“A randomized phase II trial to evaluate the antitumor activity of Enzalutamide and Talazoparib (PF-06944076) for the treatment of metastatic hormone-naïve prostate cancer”

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medica Scientia Innovation Research S.L.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Sep 2020 → 6 May 2025

Decision date (initial)

2024-08-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Pfizer, S.L.U.

External identifiers

EU CT number

2023-509387-24-00

EudraCT number

2019-003096-20

ClinicalTrials.gov

NCT04332744

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the antitumor activity of talazoparib (PF-06944076) in
combination with enzalutamide and ADT –as determined by the confirmed
prostate-specific antigen-complete response (PSA-CR)– in patients with
mHNPC.

Secondary objectives 4

1. To analyze PSA response and time to development of castrationresistance (TTCR) when ADT and enzalutamide are administered with talazoparib (PF-06944076) in this population.
2. To assess the correlation between molecular and transcriptomic signatures of DNA damage repair (DDR) function and antitumor activity in this population.
3. To assess the impact of ADT and enzalutamide treatment in DNA repair function in this population.
4. To evaluate the safety and tolerability of talazoparib (PF-06944076) in combination with enzalutamide and ADT in this population.

Conditions and MedDRA coding

Metastatic hormone–naïve prostate cancer (mHNPC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Adult patients (>18 y.o.) who signed informed consent form (ICF) prior to participation in any study-related activities.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
4. High-volume metastatic disease documented on bone scan or computed tomography (CT)/magnetic resonance imaging (MRI) scan, defined as the presence of either visceral disease and/or at least four bone metastases on bone scan, with at least one of them beyond spine/pelvis.
5. Life expectancy of ≥ 12 months.
6. Histologically confirmed adenocarcinoma of the prostate without predominance of small-cell or neuroendocrine features according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines based on local testing on the most recent analyzed biopsy. Note: Central confirmation of adenocarcinoma is not required for study entry. However, tissue blocks, or slides, must be submitted to confirm the diagnoses by a Sponsor-designated central laboratory retrospectively and/or exploratory biomarker analyses.
7. Willingness and ability to provide tumor paired biopsies during the study participation in order to perform exploratory studies. At the study entry, the most recent tumor biopsy since last progression from either metastatic or primary tissues will be provided. If not feasible, patient eligibility should be evaluated by a Sponsor’s qualified designee.
8. Adequate hematologic and organ function within 28 days before the first study treatment on Cycle 1 Day 1, defined by the following: a. Hematological: i. White blood cell (WBC) count > 3.0 x 109/L; ii. Absolute neutrophil count (ANC) > 1.5 x 109/L; iii. Platelet count > 100.0 x109/L; iv. Hemoglobin (Hb) > 9.0 g/dL. Note: Patients receiving growth factors or blood transfusions within 14 days before obtaining the hematology values at screening will be excluded. b. Hepatic: i. Total bilirubin ≤ 1.5 times the upper limit of normal (× ULN) (≤ 3 x ULN in the case of Gilbert’s disease); ii. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (in the case of liver metastases ≤ 5 × ULN); iii. Alkaline phosphatase (ALP) ≤ 2.5 × ULN (≤ 5 × ULN in the case of liver and/or bone metastases). c. Renal: i. Serum creatinine < 1.5 × ULN or creatinine clearance ≥ 30 mL/min based on Cockcroft−Gault glomerular filtration rate estimation. d. Coagulation: i. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless on medication known to alter INR and/or aPTT. e. Nutritional status: i. Serum Albumin ≥ 2.8 g/dL.
9. Bisphosphonates or denosumab dosage must have been stable for at least 4 weeks before Day 1 for patients receiving these therapies.
10. Patients must agree to use a condom when is engaged in sexual activity with a pregnant woman during the treatment period and for at least 90 days after last dose of enzalutamide or at least 120 days after last dose of talazoparib (PF-06944076), whichever occurs later. Patients must also agree to use an additional highly effective form of contraception or two effective contraceptive methods, when is engaged in sexual intercourse with a woman of childbearing potential during the treatment period and for at least 90 days after last dose of enzalutamide or at least 120 days after last dose of talazoparib (PF-06944076), whichever occurs later
11. Must agree to refrain to donate sperm during the treatment period and for at least 90 days after last dose of enzalutamide or at least 120 days after last dose of talazoparib (PF-06944076), whichever occurs later.
12. PSA ³ 4 ng/mL at diagnosis or before starting ADT therapy.

