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Radium Ra 223 dichloride

Single arm study to evaluate safety and tolerability of Enzalutamide with concurrent administration of Radium ra 223 dichloride in subjects with symptomatic metastatic prostate cancer.

Enzalutamide

Radium ra 223 dichloride

Neal D Shore, MD

This is an open label study designed to examine the effects of Enzalutamide with concurrent administration of Radium Ra 223 dichloride in Castrate-Resistant (Hormone-Refractory) Prostate Cancer subjects with symptomatic bone metastases in both the pre- and post-chemotherapy setting.

This is an open label study designed to examine the effects of Enzalutamide with concurrent administration of Radium Ra 223 dichloride in castrate resistant (hormone-refractory) prostate cancer subjects with symptomatic bone metastasis, in both the pre- and post- chemotherapy setting.

Radium Ra 223 dichloride is approved by the US Food and Drug Administration for this indication. Enzalutamide is US Food and Drug Administration approved for this indication.

Approximately 40 subjects will be enrolled to obtain 30 evaluable subjects. All subjects will receive Radium Ra 223 dichloride every 4 weeks for a total of 6 doses over 24 weeks and concurrent Enzalutamide for a minimum duration of 24 weeks. The sponsor will provide Enzalutamide after the End of Treatment visit until the last Long Term Follow Up visit has been completed. Subjects will continue to receive Enzalutamide as long as a positive response to therapy is demonstrated. Enzalutamide may be discontinued at any time per physician discretion.

Subjects will be evaluated 30 days after the last dose of Radium Ra 223 dichloride. Including screening, the total duration of the study is 32 weeks plus every 3 month follow up visits while subjects are receiving Enzalutamide.

Open Label Phase Two Study of Enzalutamide With Concurrent Administration of Radium Ra 223 Dichloride in Castration-Resistant (Hormone-Refractory) Prostate Cancer Subjects With Symptomatic Bone Metastasis

Changes and time to total-ALP progression

Progression to additional antineoplastic therapy

Astellas Pharma Inc

Carolina Research Professionals, LLC

Adenocarcinoma

Niraparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Patients receive niraparib orally daily and radium Ra 223 dichloride IV over 1 minute every 4 weeks. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Radium Ra 223 Dichloride

William Kelly, DO

This phase Ib trial studies the side effects and best dose of niraparib when given together with radium Ra223 dichloride in treating subjects with prostate cancer that keeps growing even when the amount of testosterone in the body is reduced to very low levels and has spread from the primary site to the bone. Radium Ra 223 dichloride, acts like calcium to target cancer in the bones and may deliver radiation directly to the bone tumors, limiting damage to the surrounding normal tissue. Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving radium Ra 223 dichloride and niraparib may work better in treating subjects with hormone-resistant prostate cancer metastatic to the bone.

PRIMARY OBJECTIVES:

I. To determine a safe dose of niraparib when combined with radium Ra 223 dichloride (radium-223) in patients with metastatic castrate-resistant prostate cancer (mCRPC) that have and have not received prior chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the proportion of subjects with 50% prostate-specific antigen (PSA) reduction from baseline in men treated with niraparib and radium 223.

II. To determine the radiographic PFS (rPFS) at 6 months in men treated with niraparib and radium 223.

III. To determine the proportion of subjects that have circulating tumor cell (CTC) conversion (\>= 5 to \< 5/7.5ml) confirmed in a second assessment \> 4 weeks later in men treated with niraparib and radium 223.

IV. To determine the overall progression-free survival in men treated with niraparib and radium 223.

V. To determine the time to total-ALP (alkaline phosphatase) progression defined in subjects with no total-ALP decline from baseline as \>= 25% increase from the baseline value, at least 12 weeks from baseline.

VI. To determine the time to total-ALP (alkaline phosphatase) progression defined in patient with an initial total-ALP decline from baselines as \>= 25% increase from the nadir value, which is confirmed by a second value obtained three or more weeks later.

VII. To determine the total-ALP normalization, defined as the return of total-ALP value to within normal range at 12 weeks in 2 consecutive measurements (at least 2 weeks apart) after that of treatment in subjects who have their ALP above upper limit of normal (ULN) at baseline.

VIII. To determine the long term safety-tolerability of the combination of niraparib and radium 223 in men treated with niraparib and radium 223.

