EMD 525797 in Subjects With Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer

Study Overview
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Brief Summary
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The primary objective of the trial is to evaluate the clinical anti-tumor activity of EMD 525797 administered as 1-hour intravenous infusion every 3 weeks in terms of progression free survival (PFS) time in subjects with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer (mCRPC).

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multicenter Phase II Trial Investigating Two Doses of EMD 525797 in Subjects With Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer (mCRPC)

Conditions
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Prostate Cancer Metastatic

Intervention / Treatment
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* Drug: EMD 525797
* Drug: EMD 525797
* Other: Placebo
* Other: Standard of Care (SoC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate (Gleason score) Bisphosphonate treatment Stable, ongoing adequate testosterone suppression proven by hypogonadal levels of testosterone (less than or equal to) <= 50 nanogram per deciliter [ng/dL]) for subjects without surgical castration (luteinizing hormone-releasing hormone antagonists and agonists) Other protocol defined inclusion criteria could apply Exclusion Criteria: Prior chemotherapy, biologic therapy (targeted therapy), or any experimental therapy for mCRPC Chronic and ongoing treatment with opioids Acute pathologic fracture, spinal cord compression, or hypercalcemia at Screening Visceral metastasis, brain metastasis Radiotherapy to bone lesions and/or orthopedic surgery for pathologic fractures. Any kinds of major elective surgery within 30 days prior to trial treatment Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo + Standard of care (SoC)<br> | Other: Placebo<br>* Subjects will be administered with placebo (as 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons.<br>Other: Standard of Care (SoC)<br>* All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists).<br>|
| Experimental: EMD 525797 750 mg + SoC<br> | Drug: EMD 525797<br>* Subjects will be administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons.<br>Other: Standard of Care (SoC)<br>* All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists).<br>|
| Experimental: EMD 525797 1500 mg + SoC<br> | Drug: EMD 525797<br>* Subjects will be administered with EMD 525797 at a dose of 1500 milligram (mg) (diluted with 0.9 percent [%] sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons.<br>Other: Standard of Care (SoC)<br>* All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Time | PFS was defined as time from randomization until the first documented sign of objective radiographic disease progression (ORDP) or death from any cause. Death was considered as an event only if it was reported within 12 weeks after last tumor assessment without progression. ORDP was defined as: Bone lesion progression (2 or more new bone lesions compared to baseline) assessed with bone scintigraphy. Assessment was based on Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0) modified as per Prostate Cancer Working Group 2 (PCWG-2); Soft-tissue lesion progression assessed with CT scans according to RECIST v1.0 modified as per PCWG-2; Presence of skeletal events defined as cord compression/fracture documented via a scheduled or unscheduled radiographic assessment triggered by increased pain or other signs and/or symptoms, based on the investigator's discretion; Non-radiological events, including emergency bone irradiation and surgery, were not investigated. | Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival was defined as the time from the date of randomization to the date of death from any cause. | Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years | 
| Time to Tumor Progression | Time to tumor progression was defined as the time from the date of randomization to the date of ORDP. ORDP was defined as: Bone lesion progression (2 or more new bone lesions compared to baseline) assessed with bone scintigraphy, which had to be confirmed by bone scintigraphy 6 weeks later if subjects remained asymptomatic or mildly symptomatic. Assessments were to be based on RECIST v1.0 modified according to PCWG-2; Soft-tissue lesion progression assessed with CT scans according to RECIST v1.0 modified as per PCWG-2; Presence of skeletal events defined as cord compression or fracture documented via a scheduled or unscheduled radiographic assessment triggered by increased pain or other signs and/or symptoms, based on the investigator's discretion; Non-radiological events, including emergency bone irradiation and surgery, were not investigated. | Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years | 
