Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Immune System Diseases

Prostatic Neoplasms

Hypersensitivity

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Antineoplastic Agents

Hormones

Talazoparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

talazoparib plus enzalutamide

Placebo plus enzalutamide

Pfizer CT.gov Call Center

The purpose of the study is to evaluate the safety and efficacy of talazoparib in combination with enzalutamide compared with placebo in combination with enzalutamide in participants with DDR-deficient mCSPC.

The study will have 5 periods: prescreening, screening, double-blind treatment, safety follow-up, and long-term follow-up.

Approximately 550 men with mCSPC will be randomized. Eligible participants will be randomly assigned to either of 2 treatment groups as follows:

* Talazoparib in combination with enzalutamide.
* Placebo capsules identical in appearance to talazoparib capsules in combination with enzalutamide.

Talazoparib or identical placebo treatment will be blinded. Enzalutamide (160 mg/day) will be open label. The dose of talazoparib/placebo to be given in combination with enzalutamide is 0.5 mg once daily. Participants with moderate renal impairment (eGFR 30-59 mL/min/1.73 m2 by the MDRD equation) at screening may be enrolled and the talazoparib/placebo dose will be 0.35 mg once daily.

Parallel: Participants are assigned to one of two or more groups in parallel for the duration of the study

Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC

TALAPRO-3: A PHASE 3, RANDOMIZED, DOUBLE-BLIND, STUDY OF TALAZOPARIB WITH ENZALUTAMIDE VERSUS PLACEBO WITH ENZALUTAMIDE IN MEN WITH DDR GENE MUTATED METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

time from the date of randomization to first objective evidence of radiographic progression or death, whichever occurs first

time from randomization to death from any cause

proportion of patients with measurable soft tissue disease at baseline with objective response per RECIST 1.1

duration of responses in patients with measurable soft tissue disease at baseline per RECIST 1.1

proportion of patients with PSA response grater than or equal to 50%

Time from randomization to initiation of antineoplastic therapy

time from randomization to first symptomatic skeletal event (symptomatic fractures, spinal cord compression, surgery or radiation to the bone whichever is first)

time from randomization to opiate use for prostate cancer pain

AEs and SAEs incidence by type and severity (graded by NCI CTCAE version 4.03)

plasma concentrations of enzalutamide and its metabolite

change from baseline in patient-reported pain symptoms per Brief Pain Inventory Short Form (BPI-SF)

time to deterioration in patient-reported pain symptoms per Brief Pain Inventory Short Form (BPI-SF)

change from baseline in participant-reported general health status per EQ-5D-5L

change from baseline in patient-reported Global health status/QoL per EORTC QLQ-C30

time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30

time to definitive deterioration in disease specific urinary symptoms per EORTC QLQ-PR25

Astellas Pharma Inc

Pfizer

Rare Diseases

Sarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Soft Tissue Sarcoma

Durvalumab

The experimental oral drug AZD1390 (starting dose once daily 20 mg) will be combined with radiotherapy. Drug will be taken at same day as radiotherapy for 5 weeks at weekdays.

When starting dose of 20 mg is proven safe the next cohort will be 100 and thereafter 200, 400 mg

The experimental oral drug AZD1390 (starting dose once daily 20 mg) will be combined with radiotherapy and durvalumab (fixed dose 1500 mg Q4W, until surgery). Drug will be taken at same day as radiotherapy for 5 weeks at weekdays. The dose of AZD1390 in the AZD1390 plus durvalumab cohort will follow the dosing of the AZD1390 only cohort. When starting dose of 20 mg and the next dose of AZD1390 only has been proven safe, the next cohort will be 100 and thereafter 200, 400 mg.

AZD1390 combined with preoperative radiotherapy

AZD1390 + radiotherapy

AZD1390 combined with durvalumab and preoperative radiotherapy

AZD1390 + durvlaumab + radiotherapy

Rick Haas, MD Prof

Neeltje Steeghs, MD PhD

Rick Haas, MD, PhD

To assess the safety and tolerability profile, in the pre- and perioperative period (up to 30 days post-surgery), of combined modality treatment (CMT) by administering AZD1390 with or without durvalumab and RT concurrently treating newly diagnosed, non-metastatic soft tissue sarcoma patients with DDRi-based CMT, in the specific context of systemic toxicities, wound healing post-surgery and in defining the RP2D for the combinations to support further clinical evaluation.

