of disease
progression on second-generation AR targeted agent will be made by the local
Investigator.

6. Patients must have progressive disease (PD) for study entry. This is defined by
Prostate Cancer Working Group 3 (PCWG3) as any one of the following:

- PSA progression: minimum of two rising PSA values from a baseline measurement
with an interval of = 1 week between each measurement.

- Soft tissue or visceral disease progression as per Response Evaluation Criteria
in Solid Tumours (RECIST1.1) criteria

- Bone progression: = 2 new lesions on bone scan

7. The PSA value at screening should be = 5ng/ml for all patients registered on the
study.

8. At least 3 weeks since the completion of surgery or radiotherapy prior to commencing
study treatment. Any clinically relevant sequelae from the surgery or radiotherapy
must have improved to Grade 1 prior to Cycle 1 Day 1.

9. Prior surgical orchiectomy or chemical castration maintained on luteinizing
hormone-releasing hormone (LHRH) analogue (agonist or antagonist). Patients without
prior surgical castration must be currently taking and willing to continue LHRH
analogue (agonist or antagonist) therapy throughout the duration of study treatment.

10. Serum testosterone levels = 50ng/dL (= 1.75nmol/L) within 28 days prior to Cycle 1 Day
1.

11. Imaging evidence of metastatic disease documented with either bone scan or
computerised tomography (CT) scan.

12. At least 3 weeks since completion of prostate cancer vaccine therapy, radiation
therapy or systemic therapy prior to Cycle 1 Day 1.

13. Patients must have a life expectancy = 24 weeks.

14. Male patients must use barrier contraception during treatment and for 3 months after
the last dose of study drug when having sexual intercourse with a woman of
childbearing potential. Female partners of male patients should also use a highly
effective form of contraception.

15. Patients must be willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled assessments.

16. Patients must have adequate bone marrow, hepatic and renal function documented within
7 days prior to Cycle 1 Day 1, defined as:

- Haemoglobin =100 g/L independent of transfusions (no red blood cell (RBC)
transfusion in last 8 weeks)

- Absolute neutrophil count (ANC) =1.2 x109/L

- Platelets =120 x109/L

- Total bilirubin =1.5 x upper limit of normal (ULN) except for patients with known
Gilbert's syndrome where this applies to the conjugated bilirubin level.

- Aspartate transaminase (AST) and alanine transaminase (ALT) =2.5 x ULN if there
is no evidence of liver metastasis or =5 x ULN in the presence of liver
metastases.

- Albumin = 30 g/L

- Adequate renal function: patients must have creatinine clearance (CrCl) estimated
of = 50 mL/min using the Cockcroft-Gault equation
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Extensive marrow disease defined by a "Super Scan" on bone scintigraphy or diffuse
marrow infiltration on prostate specific membrane antigen (PSMA) positron emission
tomography (PET).

2. Previous history or presence of brain metastases or leptomeningeal metastases. A scan
to confirm the absence of brain metastases is not required if there is no clinical
suspicion on history.

3. Surgery or radiotherapy within < 3 weeks prior to Cycle 1 Day 1 (except for palliative
reasons). Patients must have recovered from effects of any major surgery.

4. Patients with symptomatic or impending cord compression unless adequately treated and
clinically stable for = 4 weeks.

5. Any prior exposure to platinums, poly (ADP-ribose) polymerase (PARP) inhibitors,
mitoxantrone or cyclophosphamide.

6. Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression,
superior vena cava syndrome, extensive interstitial lung disease on High Resolution CT
scan or psychiatric illness/social situations that are likely to impede participation
and/or compliance in the study.

7. Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE] Grade 2)
caused by previous cancer therapy, excluding alopecia.

8. Other malignancies within the previous 2-years that have a high risk of recurrence
other than basal cell, squamous cell carcinomas of skin, melanoma in situ or other
cancers that are unlikely to recur within 24 months.

