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Prostatic Neoplasms

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Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

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Hormones

Subjects will be administered with 250 milligram (mg), 500 mg, 1000 mg or 1500 mg of EMD 525797 intravenously over 1 hour every 2 weeks for 6 weeks. Subjects who will be clinically benefitted at the end of week 6 were continued at the same dose-level until disease progression, intolerance to treatment, withdrawal of consent or if the subject is no longer benefitted from the treatment as per Investigator's discretion.

EMD 525797

Wolfgang Uhl, Dr, Dipl. Chem., Physician

This study is intended to test an experimental new drug called, EMD 525797 (Study Drug). This drug is not yet approved for sale and has only been tested in a small number of people to date (prior to this study starting another research study was carried out involving 37 healthy volunteers receiving the Study Drug). Until more is known about this Study Drug, it can only be used in research studies.

This research study is planned to answer important questions about how the Study Drug is tolerated and how it may work in patients with prostate cancer with bone metastases.

This is a small study which is expected to include 24 patients, and will be conducted in approximately 3 hospitals in Germany and 1 hospital in Brussels, Belgium. The study will last until the last patient has had their last study visit which is expected to be about 18 months in total.

A Study to Determine the Safety, Tolerability, Pharmacokinetics and Dynamic Effects of Different Doses of the Study Drug EMD 525797 in Prostate Cancer

Phase I, Open-label Study to Investigate Safety, Tolerability, PK, and PD of EMD 525797 After Single and Repeated Dosing at Different Dose Levels in Subjects With Hormone-resistant Prostate Cancer With Bone Mets and Progressive Disease Following Prior CTX

DLT was defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3.0 as any Grade 3 or 4 hematological or non-hematological toxicity occurring at any dose level until the end of Week 6, and suspected to be reasonably related to the investigational product by the Investigator and/or Sponsor except for allergic/ hypersensitivity reactions and any Grade 3/4 out-of-range laboratory values without any clinical correlate, which were reversible within 7 days.

An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) 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 or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs.Treatment-related are events which had causal relationship to study drug as assessed by the Investigator and were suspected to be reasonably related to the study drug.

Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above lower limit of quantification (LLQ). AUC0-t was calculated according to the mixed log linear trapezoidal rule.

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Total body clearance of drug from serum, calculated as CL = dose/AUC0-inf. Where AUC0-inf is area under the serum concentration time curve from time zero to infinity, calculated as AUC0 t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above lower limit of quantification (LLQ) and λz is elimination rate constant.

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as = Dose/(AUC0-inf \*λz) after first infusion. Where 'λz' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Where AUC0-inf is area under the serum concentration time curve from time zero to infinity, calculated as AUC0 t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above lower limit of quantification (LLQ) and λz is elimination rate constant.

Ctrough is the concentration prior to study drug administration.

Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base e (Log e) multiplied by (\*) 2/ λz, where 'λz' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data.

Observed minimum serum concentration determined directly from the serum concentration-time profile of each subject.

The average serum concentration at steady state, calculated as Cav = AUCtau/tau, where tau is the dosing interval (336 hours).

Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (168 hours).

Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (336 hours).

Area under the serum concentration time curve from time zero to infinity, calculated as AUC0 t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above LLQ and λz is elimination rate constant.

The peak trough fluctuation over one dosing interval at steady state, calculated as PTF (%) = ( \[ Cmax - Cmin \] / Cav )\*100

Mean residence time of drug in the body calculated as: AUMC0-inf / AUC0-inf, where AUMC0-inf is the area under the first moment curve from time zero to infinity. Where AUC0-inf is area under the serum concentration time curve from time zero to infinity, calculated as AUC0 t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above lower limit of quantification (LLQ) and λz is elimination rate constant.

Apparent volume of distribution at steady-state was reported. Apparent volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug.

Accumulation ratio for Cmax was calculated as Cmax, after third dose/Cmax, after first dose.

Accumulation ratio for AUC, calculated as area under the serum concentration-time curve within one complete dosing interval at third dose divided by area under the serum concentration-time curve within one complete dosing interval at first dose.

Number of subjects with BOR in each category (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) was reported. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: defined as at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. PD:defined as at least a 20% increase in sum of longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of longest diameter while on study.

PFS PCWG1 criteria: time from the day treatment is initiated up to progression (for subject's whose prostate specific antigen \[PSA\] level did not decrease after baseline, progression defined as 50% PSA increase relative to baseline; for subject's whose PSA decreased after baseline, progression defined as 50% PSA increase relative to nadir \[smallest PSA value post-baseline\]. Progression was confirmed if progression criterion was met in next 2 assessments as well.) PFS PCWG2 criteria: time from study entry to disease progression or death. Progression was defined as first appearance of progression according to PSA (for subject's whose PSA decreased after baseline, progression was defined as 25% PSA increase relative to nadir. Progression was confirmed if another assessment measured at least 3 weeks later met the criterion as well; for subject's whose PSA did not decrease after baseline, progression was defined as 25% PSA increase relative to baseline assessed 12 weeks after baseline).