Despite improvements in surgery and radiation for soft tissue sarcoma (STS) patients, local relapses remain an important event for these patients. Most STS subtypes are considered radioresistant and immune cold tumor due to a lack of T-cell infiltration. Investigations into radiosensitization mediated by combining systemic compounds with neoadjuvant radiotherapy (RT) may translate into an increased rate of pathological responses, an increased rate of R0 resections and thus fewer local relapses.

RT is highly potent in inducing DNA damage. Normal cells are usually sufficiently able to repair this damage timely before the next fraction because of an intact DNA Damage Response (DDR) pathway. Frequently, tumor cells have (partial or complete) defects in the DDR pathways rendering them more sensitive to radiation than normal tissues. Inhibition of constituents of the DDR pathways may further widen the therapeutic window of fractionated radiotherapy, and combined with radiotherapy may result in increased tumor T-cell infiltration, creating an opportunity for immunotherapy. Clinical studies into radiosensitization of STS by combinations of radiotherapy and DDR inhibitors with or without immunotherapy are warranted. In this study the DDR candidate inhibitor is new drug candidate AZD1390 targeting ATM (Ataxia Telangiectasia Mutated). The immunotherapy candidate of this study is durvalumab (MEDI4736) targeting PD-L1 (programmed death-ligand 1).

I: AZD1390 and RT II: AZD1390, durvalumab and RT

Sarcomas and DDR-Inhibition; a Combined Modality Study

Sarcomas and DDR-Inhibition; a Neoadjuvant Phase I Combined Modality Study.

adverse events and more specific woundhealing

Histological examination of surgical specimens

Leiden University Medical Center

University Medical Center Nijmegen

The Netherlands Cancer Institute

Carcinoma

Carcinoma, Transitional Cell

Urinary Bladder Neoplasms

Neoplasms, Glandular and Epithelial

Transitional Cell Carcinoma

Bladder cancer (BC) is a heterogeneous malignancy with dismal outcome.Despite treatment, the 5-year overall survival rates for MIBC are \<50%, with many patients unresponsive or inapt, necessitating biomarkers to select those most likely to respond or fit for treatment

In this study was assessed the associations among most frequently mutated genes and with clinicopathological features, as well as the prognostic significance of the presence of mutations in the top mutated and DNA Damage response (DDR) mutated genes in terms of Overall Survival (OS). Moreover, overall tumor-infiltrating lymphocytes (TILs) density was measured, analyzed immunohistochemically the expression of PD-L1, the four MMR proteins (MLH1, MSH2, MSH6 and PMS2) and tumor or stromal CD8+ cytotoxic T lymphocyte infiltrates and assessed their association with each other, top mutated genes and available clinicopathological parameters together with their role in prognosis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC	NCT04821622	Prostate Cancer	talazoparib plu... Placebo plus en...	18 Years -	Pfizer
Sarcomas and DDR-Inhibition; a Combined Modality Study	NCT05116254	Soft Tissue Sar...	AZD1390 + radio... AZD1390 + durvl...	18 Years -	The Netherlands Cancer Institute
Prognostic Biomarkers in Patients With Urothelial Carcinoma	NCT04872036	Bladder Cancer		18 Years -	Hellenic Cooperative Oncology Group
Sarcomas and DDR-Inhibition; a Combined Modality Study	NCT05116254	Soft Tissue Sar...	AZD1390 + radio... AZD1390 + durvl...	18 Years -	The Netherlands Cancer Institute
Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC	NCT04821622	Prostate Cancer	talazoparib plu... Placebo plus en...	18 Years -	Pfizer
Prognostic Biomarkers in Patients With Urothelial Carcinoma	NCT04872036	Bladder Cancer		18 Years -	Hellenic Cooperative Oncology Group

Spots Global Cancer Trial Database for dna damage response