| Number of Subjects With Presence of Tumor Response and Disease Control (DC) in Soft Tissue Lesions | Presence of tumor response in soft tissue lesions was defined as the presence of at least 1 confirmed complete response (CR) or confirmed partial response (PR) in soft tissue lesions, documented by computed tomography (CT) scans. Presence of DC in soft tissue lesions was defined as the presence of at least 1 confirmed CR or confirmed PR or stable disease (SD) lasting at least 12 weeks after randomization. Tumor response assessments were based on RECIST v1.0 modified according to the PCWG-2. The response was evaluated for subjects with measurable disease at baseline. According to RECIST v1.0, CR=disappearance of all target and non-target lesions; PR=at least 30% decrease in the sum of the longest diameter of target lesions and non-complete response/non-progressive disease in non-target lesions. | Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years | 
| Number of Subjects With New Bone Lesions Compared to Baseline | New bone lesions were evaluated by bone scintigraphy for subjects with bone lesions at baseline. | Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years | 
| Number of Subjects With Presence of DC in Bone Lesions | Presence of DC in bone lesions was defined as the appearance of less than 2 new bone lesions, documented by bone scintigraphy. | At Weeks 13, 19 and 25 | 
| Bone and Soft Tissue Lesions Composite Tumor Response | Bone and soft tissue lesions composite tumor response was defined as the presence of both a confirmed CR or PR, documented by CT scans, and a DC in bone lesions, documented by bone scintigraphy. CR was defined as disappearance of all target and non-target lesions and PR was defined as at least 30% decrease in the sum of the longest diameter of target lesions and non-complete response/non-progressive disease in non-target lesions. Presence of DC in bone lesions was defined as the appearance of less than 2 new bone lesions. | Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years | 
| Number of Subjects With Presence of Skeletal Related Events | Presence of skeletal related events was defined as cord compression or fracture documented via a scheduled or unscheduled radiographic assessment triggered by increased pain or other signs and/or symptoms at the investigator discretion. Non-radiological events, including emergency bone irradiation and surgery, were not investigated. | Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years | 
| Number of Subjects With Presence of Prostate Specific Antigen (PSA) Response | PSA response was defined as a decrease greater than 50 percent (%) in PSA value from baseline for 2 consecutive evaluations greater than or equal to (>=) 3 Weeks apart. | Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years | 
| Minimum Percentage Change From Baseline in PSA Serum Concentration |  | Baseline, up to data cut-off date (30 April 2013), assessed up to 2 years | 
| Minimum Percentage Change From Baseline in the Number of Circulating Tumor Cells (CTCs) |  | Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years | 
| Overall Minimum Percentage Change From Previous Time Point in Circulating Tumor Cells (CTC) |  | Cycle 1, Day 1 (Week 1): pre-dose, Cycle 3, Day 1 (Week 7): pre-dose, and Cycle 5, Day 1 (Week 13): pre-dose | 
| Number of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation | An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as those AEs that started between first dose of study drug and up to 50 days after last dose. | From the first dose of study drug administration until 50 days after the last dose of study drug administration or until cut-off date (30 April 2013), assessed up to 2 years | 
| Pharmacokinetic Parameter: Clearance of Intravenously Administered EMD 525797 After First Dose (CL) and Clearance in Steady State of EMD52597 After Fifth Dose (CLss) | The apparent total body clearance of drug following intravenous administration (CL); The apparent total body clearance of drug at steady state following intravenous administration (CLss). | Cycle 1 (Week 1) and cycle 5 (Week 13): Day 1: pre-dose, End of Infusion (EOI), 4, 8, 24, 48, 96, 168, 336, and 504 hours after start of infusion; Cycles 3 and 4 (Weeks 7 and 10), Day 1: pre-dose; Cycle 7 (Week 19), Day 1: pre-dose and EOI | 
| Pharmacokinetic Parameter: Volume of Distribution of EMD 525797 After the First Dose (V) and in Steady State After the Fifth Dose (Vss) of Intravenous Infusion | The apparent volume of distribution during the terminal phase following intravenous administration (V). The estimate of the apparent volume of distribution at steady state following intravenous administration (Vss). | Cycle 1 (Week 1) and cycle 5 (Week 13): Day 1: pre-dose, End of Infusion (EOI), 4, 8, 24, 48, 96, 168, 336, and 504 hours after start of infusion; Cycles 3 and 4 (Weeks 7 and 10), Day 1: pre-dose; Cycle 7 (Week 19), Day 1: pre-dose and EOI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asymptomatic, mildly symptomatic, metastatic castrate-resistant prostate cancer, mCRPC