Exclusion criteria 19

1. Prior treatment with enzalutamide, apalutamide, darolutamide or abiraterone acetate.
2. History of malabsorption syndrome or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills.
3. Known hypersensitivity to recombinant proteins, or any excipient contained in the drug formulation for talazoparib (PF-06944076) and enzalutamide.
4. Prior systemic therapy for metastatic prostate cancer (mPCa). Note: Initiation of androgen deprivation therapy (ADT) within 4 weeks prior to study entry would be allowed (with or without first-generation antiandrogens), providing a tumor biopsy sample was taken prior to initiation of ADT is made available for biomarker studies and upon approval by the sponsor. If patient was started on first-generation antiandrogens, these would be discontinued on prior to randomization. Note: Patients relapsing after having received an ADT-based regimen in neoadjuvant or adjuvant setting will be suitable for the study if metastatic progression occured while on non-castrate testosterone levels or at least 12 months after discontinuation of ADT
5. Treatment with approved or investigational cancer therapy within 28 days (or 5 half-lives of the drug‒ whichever is longer) prior to initiation of study treatment.
6. Known or suspected brain metastases or active leptomeningeal disease
7. Symptomatic or impending spinal cord compression or cauda equina syndrome.
8. Subject has a history of seizure or any condition that may predispose to seizure (i.e. prior significant brain trauma, brain vascular malformations, …), or subjects that have had unexplained loss of consciousness or transient ischemic attacks within 1 year prior to scheduled Day 1 of treatment.
9. Therapeutic radiation therapy within 14 days (seven days for limited-field palliative radiotherapy) prior to study enrolm National Cancer Insitute´s Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v.)5.0.ent, or patients who have not recovered from radiotherapy-related toxicities to grade ≤ 1 according to
10. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 14 days of start of study drugs, or patients who have not recovered from the side effects of any major surgery.
11. History of another malignancy within three years of study enrollment with the exception of carcinoma in situ, non-melanoma skin carcinoma, or American Joint Committee on Cancer stage 0 or stage 1 cancer that has a remote probability of recurrence in the opinion of the investigator and the Sponsor’s Medical Monitor is required, or any concurrent malignancy for which the patient is receiving therapy
12. Active uncontrolled infection at the time of enrollment.
13. Congenital long QT syndrome or Electrocardiogram (ECG) at screening with QT interval corrected using Fridericia's formula (QTcF) > 500 milliseconds.
14. Patients with clinically significant cardiovascular disease including but not limited to any of the following: a. Stroke, transient ischemic attack, unstable angina pectoris, or documented myocardial infarction within 12 months prior to study entry. b. Symptomatic pericarditis or clinically significant pericardial effusion or myocarditis. c. Documented congestive heart failure (New York Heart Association functional classification III- IV). d. Uncontrolled, persistent hypertension defined as systolic blood pressure > 170 mmHg or diastolic blood pressure > 100 mmHg.
15. Patients have any of the following cardiac conduction abnormalities: a. Ventricular arrhythmias except for benign premature ventricular contractions. b. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication. c. Conduction abnormality requiring a pacemaker. d. Other cardiac arrhythmia not controlled with medication.
16. Patients have any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment contraindicate patient participation in the clinical study.
17. Treatment with estrogens, cyprotoerone acetate or glucocorticoids (at a dose greater than the equivalent to 10 mg/day of prednisone) in the 4 weeks prior to scheduled Day 1 of treatment.
18. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are employees of the trial sponsor, including their family members, directly involved in the conduct of the study.
19. Concurrent participation in other clinical trial, except other translational studies or observational studies (defined as those with no therapeutic intervention)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PSA-CR defined as the percentage of patients with PSA < 0.2 ng/mL at month 12 of therapy.

Secondary endpoints 3

1. Rate of PSA complete response (CR) at any time point and at month 7 (<0.2 ng/mL), PSA response (< 4ng/ml) at 7 and 12 months, PSAprogression-free survival (PSA-PFS) based on Prostate Cancer Working Group 3 (PCWG3) criteria (PSA ≥ 25% and ≥ 2 ng/mL from nadir confirmed by a second value obtained 3 or more weeks later),
2. radiologic PFS (rPFS) based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v.)1.1, time to castration resistance (TTCR), based on PSA-PFS and RECIST rPFS, and overall survival (OS)
3. Incidence of adverse events (AEs), incidence of prespecified AEs as per National Cancer Insitute’s Common Terminology Criteria for Adverse Events (CTCAE) v.5.0, change from baseline in targeted vital signs, and change from baseline in targeted clinical laboratory test results.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medica Scientia Innovation Research S.L.

Sponsor organisation

Medica Scientia Innovation Research S.L.

Address

Carrer De Pere IV 128 3rd Floor

City

Barcelona

Postcode

08005

Country

Spain

Scientific contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Alicia Garcia

Public contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Zuzanna Piwowarska

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications