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

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02384382
• Collaborator: Astellas Pharma Inc (Industry), Medivation LLC, a wholly owned subsidiary of Pfizer Inc. (Industry)
• Enrollment: 23
• Locations: 5
• Arm: 1
• Actual Duration (Months): 41.1
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Carcinoma Metastatic to the Bone; Castration Resistant Prostate Cancer	Drug: Enzalutamide	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Nov 30, 2015
• Actual Primary Completion Date: May 3, 2019
• Actual Study Completion Date: May 3, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enzalutamide monotherapy Enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily	Drug: Enzalutamide; Other Names: MDV3100 Xtandi

Outcome Measures

Primary Outcome Measures

1. 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 [At NaF-3 schedule: at time of PSA, or radiographic(bone or soft tissue), or clinically relevant progression, or at 2years without progression after treatment initiation, whichever occurred first(From first dose of study drug up to maximum of 34.1 months)]

   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.

Secondary Outcome Measures

1. 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 [At NaF-3 schedule: at time of PSA, or radiographic(bone or soft tissue), or clinically relevant progression, or at 2years without progression after treatment initiation, whichever occurred first(From first dose of study drug up to maximum of 34.1 months)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, or signet cell or small cell features;

• Presence of bone metastatic disease as assessed by at least two lesions on whole body metastable technetium-methylene diphosphonate (99mTc-MDP) bone scintigraphy;

• Throughout the study, ongoing androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) analogue or prior bilateral orchiectomy (medical or surgical castration);

• Testosterone ≤ 1.73 nmol/L (≤ 50 ng/dL) at screening;

• Progressive disease on androgen deprivation therapy at screening defined as a minimum of two sequentially rising prostate-specific antigen (PSA) values (PSA1 < PSA2 < PSA3);

• The screening PSA (PSA3) must be ≥ 2 μg/L (≥ 2 ng/mL).

Exclusion Criteria:

• Prior enzalutamide, abiraterone acetate, aminoglutethimide, ketoconazole, radium Ra 223 dichloride or other bone-targeting radionuclides, or cytotoxic chemotherapy in the CRPC setting for the treatment of prostate cancer or participation in a clinical trial of an investigational agent that inhibits the androgen receptor or androgen synthesis (unless treatment was placebo);

• Treatment with hormonal therapy (eg, androgen receptor inhibitors, 5-alpha reductase inhibitors) or biologic therapy for prostate cancer (other than LHRH analogue therapy) within 4 weeks before enrollment;

• Initiation of new treatment with denosumab, bisphosphonates, or systemic corticosteroids for treatment of prostate cancer within 4 weeks before enrollment;

• Use of an investigational agent within 4 weeks before the screening visit;

• Radiation therapy to bone within 4 weeks before enrollment;

• Use of opiate analgesics for prostate cancer pain within 4 weeks before enrollment;

• Screening 99mTc-MDP bone scintigraphy showing a superscan;

• Visceral (eg, lung, liver) metastatic disease. Adenopathy is allowed;

• Current or previously treated brain metastasis or active leptomeningeal disease;

• History of seizure any time in the past for any reason or any condition that may predispose to seizures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
2	Karmanos Cancer Institute Weisberg Cancer Treatment Center	Farmington Hills	Michigan	United States	48334
3	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
4	Wimr Pet/Ct	Madison	Wisconsin	United States	53763
5	UW Clinical Sciences Center	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• Pfizer
• Astellas Pharma Inc
• Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Investigators

• Study Director: Pfizer Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol - Dec 8, 2016
• Statistical Analysis Plan - Sep 24, 2018

More Information

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02384382
• Other Study ID Numbers: MDV3100-18; C3431012
• First Posted: Mar 10, 2015
• Last Update Posted: May 5, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Pfizer: Cancer of the Prostate
• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

Participant Flow

Arm/Group Title	Enzalutamide 160 Milligram (mg) (18F-NaF PET/CT)
Arm/Group Description	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.
Period Title: Overall Study
STARTED	23
COMPLETED	0
NOT COMPLETED	23

Baseline Characteristics

Arm/Group Title	Enzalutamide 160 mg (18F-NaF PET/CT)
Arm/Group Description	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.
Overall Participants	23
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.0 (10.07)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	23 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	22 95.7%
Unknown or Not Reported	1 4.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 8.7%
White	21 91.3%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	At NaF-3 schedule: at time of PSA, or radiographic(bone or soft tissue), or clinically relevant progression, or at 2years without progression after treatment initiation, whichever occurred first(From first dose of study drug up to maximum of 34.1 months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Enzalutamide 160 mg (18F-NaF PET/CT)
Arm/Group Description	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.
Measure Participants	22
Number (95% Confidence Interval) [percentage of participants]	100.0 434.8%

2. Secondary Outcome

Title	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
Description	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.
Time Frame	At NaF-3 schedule: at time of PSA, or radiographic(bone or soft tissue), or clinically relevant progression, or at 2years without progression after treatment initiation, whichever occurred first(From first dose of study drug up to maximum of 34.1 months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Enzalutamide 160 mg (18F-NaF PET/CT)
Arm/Group Description	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.
Measure Participants	22
Mean (Standard Deviation) [unit on SUVhetero score]	3.9 (3.17)

Adverse Events

Time Frame	From first dose of study drug up to 30 days after the last dose of study treatment or initiation of cytotoxic chemotherapy, (lutamide- bicalutamide, nilutamide,or flutamide), or initiation of new investigational therapy, whichever occurred first (up to 35.1 months)
Adverse Event Reporting Description	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.
Arm/Group Title	Enzalutamide 160 mg
Arm/Group Description	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.
All Cause Mortality
	Enzalutamide 160 mg
	Affected / at Risk (%)	# Events
Total	1/23 (4.3%)
Serious Adverse Events
	Enzalutamide 160 mg
	Affected / at Risk (%)	# Events
Total	9/23 (39.1%)
Cardiac disorders
Mitral valve incompetence	1/23 (4.3%)
Gastrointestinal disorders
Diarrhoea	1/23 (4.3%)
Upper gastrointestinal haemorrhage	1/23 (4.3%)
General disorders
Asthenia	1/23 (4.3%)
Infections and infestations
Cellulitis	1/23 (4.3%)
Musculoskeletal and connective tissue disorders
Back pain	1/23 (4.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Laryngeal squamous cell carcinoma	1/23 (4.3%)
Psychiatric disorders
Completed suicide	1/23 (4.3%)
Renal and urinary disorders
Haematuria	1/23 (4.3%)
Urinary retention	1/23 (4.3%)
Urinary tract obstruction	1/23 (4.3%)
Vascular disorders
Deep vein thrombosis	1/23 (4.3%)
Hypotension	1/23 (4.3%)
Other (Not Including Serious) Adverse Events
	Enzalutamide 160 mg
	Affected / at Risk (%)	# Events
Total	22/23 (95.7%)
Blood and lymphatic system disorders
Anaemia	1/23 (4.3%)
Microcytic anaemia	1/23 (4.3%)
Cardiac disorders
Atrial tachycardia	1/23 (4.3%)
Ventricular tachycardia	1/23 (4.3%)
Eye disorders
