Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Androgens

Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth. Study drug treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal.

Enzalutamide

Participants received placebo, administered as four capsules, once per day by mouth. Study drug treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal.

Placebo

Pfizer CT.gov Call Center

The purpose of this study is to determine the benefit of enzalutamide versus placebo as assessed by overall survival and progression-free survival in patients with progressive metastatic prostate cancer who have failed androgen deprivation therapy but not yet received chemotherapy.

A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer

PREVAIL: A MULTINATIONAL PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED EFFICACY AND SAFETY STUDY OF ORAL MDV3100 IN CHEMOTHERAPY-NAÏVE PATIENTS WITH PROGRESSIVE METASTATIC PROSTATE CANCER WHO HAVE FAILED ANDROGEN DEPRIVATION THERAPY

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.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to a maximum of 6.5 years that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious AEs.

An AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. As per NCI CTCAE, Grade 3 events =medically significant but not immediately life-threatening, unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment, Grade 4 events =participant to be in imminent danger of death. Grade 5 events =death. A treatment-emergent AE (TEAE) was defined as an AE that occurred from the date and time of the first dose of study drug up to a maximum duration of 6.5 years. Number of participants with AEs of any of the Grade 3 or above (Grade 4, 5) were reported.

Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to a maximum duration of 6.5 years that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator.

Overall survival was defined as the time from randomization to death due to any cause. For patients who were alive at the time of the analysis data cutoff, overall survival was censored at the last date the patient was known to be alive or analysis data cutoff date, whichever was first. This included patients who were known to have died after the data analysis cutoff date. Patients with no post-baseline survival information were censored on the date of randomization.

Radiographic progression-free survival was defined as the time from randomization to the first objective evidence of radiographic disease progression assessed by independent central radiology review or death due to any cause within 168 days after treatment discontinuation, whichever was first. Radiographic disease progression was evaluated by CT scan or MRI and radionuclide bone scans at regularly scheduled visits. Radiographic disease progression in bone required a confirmatory scan. Radiographic disease progression in soft tissue did not require a confirmatory scan for purposes of analysis. Radiographic disease progression was evaluated by independent central radiology review using RECIST 1.1 for soft tissue disease and PCWG2 guidelines for bone disease. Patients who did not reach the endpoint were censored at their last assessment.

Time to first skeletal-related event was defined as the time from randomization to the date of the first occurrence of a skeletal-related event for each patient. A skeletal-related event was defined as radiation therapy or surgery to bone for prostate cancer, pathological bone fracture, spinal cord compression, or initiation/change in antineoplastic therapy to treat bone pain from prostate cancer. Skeletal-related events were recorded at each scheduled and unscheduled study visit and during long-term follow-up if a skeletal-related event was not documented previously. Patients who did not have a skeletal-related event at the time of the analysis data cutoff were censored at the date of last assessment indicating no evidence of skeletal-related event. Patients with no postbaseline assessments were censored on the date of randomization.

The time to initiation of cytotoxic chemotherapy is defined as the time from randomization to the date of initiation of cytotoxic chemotherapy for the treatment of prostate cancer for each patient. For patients who did not start cytotoxic chemotherapy at the time of the analysis data cutoff, time to initiation of cytotoxic chemotherapy was censored at the date of last assessment where no cytotoxic chemotherapy was indicated or at the analysis data cutoff date, whichever was first. Time to initiation of cytotoxic chemotherapy for patients with no postbaseline assessments was censored on the date of randomization.

Time to PSA progression was defined as the time from randomization to date of first confirmed observation of PSA progression for each patient. For patients with PSA declines at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir was documented, and confirmed 3 or more weeks later. For patients with no PSA decline at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above baseline was documented, and confirmed 3 or more weeks later. For patients who did not have confirmed PSA progression at the time of the analysis data cutoff, time to PSA progression was censored at the date of the last PSA assessment showing no evidence of confirmed PSA progression or the analysis data cutoff date, whichever was first. Time to PSA progression for patients with no postbaseline assessments was censored on the date of randomization.

PSA response was defined as a ≥ 50% reduction in PSA from baseline to the lowest postbaseline PSA value and required confirmation by a consecutive assessment at least 3 weeks later. Patients were evaluable for PSA response rate if a patient had a PSA level measured at baseline and at least one postbaseline assessment.

The best overall soft tissue objective response is defined as partial response \[PR\] or complete response \[CR\] while on study treatment based on investigator assessments of target, nontarget, and new lesions using RECIST 1.1. Soft tissue was assessed by CT or MRI at regularly scheduled visits. Only patients with measurable soft tissue disease (ie, at least 1 target lesion identified per RECIST 1.1) at screening are included in this analysis. All percentages are based on number of participants with measurable soft tissue disease at screening in each treatment group.

Astellas Pharma Inc

Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Pfizer

Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Analysis was performed on safety set.

Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.

Participants received placebo, administered as four capsules, once per day by mouth.

Participants who received placebo in double-blind period and who agreed to proceed to open-label phase period, received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.

Placebo Participants Crossover to Enzalutamide

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Slovakia

Finland

Spain

Lithuania

Austria

Russian Federation

Israel

United Kingdom

Italy

France

Canada

Poland

Belgium

Singapore

Australia

Denmark

Netherlands

Germany

Japan

Sweden

Korea, Republic of

Region of Enrollment

Pfizer ClinicalTrials.gov Call Center

Intent to Treat (ITT) - All patients randomly assigned to treatment.

Overall Survival

Intent to Treat (ITT) - All patients randomly assigned to treatment excluding 84 patients who were not randomized before the radiographic Progression-free Survival data cutoff date of 06 May 2012.

Radiographic Progression-free Survival (rPFS)

Time to First Skeletal-related Event

Time to Initiation of Cytotoxic Chemotherapy

Intent to Treat (ITT) - All patients randomized.

Time to Prostate-specific Antigen (PSA) Progression

Evaluable intent to treat (ITT) population - All patients randomly assigned to treatment with PSA values at baseline and at least one postbaseline assessment.

Percentage of Patients With Prostate Specific Antigen (PSA) Response ≥ 50%

Intent to treat (ITT) population With Measurable Disease - All participants who were randomly assigned to treatment and had at least one target lesion at screening.

Best Overall Soft Tissue Response

SAEs

The safety analysis set included all randomized participants who received at least 1 dose or partial dose of study drug.

Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Number of Participants With Treatment-Emergent Adverse Events (AEs) Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute Common Terminology Criteria for AEs (CTCAE), Version 4.0

Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

Double-blind

Open-label

Rare Diseases

Kennedy Disease

Participants received 160 mg of enzalutamide orally once a day during double blind period until Prostate-Specific Antigen (PSA) progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer. Eligible participants who received enzalutamide during double blind and who provided consent to take part in open-label period continued to receive 160 mg of enzalutamide in open-label period orally once a day until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer.

Participants received enzalutamide matching placebo orally once a day during double-blind period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer.

Eligible participants who received enzalutamide matching placebo during double-blind period and who provided consent to take part in open-label period, received 160 mg of enzalutamide orally once a day during open-label period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer.

Central Contact

Purpose of the study was to assess the effect of enzalutamide on time to Prostate Specific Antigen (PSA) progression as compared to placebo in chemotherapy naïve participants with progressive metastatic prostate cancer who have failed androgen deprivation therapy.

The study was a multinational Phase 3, randomized, double-blind, placebo-controlled efficacy and safety study of oral enzalutamide (formerly MDV3100) in asymptomatic or mildly symptomatic participants with progressive metastatic prostate cancer who have disease progression despite androgen deprivation therapy. In order to join the study, participants could not have been previously treated with cytotoxic chemotherapy. Approximately 30 Chinese participants were allocated to the pharmacokinetic (PK) cohort. Participants in the PK cohort were required to be hospitalized from Day 1 before the randomization date to at least the completion of all the assessments planned on Day 3. All participants in the PK cohort underwent blood sampling for the PK analysis. Data reported in the results section was based on data cutoff dates of 20 Sept 2015 for efficacy and safety data and 20 Jan 2016 for PK outcome measures. The study completed double-blind period and is now in the open-label period.

An Asian Study to Evaluate Efficacy and Safety of Oral Enzalutamide in Progressive Metastatic Prostate Cancer Participants

Asian Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral Enzalutamide in Chemotherapy Naïve Subjects With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

The time to Prostate Specific Antigen (PSA) progression was defined as the time from randomization to the PSA progression. The PSA progression was defined according to the consensus guidelines of Prostate Cancer Clinical Trials Working Group 2 (PCWG2).For participants with PSA decline at Week 13, the PSA progression date was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir, which would be confirmed by a second consecutive value obtained 3 or more weeks later. For participants with no PSA decline at Week 13, the PSA progression date was defined as the date when a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline was documented, which was confirmed by a second consecutive value 3 or more weeks later. PSA progression at the time of the data analysis cutoff date could only be declared on or after week 13. Time to PSA progression was estimated using the Kaplan-Meier method. Participants without confirmed PSA progression were censored.

Duration of overall survival was defined as the time from the randomization to deaths from any cause. For participants who were alive at the time of the data analysis, overall survival time was censored to the last know date the participants were known to be alive or data analysis cutoff date, whichever occurred first.

Duration of Radiographic Progression-free Survival (rPFS) was defined as the time from randomization to the rPFS event (deaths from any cause and radiographic disease progression). Radiographic disease progression is defined by RECIST 1.1 for soft tissue disease, or PCWG2 for bone lesions. If a participant met the criteria for more than 1 censoring rule, they were censored with the earliest censoring date. The radiographic progression date was the first date when progression definition was met, not confirmed.

Time to first skeletal-related event (SRE) was defined as the time from randomization to the first skeletal-related event, defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of anti-neoplastic therapy to treat bone pain. Participants who have not had a SRE at the time of the analysis were censored at their last assessment indicating no evidence of SRE.

Time to initiation of cytotoxic chemotherapy was defined as the time from randomization to initiation of cytotoxic chemotherapy. It included only therapies for prostate cancer. When multiple cytotoxic chemotherapies were initiated, the first chemotherapy was used to determine the time to event. Participants who did not start cytotoxic chemotherapy at the time of analysis data cutoff were censored at the date of their last assessment indicating no evidence of cytotoxic chemotherapy usage.

Best PSA response was defined as as ≥50% reductions in PSA level from baseline to the lowest post-baseline PSA result as determined by the central laboratory, with a consecutive assessment conducted at least 3 weeks later to confirm the PSA response. Only participants who had both baseline and post-baseline assessments were included in the analysis.

Participants with measurable soft tissue disease at screening visit (i.e., at least one target lesion per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) who have an objective response (complete response (CR) or partial response (PR)) during the study were included in the best overall soft tissue response assessment. The best overall soft tissue response was based on the investigator assessment using RECIST 1.1.

N is the number of participants with available data at this time point.

The Treatment-Emergent Adverse Events are defined as AEs with a possible or probable relationship to study drug. If participant was still on study drug at the analysis data cutoff date, then the length of the treatment-emergent period was calculated through the cutoff date.

Data reported for deaths are the number of participants who died regardless of time (could be beyond treatment emergent adverse event time frame).

Participants received 160 mg of enzalutamide orally once a day during double blind period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 29.4 months). Eligible participants who received enzalutamide during double blind and who provided consent to take part in open-label period continued to receive 160 mg of enzalutamide in open-label period orally once a day until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 54.3 months). This arm represents both double blind and open-label period.

Participants received enzalutamide matching placebo orally once a day during double-blind period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 18.6 months). This arm represents only double blind period.

Eligible participants who received enzalutamide matching placebo during double-blind period and who provided consent to take part in open-label period, received 160 mg of enzalutamide orally once a day during open-label period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 53.8 months). This arm represents only open-label period.

Placebo Followed by Enzalutamide

Participants received 160 mg of enzalutamide orally once a day during double blind period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 29.4 months). Eligible participants who received enzalutamide during double blind and who provided consent to take part in open-label period continued to receive 160 mg of enzalutamide in open-label period orally once a day until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 54.3 months).

Participants received enzalutamide matching placebo orally once a day during double-blind period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 18.6 months). Eligible participants who received enzalutamide matching placebo during double-blind period and who provided consent to take part in open-label period, received 160 mg of enzalutamide orally once a day during open-label period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 53.8 months).

Race (NIH/OMB)

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

Intent-to-treat (ITT) population consisted of all randomized participants in the study. Data cutoff date was 04 Nov 2020.

Clinical Trial Disclosure

P-value is based on an unstratified log-rank test. Hazard ratio calculated using unstratified Cox Proportional Hazards model with treatment as the only covariate for enzalutamide group versus placebo group.