9. Previous history of interstitial lung disease or non-infectious pneumonitis.

10. Patients with a history or clinical features suggestive of myelodysplastic syndrome
(MDS)/acute myeloid leukaemia (AML).

11. Patients unable to swallow orally administered medications or with gastrointestinal
disorders likely to interfere with the absorption of the study medication.

12. Resting Electrocardiogram (ECG) indicating uncontrolled, potentially reversible
cardiac conditions, as judged by the Investigator (e.g., unstable angina, uncontrolled
or symptomatic arrhythmia, congestive heart failure, corrected QT interval by
Frederica [QTcF] prolongation >500ms, electrolyte disturbances, etc.), or patients
with congenital long QT syndrome.

13. Known hypersensitivity to talazoparib or pidnarulex or any of the excipients of
talazoparib or pidnarulex.

14. Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV) 1/2. Serology only required if there is
clinical suspicion on history. HIV-infected (HIV1/2 antibody-positive) patients may
participate if they meet all the following eligibility requirements:

- They must be on an anti-retroviral regimen with evidence of at least two
undetectable viral loads within the past 6 months on the same regimen; the most
recent undetectable viral load must be within the past 12 weeks They must have a
CD4 count =250 cells/µL over the past 6 months on the same anti-retroviral
regimen and must not have had a CD4 count <200 cells/µl over the past 2 years,
unless it was deemed related to the cancer and/or chemotherapy-induced bone
marrow suppression

- For patients who have received chemotherapy in the past 6 months, a CD4 count
<250 cells/µl during chemotherapy is permitted as long as viral loads were
undetectable during this same treatment period

- They must have an undetectable viral load and a CD4 count =250 cells/µL within 7
days prior to Cycle 1 Day 1

- They must not be currently receiving prophylactic therapy for an opportunistic
infection and must not have had an opportunistic infection within the past 6
months

15. Patients with active or uncontrolled infection, including hepatitis A, B or C. NOTE:
Patients with controlled infection on antibiotic or antifungal therapy are eligible
i.e. the patient should be afebrile for at least 72 hours and be haemodynamically
stable.

16. Participation in another clinical study with an investigational product or another
systemic therapy administered within 3 weeks prior to Cycle 1 Day 1.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Suspended
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
21/10/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/12/2025
Actual
Sample size
Target
48
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
St Vincent's Hospital Sydney - Sydney
Recruitment hospital [2] 0 0
Box Hill Hospital - Box Hill
Recruitment hospital [3] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [4] 0 0
Royal Melbourne Hospital - Melbourne
Recruitment hospital [5] 0 0
Alfred Hospital - Prahran
Recruitment postcode(s) [1] 0 0
2010 - Sydney
Recruitment postcode(s) [2] 0 0
3128 - Box Hill
Recruitment postcode(s) [3] 0 0
3000 - Melbourne
Recruitment postcode(s) [4] 0 0
3000 - Prahran

Funding & Sponsors
Primary sponsor type
Other
Name
Peter MacCallum Cancer Centre, Australia
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is phase I, open label, multicentre, dose-escalation study where both doses of
talazoparib and pidnarulex will be escalated to define the maximum tolerated dose (MTD) and
recommended phase 2 dose (RP2D) for the combination. It is possible that either 1 or 2 RP2D
of the combination will be defined at the end of the study. Patients with disease that is
deemed to be amendable to repeated tumour biopsies will be invited to undergo optional paired
biopsies: at baseline and Cycle 1 Day 9 + 3 days and at the time of progression. Pidnarulex
will be given as an IV infusion on days 1 and 8 of a 28 day cycle and talazoparib will be
taken once daily continuously. Disease status will be assessed at regular intervals by CT
scans, radionuclide bone scans, and PSA. Throughout the study, safety and tolerability will
be assessed and established procedures for management of toxicities will be applied
Trial website
https://clinicaltrials.gov/ct2/show/NCT05425862
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Shahneen Sandhu
Address 0 0
Peter MacCallum Cancer Research
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05425862