Pidnarulex and Talazoparib in Patients With Metastatic Castration Resistant Prostate Cancer

NCT05425862 | Suspended Phase 1 DMC

• 1 other identifier: 20/019
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 5

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

Conditions

Metastatic Castration Resistant Prostate Cancer (mCRPC)

Outcome Measures

Primary Outcomes (1)

• 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).

  From study start to end of 2 years of recruitment period.

Secondary Outcomes (8)

• 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.

  From the time of signing consent until 28 days after the last dose of protocol treatment.

• 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.

  From Cycle 1 Day 1 of treatment until the date of first documented progression, assessed up to 36 months.

• Radiographic Progression Free Survival (rPFS)

  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

• Prostate Surface Antigen Progression Free Survival (PSA-PFS).

  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.

• Overall response (OR) is only applicable for the subset of patients with measurable disease by RECIST1.1.

  From Cycle 1 Day 1 of treatment to the time of subsequent systemic anti-cancer treatment, assessed up to 36 months.

Study Arms (1)

Treatment with both talazoparib and pidnarulex

EXPERIMENTAL

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

Drug: Pidnarulex; Drug: Talazoparib

Interventions

Pidnarulex DRUG

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.

Also known as: CX-5461

Treatment with both talazoparib and pidnarulex

Talazoparib DRUG

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.

Treatment with both talazoparib and pidnarulex

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must be ≥18 years of age and must have provided written informed consent.
• Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell differentiation.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
• 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.
• 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.
• 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
• The PSA value at screening should be ≥ 5ng/ml for all patients registered on the study.
• 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.
• 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.
• Serum testosterone levels ≤ 50ng/dL (≤ 1.75nmol/L) within 28 days prior to Cycle 1 Day 1.
• Imaging evidence of metastatic disease documented with either bone scan or computerised tomography (CT) scan.
• At least 3 weeks since completion of prostate cancer vaccine therapy, radiation therapy or systemic therapy prior to Cycle 1 Day 1.

You may not qualify if:

• 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).
• 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.
• 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.
• Patients with symptomatic or impending cord compression unless adequately treated and clinically stable for ≥ 4 weeks.
• Any prior exposure to platinums, poly (ADP-ribose) polymerase (PARP) inhibitors, mitoxantrone or cyclophosphamide.
• 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.
• Persistent toxicities (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade 2) caused by previous cancer therapy, excluding alopecia.
• 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.
• Previous history of interstitial lung disease or non-infectious pneumonitis.
• Patients with a history or clinical features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML).
• Patients unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with the absorption of the study medication.
• 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.
• Known hypersensitivity to talazoparib or pidnarulex or any of the excipients of talazoparib or pidnarulex.
• 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

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (5)

St Vincent's Hospital Sydney

Sydney, New South Wales, 2010, Australia

Location

Box Hill Hospital

Box Hill, Victoria, 3128, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

Royal Melbourne Hospital

Melbourne, Victoria, 3000, Australia

Location

Alfred Hospital

Prahran, Victoria, 3000, Australia

Location

MeSH Terms

Interventions

CX 5461; talazoparib

Study Officials

• Shahneen Sandhu

  Peter MacCallum Cancer Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is phase I, open label, multicentre, dose-escalation study where both doses of talazoparib and pidnarulex will be escalated to define the MTD and RP2D for the combination.

Study Record Dates

• First Submitted: June 10, 2022
• First Posted: June 21, 2022
• Study Start: October 21, 2022
• Primary Completion: July 12, 2024
• Study Completion: December 30, 2025
• Last Updated: December 11, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

AU (5)