Participants received enzalutamide matching placebo orally once a day during double-blind period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 18.6 months).

Participants who were not known to have had died at the analysis date were censored at date last known alive or data analysis cutoff date, whichever occurred first. Hazard ratio calculated using unstratified Cox Proportional Hazards model with treatment as the only covariate for enzalutamide group versus placebo group.

Duration of Overall Survival

Participants who were not known to have had an rPFS event at the time of data cutoff were censored at the date of the last assessment showing no objective evidence of rPFS prior to scan modality change, new antineoplastic treatment, initiation of radiation therapy for prostate cancer, skeletal-related event (SRE) and 2 or more consecutive missed tumor assessments. Hazard ratio calculated using unstratified Cox Proportional Hazards model with treatment as the only covariate for enzalutamide.

Duration of Radiographic Progression-free Survival (rPFS) Based on Independent Central Review Facility Assessment

Participants who did not have an SRE at the time of analysis data cutoff were censored at the date of the last assessment indicating no evidence of SRE. Hazard ratio calculated using unstratified Cox Proportional Hazards model with treatment as the only covariate for enzalutamide group versus placebo group.

Time to First Skeletal-Related Event

Participants who did not start cytotoxic chemotherapy at the time of analysis data cutoff were censored at the date of the last assessment indicating no evidence of cytotoxic chemotherapy usage. Hazard ratio calculated using unstratified Cox Proportional Hazards model with treatment as the only covariate for enzalutamide group versus placebo group.

Number of Participants With Confirmed Best PSA Response (≥50% Decrease From Baseline)

When deriving the response category, it was based on the target, non-target and new lesions without confirming CR, PR, and Progressive disease (PD). Participants with no post baseline assessment were included in the category of Nonevaluable (NE). The best overall soft tissue objective response was defined as PR or CR based on the investigator assessments of target, non-target and new lesions while on the study treatment.

Day 1

Day 85

M1- Carboxylic Acid Metabolite

N-desmethyl enzalutamide (active metabolite)

M2- N-Desmethyl Enzalutamide

Enzalutamide Plus M2

The Pharmacokinetic Analysis Set (PKAS) population consisted of all participants who received at least 1 dose of study drug and who provided blood samples for drug concentrations at at least 1 time point.

Time to Maximum Concentration (Tmax) of Enzalutamide, M1,M2 and Enzalutamide Plus M2

Maximum Observed Plasma Concentration During the First 24 Hours After Dosing (Cmax) Enzalutamide, M1,M2 and Enzalutamide Plus M2

The Pharmacokinetic Analysis Set (PKAS) population consisted of all participants who received at least 1 dose of study drug and who provided blood samples for drug concentrations at at least 1 time point. Number of participants analyzed is the number of participants with available data at this time point.

AUC From the Time of Dosing to 24 h After Dosing (AUC24h) Enzalutamide, M1,M2 and Enzalutamide Plus M2

Concentration 24 h After Dosing (C24h) Enzalutamide, M1,M2 and Enzalutamide Plus M2

Day 2 predose

Day 3 predose

Day 8 predose

Day 22 predose

Day 29 predose

Day 43 predose

Day 57 predose

Day 85 predose

Day 86 predose

Day 113 predose

Day 141 predose

Day 169 predose

N-desmethyl enzalutamide (active metabolite).

The Pharmacokinetic Analysis Set (PKAS) population consisted of all participants who received at least 1 dose of study drug and who provided blood samples for drug concentrations at least 1 time point.

Observed Plasma Concentration in Predose Samples Obtained During Multiple-dose Administration of Minimum Concentration (Plasma Concentration at Pre Dose) (Cmin) Enzalutamide, M1,M2 and Enzalutamide Plus M2

Apparent Total Systemic Clearance After Multiple Dosing (CL/F) Enzalutamide, M1,M2 and Enzalutamide Plus M2 (For Unchanged Enzalutamide Only)

Peak-Trough Ratio (PTR) Enzalutamide, M1,M2 and Enzalutamide Plus M2

AUC From the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) Enzalutamide, M1,M2 and Enzalutamide Plus M2

Treatment Emergent Adverse Events (TEAEs)

Grade 3 or Higher TEAE

TEAE Leading to Death

Serious TEAE

TEAE That Was Primary Reason for Treatment Discontinuation

TEAE Leading to Study Drug Discontinuation

TEAE Leading to Dose Reduction of Study Drug

TEAE Leading to Dose Interruption of Study Drug

TEAE Related to Study Drug

Grade 3 or Higher TEAE Related to Study Drug

Serious TEAE Related to Study Drug

Safety Analysis Set consisted of all randomized participants who received at least 1 dose of study drug.

Number of Participants With Adverse Events (AE)

Participants received 160 mg of enzalutamide orally once a day during double blind period until Prostate-Specific Antigen (PSA) progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 29.4 months). Eligible participants who received enzalutamide during double blind and who provided consent to take part in open-label period continued to receive 160 mg of enzalutamide in open-label period orally once a day until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer (up to 54.3 months).

Double-blind Period (up to 29.4 Months)

Open-label Period (up to 54.3 Months)

Antineoplastic Agents

Antirheumatic Agents

Antibodies

Antibodies, Monoclonal

Cyclophosphamide

Immunoglobulins

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Cyclophosphamide 300 mg/m2 IV on Day 1; Radiation Therapy 8.0 Gy in 1 fraction to a maximum of three bone metastatic deposits will be administered on Day 4 of treatment; Anti-OX40 will be administered intravenously at 0.4 mg/kg on days 4, 6 and 8.

Cyclophosphamide 600 mg/m2 IV on Day 1; Radiation Therapy 8.0 Gy in 1 fraction to a maximum of three bone metastatic deposits will be administered on Day 4 of treatment; Anti-OX40 will be administered intravenously at 0.4 mg/kg on days 4, 6 and 8.

Cyclophosphamide 900 mg/m2 IV on Day 1; Radiation Therapy 8.0 Gy in 1 fraction to a maximum of three bone metastatic deposits will be administered on Day 4 of treatment; Anti-OX40 will be administered intravenously at 0.4 mg/kg on days 4, 6 and 8.

Anti-OX40 will be administered intravenously at 0.4 mg/kg on days 4, 6 and 8 of the study. The total anti-OX40 dose will be reconstituted in 100 ml 0.9% saline and infused over no more than 60 minutes intravenously. A single-use non-pyrogenic durapore membrane low protein binding filter (e.g.: Braun 1.2 micron air eliminating filter or equivalent) shall be used to filter the study product in the line between infusion bag and patient.

Anti-OX40

8.0 Gy in 1 fraction to a maximum of three bone metastatic deposits will be administered on Day 4 of treatment. Imaging such as bone scan, MRI, CT scan, or radiograph must identify the target lesion as consistent with metastatic disease. Any bone lesion that is inducing pain or where there may be a clinical concern for potential pathological fracture will be selected over asymptomatic lesions.

Radiation

CTX will be administered on day 1 (Friday only) at a dose determined by cohort assignment. The drug should be diluted per institutional standards. An added dose of IV fluids may help prevent bladder toxicity. In this protocol, CTX will be administered intravenously over 30 - 60 minutes.

Brendan D Curti, MD

This clinical trial will examine a novel combination of anti-OX40 to induce proliferation of memory and effector T cells in conjunction with cyclophosphamide (CTX) and radiation to induce tumor antigen release with the overall goal of promoting an immune response against prostate cancer.

A Phase Ib trial design will be employed in patients with metastatic PC who have failed prior androgen ablation and docetaxel. CTX will be administered also on Day 1. All patients will receive RT (800 cGy in a single fraction) to up to 3 bone metastatic sites on Day 4 in the AM. Anti-OX40 at 0.4 mg/kg IV will be given on days 4, 6 and 8. The timing of CTX, RT and anti-OX40 are based on the pre-clinical models and the observation that the synergies of CTX and RT are reduced when they are given more than one week after anti-OX40 and are maximized when given within 3 days of starting anti-OX40. The proposed radiation dose is commonly used to palliate bone pain in PC and generally will not induce significant cytopenias. The CTX dose will be escalated in successive cohorts of 3 - 6 patients to assure patient safety. The dose levels of CTX will be 300, 600 and 900 mg/m2 intravenously in the initial stage of the study. The range of CTX doses is commonly used in general oncology practice and is not expected to induce prolonged myelosuppression, although transient cytopenias are likely. Concurrent CTX and RT has been well-tolerated at much higher dose-intensities than the investigators are proposing (52-54), thus the investigators are not expecting significant adverse events from the combination before anti-OX40. As a safety consideration, the investigators are not giving CTX and RT on the same day as a high proportion of men with prostate cancer have bone metastases in the pelvis. RT to the pelvis could cause radiation cystitis that would be exacerbated by the metabolites of CTX (e.g., acrolein) that can accumulate in the bladder in the 24-36 hours after administration. After the dose-escalation portion of the trial then up to 20 additional patients can enroll in the study at the maximum tolerated CTX dose if clinical responses are seen, for a maximum total of 37 patients using a Simon two-stage design (see Section 10 for details).

The main clinical objective of the trial will be to characterize toxicity and estimate the response rate of the combination of anti-OX40, CTX and RT. Both radiographic and PSA responses will be followed. RECIST will be used for radiographic assessment and a significant PSA response will be defined as a 50% or greater decrease from baseline measured at 3 and 6 weeks after the start of treatment based on the PCWG2 guidelines (55).

Patients will enroll consecutively to each cohort assuming no dose-limiting toxicities. Three patients will be treated per cohort and if there are no dose-limiting toxicities, then enrollment to the next cohort can begin. If a dose-limiting toxicity is encountered in the first three patients in any cohort, then an additional three patients will be enrolled in that cohort.\* This dosing strategy will allow for a three-fold escalation of CTX.

The main hypothesis of this study is that CTX and RT will induce tumor breakdown providing a source of antigen for self-vaccination and anti-OX40 will amplify CD8-mediated effector responses across a broad spectrum of prostate cancer antigens resulting in further regression of prostate cancer. The investigators predict that anti-OX40 will not increase circulating or intratumoral Treg, and this should help to further augment immune responses.

\*For the dose escalation portion of the study, the first 2 patients in any cohort can be treated on consecutive weeks. If there are no Dose Limiting Toxicities, then the third patient can begin treatment 28 days after the second patient has completed anti-OX40. If the third patient has no DLT, then the next cohort can open 28 days after the third patient has completed anti-OX40. If a DLT occurs with patient 3 in any cohort, then up to 3 more patients will enroll to the same cohort at a frequency of one patient every 28 days after the previous patient has completed anti-OX40 assuming no DLT.

Anti-OX40, Cyclophosphamide (CTX) and Radiation in Patients With Progressive Metastatic Prostate Cancer

Phase Ib Study of Monoclonal Antibody to OX40, Cyclophosphamide (CTX) and Radiation in Patients With Progressive Metastatic Prostate Cancer After Systemic Therapy

The primary objective of this trial is to determine the maximum tolerated dose (within the range expected to induce anti-tumor and immunological effects) of CTX administered in combination with radiation and anti-OX40 in men with metastatic castrate- and chemotherapy-resistant prostate cancer.

Secondary objectives are as follows:

1. Determine the effect of anti-OX40, CTX and radiation on circulating numbers and phenotypes of CD4 and CD8 T cells.
2. Measure the proliferation and activity of effector and memory T cells after CTX, radiation and anti-OX40.
3. Perform exploratory studies of cellular and humoral immune responses against prostate cancer cell lines.
4. Estimate the response rate of the regimen that includes the highest dose of CTX determined to be safe.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer	NCT01212991	Prostate Cancer	Enzalutamide Placebo	18 Years -	Pfizer
An Asian Study to Evaluate Efficacy and Safety of Oral Enzalutamide in Progressive Metastatic Prostate Cancer Participants	NCT02294461	Progressive Met...	Enzalutamide Placebo	18 Years -	Astellas Pharma Inc
An Asian Study to Evaluate Efficacy and Safety of Oral Enzalutamide in Progressive Metastatic Prostate Cancer Participants	NCT02294461	Progressive Met...	Enzalutamide Placebo	18 Years -	Astellas Pharma Inc
Anti-OX40, Cyclophosphamide (CTX) and Radiation in Patients With Progressive Metastatic Prostate Cancer	NCT01303705	Metastatic Pros... Cancer of the P... Prostate Cancer	Anti-OX40 Radiation Cyclophosphamid...	18 Years -	Providence Health & Services

Spots Global Cancer Trial Database for progressive metastatic prostate cancer