TERTIARY OBJECTIVES:

I. Study of deoxyribonucleic acid (DNA) repair aberrations; whole exome and transcriptome in pre-therapy tumor biopsy samples.

II. Compare changes in bone marrow micro-environment (hematopoietic stem cell \[HSC\] niche\\ C-X-C motif chemokine ligand 12 \[CXCL12\]/C-X-C motif chemokine receptor 4 \[CXCR4\] axis) pre and post therapy in up to 10 men treated with niraparib and radium 223.

III. Evaluate the baseline plasma cell-free (cf)-DNA for aberrations in DNA repair genes such as breast cancer (BRCA)1, BRCA2, ataxia telangiectasia mutated (ATM), ataxia-telangiectasia and rad3-related (ATR), partner and localizer of brca2 gene (PALB2) as well as the androgen receptor (AR) gene via next generation sequencing.

IV. Compare gene expression changes in baseline and serial (at end of cycle 1 and 3) whole blood ribonucleic acid (RNA) (collect blood in edetic acid \[EDTA\] tubes and RNA-later) using Nanostring PanCancer and immunology panel.

V. Evaluate the baseline CTCs for nuclear androgen receptor (AR), phosphorylated (p) nuclear factor kappa-beta (NF-kB), and gamma-H2A histone family member X (H2AX) foci via immunostaining.

Phase IB Trial of Radium-223 and Niraparib in Patients With Castrate Resistant Prostate Cancer (NiraRad)

There will be three dose levels of niraparib combined with standard doses of Radium 223 to be evaluated for safety

Janssen, LP

Prostate Cancer Clinical Trials Consortium

Bayer

Sidney Kimmel Cancer Center at Thomas Jefferson University

Anti-Infective Agents

Fluorides

Listerine

Sodium Fluoride

Enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily

Pfizer Pfizer CT.gov Call Center

The purpose of this study is to evaluate 18F-sodium fluoride positron-emission tomography / computed tomography (18F-NaF PET/CT) imaging as a method for determining treatment response in metastatic bone lesions in patients who are receiving enzalutamide for castration-resistant prostate cancer.

A Positron Emission Tomography/Computed Tomography (PET/CT) Bone Imaging Study in Patients Receiving Enzalutamide for Castration-Resistant Prostate Cancer (CRPC)

A PHASE 2, OPEN-LABEL, SINGLE-ARM STUDY OF 18F-SODIUM FLUORIDE PET/CT BONE IMAGING IN ENZALUTAMIDE-TREATED CHEMOTHERAPY-NAÏVE PATIENTS WITH BONE-METASTATIC CASTRATION-RESISTANT 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.

Bone lesion responded: if its change from baseline in SUVtotal is below limit of agreement (LOA, no specific value, based upon test/retest analysis using software). SUVtotal: total NaF uptake,indicated tumor burden across all bone lesions/in individual lesions reflecting bone-metastatic prostate cancer.NaF-3 performed on any of these: 1) prostate-specific antigen (PSA) progression(increase of \>=25% and absolute increase of \>=2.0 ng/mL above nadir); 2) bone progressive disease(PD)(appearance of \>=2 new lesions after screening assessed by technetium Tc 99m medronate \[99mTc-MDP\] bone scintigraphy); 3) soft tissue PD; 4) clinically relevant progression by investigator; 5) at 2 years without progression after treatment initiation. PD, RECIST1.1:\>=20% increase in sum of diameters of target lesions,(reference smallest sum on study, included baseline sum if that is smallest on study),relative increase of 20%,sum of diameters indicated absolute increase of \>=5mm, appearance of \>=1 new lesions.

Global SUVhetero score:Sum of(SUVmean of each lesion minus global SUVmean of all lesion)\^2/number of lesions,measure of heterogeneity of tumor activity across all bone lesions.SUVmean(mean NaF uptake)indicated average activity of each lesions.Real limits for SUVhetero score ranged:0(minimum) to infinite(maximum).Higher global SUVhetero score:more heterogeneity in bone lesion activity.NaF-3 performed on any of these 1)PSA progression(increase of\>=25% and absolute increase of\>=2.0ng/mL above nadir);2)bone PD(appearance of\>=2 new lesions after screening assessed by 99mTc-MDP bone scintigraphy);3)soft tissue PD(RECIST1.1);4)clinically relevant progression by investigator;5)at 2years without progression after treatment initiation.PD perRECIST1.1:\>=20%increase in sum of diameters of target lesions,(reference smallest sum on study,this included baseline sum if that is smallest on study),relative increase of20%,sum of diameters indicated absolute increase of\>=5mm,appearance of\>=1 new lesions.

Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Pfizer

Same event may appear as adverse events (AEs) and serious adverse events (SAEs), what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another participant or 1 participant may have experienced both serious and non serious event during study. As treated population included all enrolled participants who received any amount of study medication.

Chemotherapy naive participants with progressive bone-metastatic CRPC were enrolled to receive enzalutamide 160 mg per day as 4 capsules (each capsule of 40 mg), orally, once daily. 18F-NaF PET/CT was evaluated to determine treatment response in metastatic bone lesions of enrolled participants in the study. Maximum treatment exposure was 34.1 months.

Enzalutamide 160 mg

Enzalutamide 160 mg (18F-NaF PET/CT)

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

As treated population included all enrolled participants who received any amount of study medication.

Pfizer ClinicalTrials.gov Call Center

Analysis population included all enrolled participants who received any amount of study medication and who also have non-missing scans at both NaF-1 and NaF-3. Here, Overall Number of participants analyzed signifies participants who were evaluable for this outcome measure.

Percentage of Participants With at Least (>=) 1 Responding Bone Lesion Assessed by Total Sodium Fluoride (NaF) Standardized Uptake Value [SUVtotal] at Third 18F-NaF PET/CT Imaging (NaF-3) Schedule

Mean Heterogeneity of Response Across All Bone Lesions as Measured by Global Heterogeneity of NaF Standardized Uptake (SUVhetero) Score at Third 18F-NaF PET/CT Imaging (NaF-3) Schedule

Chemotherapy naive participants with progressive bone-metastatic castration-resistant prostate cancer (CRPC) were enrolled to receive enzalutamide 160 milligram (mg) per day as 4 capsules (each capsule of 40 mg), orally, once daily. 18F-sodium fluoride positron-emission tomography/computed tomography bone imaging (18F-NaF PET/CT) was evaluated to determine treatment response in metastatic bone lesions of enrolled participants in the study. Maximum treatment exposure was 34.1 months.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Open Label Phase Two Study of Enzalutamide With Concurrent Administration of Radium Ra 223 Dichloride in Castration-Resistant (Hormone-Refractory) Prostate Cancer Subjects With Symptomatic Bone Metastasis	NCT02507570	Prostate Carcin...	Enzalutamide Radium ra 223 d...	18 Years -	Carolina Research Professionals, LLC
Phase IB Trial of Radium-223 and Niraparib in Patients With Castrate Resistant Prostate Cancer (NiraRad)	NCT03076203	Prostate Carcin... Stage IV Prosta... Hormone-refract...	Niraparib Radium Ra 223 D...	18 Years -	Thomas Jefferson University
Open Label Phase Two Study of Enzalutamide With Concurrent Administration of Radium Ra 223 Dichloride in Castration-Resistant (Hormone-Refractory) Prostate Cancer Subjects With Symptomatic Bone Metastasis	NCT02507570	Prostate Carcin...	Enzalutamide Radium ra 223 d...	18 Years -	Carolina Research Professionals, LLC
Open Label Phase Two Study of Enzalutamide With Concurrent Administration of Radium Ra 223 Dichloride in Castration-Resistant (Hormone-Refractory) Prostate Cancer Subjects With Symptomatic Bone Metastasis	NCT02507570	Prostate Carcin...	Enzalutamide Radium ra 223 d...	18 Years -	Carolina Research Professionals, LLC
Phase IB Trial of Radium-223 and Niraparib in Patients With Castrate Resistant Prostate Cancer (NiraRad)	NCT03076203	Prostate Carcin... Stage IV Prosta... Hormone-refract...	Niraparib Radium Ra 223 D...	18 Years -	Thomas Jefferson University
A Positron Emission Tomography/Computed Tomography (PET/CT) Bone Imaging Study in Patients Receiving Enzalutamide for Castration-Resistant Prostate Cancer (CRPC)	NCT02384382	Prostate Carcin... Castration Resi...	Enzalutamide	18 Years -	Pfizer

Spots Global Cancer Trial Database for prostate carcinoma metastatic to the bone