Cataract	2/23 (8.7%)
Retinal haemorrhage	1/23 (4.3%)
Gastrointestinal disorders
Abdominal discomfort	2/23 (8.7%)
Abdominal pain	2/23 (8.7%)
Constipation	3/23 (13%)
Diarrhoea	5/23 (21.7%)
Dyspepsia	1/23 (4.3%)
Dysphagia	1/23 (4.3%)
Nausea	2/23 (8.7%)
Oesophagitis	1/23 (4.3%)
Toothache	1/23 (4.3%)
Umbilical hernia	1/23 (4.3%)
Vomiting	1/23 (4.3%)
General disorders
Asthenia	3/23 (13%)
Chest pain	3/23 (13%)
Fatigue	19/23 (82.6%)
Gait disturbance	1/23 (4.3%)
Inflammation	1/23 (4.3%)
Influenza like illness	2/23 (8.7%)
Malaise	1/23 (4.3%)
Oedema peripheral	1/23 (4.3%)
Pain	2/23 (8.7%)
Pyrexia	1/23 (4.3%)
Infections and infestations
Diverticulitis	1/23 (4.3%)
Fungal skin infection	1/23 (4.3%)
Gastroenteritis Escherichia coli	1/23 (4.3%)
Infected skin ulcer	1/23 (4.3%)
Nasopharyngitis	1/23 (4.3%)
Post procedural infection	1/23 (4.3%)
Sepsis	1/23 (4.3%)
Sinusitis	2/23 (8.7%)
Upper respiratory tract infection	2/23 (8.7%)
Urinary tract infection	2/23 (8.7%)
Injury, poisoning and procedural complications
Arthropod bite	1/23 (4.3%)
Chest injury	1/23 (4.3%)
Fall	6/23 (26.1%)
Procedural pain	2/23 (8.7%)
Rib fracture	2/23 (8.7%)
Spinal compression fracture	1/23 (4.3%)
Sternal fracture	1/23 (4.3%)
Investigations
Blood creatinine increased	1/23 (4.3%)
Weight decreased	1/23 (4.3%)
Metabolism and nutrition disorders
Decreased appetite	4/23 (17.4%)
Hyperglycaemia	1/23 (4.3%)
Hyperkalaemia	1/23 (4.3%)
Hypocalcaemia	1/23 (4.3%)
Hypophosphataemia	3/23 (13%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/23 (26.1%)
Arthritis	1/23 (4.3%)
Back pain	6/23 (26.1%)
Bone pain	2/23 (8.7%)
Flank pain	3/23 (13%)
Groin pain	3/23 (13%)
Joint range of motion decreased	1/23 (4.3%)
Joint swelling	1/23 (4.3%)
Muscle spasms	2/23 (8.7%)
Muscular weakness	1/23 (4.3%)
Musculoskeletal chest pain	1/23 (4.3%)
Musculoskeletal pain	4/23 (17.4%)
Myalgia	1/23 (4.3%)
Neck pain	2/23 (8.7%)
Pain in extremity	3/23 (13%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/23 (4.3%)
Lung neoplasm malignant	1/23 (4.3%)
Nervous system disorders
Ageusia	1/23 (4.3%)
Balance disorder	1/23 (4.3%)
Dizziness	3/23 (13%)
Dysgeusia	2/23 (8.7%)
Headache	1/23 (4.3%)
Hypoaesthesia	2/23 (8.7%)
Memory impairment	2/23 (8.7%)
Neuropathy peripheral	1/23 (4.3%)
Paraesthesia	3/23 (13%)
Parosmia	1/23 (4.3%)
Peripheral sensory neuropathy	1/23 (4.3%)
Sciatica	1/23 (4.3%)
VIIth nerve paralysis	2/23 (8.7%)
Psychiatric disorders
Anxiety	1/23 (4.3%)
Insomnia	2/23 (8.7%)
Renal and urinary disorders
Acute kidney injury	1/23 (4.3%)
Bladder pain	1/23 (4.3%)
Cystitis noninfective	1/23 (4.3%)
Haematuria	3/23 (13%)
Stress urinary incontinence	1/23 (4.3%)
Urinary incontinence	2/23 (8.7%)
Urinary tract obstruction	1/23 (4.3%)
Urinary tract pain	1/23 (4.3%)
Reproductive system and breast disorders
Pelvic pain	1/23 (4.3%)
Respiratory, thoracic and mediastinal disorders
Cough	3/23 (13%)
Dysphonia	1/23 (4.3%)
Dyspnoea	2/23 (8.7%)
Dyspnoea exertional	1/23 (4.3%)
Oropharyngeal pain	1/23 (4.3%)
Rhinorrhoea	1/23 (4.3%)
Sinus congestion	2/23 (8.7%)
Skin and subcutaneous tissue disorders
Dry skin	1/23 (4.3%)
Pruritus	1/23 (4.3%)
Rash	2/23 (8.7%)
Skin burning sensation	1/23 (4.3%)
Swelling face	1/23 (4.3%)
Surgical and medical procedures
Cyst drainage	1/23 (4.3%)
Vascular disorders
Hot flush	4/23 (17.4%)
Hypertension	4/23 (17.4%)
Hypotension	2/23 (8.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.