TTP was calculated as the time between the date of imaging for the earliest visit where progressive disease was detected and the first dose date plus 1 day. Participants without event are censored on the date of last tumor assessment.

ECOG performance status measured to assess subject's performance status on a scale of 0 to 4, where 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity, ambulatory and able to carry out light or sedentary work; 2=Ambulatory (\>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=Capable of only limited self-care, confined to bed/chair \>50% of waking hours; 4=Completely disabled, cannot carry on any self-care, totally confined to bed/chair. ECOG performance status was reported in terms of number of subjects with Baseline value vs. worst post-baseline value (i.e. highest score) combination.

ECOG performance status measured to assess subject's performance status on a scale of 0 to 4, where 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity, ambulatory and able to carry out light or sedentary work; 2=Ambulatory (\>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=Capable of only limited self-care, confined to bed/chair \>50% of waking hours; 4=Completely disabled, cannot carry on any self-care, totally confined to bed/chair. ECOG performance status was reported in terms of number of subjects with Baseline value vs. best post-baseline value (i.e. lowest score) combination.

BPI-sf is an 11-item self-report questionnaire that is designed to assess the severity and impact of pain on daily functions. BPI-sf has 4 questions that assess pain intensity (worst, least, average, right now) and 7 questions that assess impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each question is answered on a scale ranging from 0 to 10;'0=No pain and 10=Pain as bad as you can imagine'.Total score is reported as average of individual questions ranges from 0 to 10, with lower scores being indicative of less pain or pain interference.Data was not available for "EMD 525797 250 mg" arm for FUP Weeks 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75 and "EMD 525797 1000 mg" arm for FUP Weeks 47, 51, 55, 59, 63, 67, 71 and "EMD 525797 1500 mg arm" for FUP Weeks 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75 respectively as no subjects were evaluable at the specified FUP visits.

Maximum percent change from Baseline in PSA Level during the study was reported.

Minimum percent change from Baseline in PSA Level during the study was reported.

Merck KGaA, Darmstadt, Germany

Subjects were administered with 250 milligram (mg) of EMD 525797 intravenously over 1 hour every 2 weeks for 6 weeks. Subjects who were clinically benefitted at the end of Week 6 continued at the same dose-level until disease progression, intolerance to treatment, withdrawal of consent or if the subject was no longer benefitted from the treatment as per Investigator's discretion.

EMD 525797 250 mg

Subjects were administered with 500 mg of EMD 525797 intravenously over 1 hour every 2 weeks for 6 weeks. Subjects who were clinically benefitted at the end of Week 6 continued at the same dose-level until disease progression, intolerance to treatment, withdrawal of consent or if the subject was no longer benefitted from the treatment as per Investigator's discretion.

EMD 525797 500 mg

Subjects were administered with 1000 mg of EMD 525797 intravenously over 1 hour every 2 weeks for 6 weeks. Subjects who were clinically benefitted at the end of Week 6 continued at the same dose-level until disease progression, intolerance to treatment, withdrawal of consent or if the subject was no longer benefitted from the treatment as per Investigator's discretion.

EMD 525797 1000 mg

Subjects were administered with 1500 mg of EMD 525797 intravenously over 1 hour every 2 weeks for 6 weeks. Subjects who were clinically benefitted at the end of Week 6 continued at the same dose-level until disease progression, intolerance to treatment, withdrawal of consent or if the subject was no longer benefitted from the treatment as per Investigator's discretion.

EMD 525797 1500 mg

Total

Age, Continuous

Sex: Female, Male

Safety analysis set included all subjects who received at least 1 dose of the study medication and had at least 1 follow-up safety measure.

Merck KGaA Communication Center

DLT analysis set: all subjects who experienced any DLT during first 6 weeks, regardless of number of doses of drug administered or who were considered completers (did not discontinue treatment for any reason other than DLT, were compliant, did not deviate in drug administration for more than +/-2 days due to any reason other than related toxicity).

Number of Subjects With Dose Limiting Toxicity (DLT)

TEAEs

Serious TEAEs

Related TEAEs

Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs

Pharmacokinetic (PK) analysis set included all subjects who received at least first dose of the study drug according to the protocol and who provided sufficient data for a concentration time profile for EMD 525797.Here "Number of Participants analyzed" signifies those subjects who were evaluable for this outcome measure for each arm, respectively.

Observed Maximum Serum Concentration (Cmax) of EMD 525797 After First Infusion

PK analysis set included all subjects who received at least the first dose of the study drug according to the protocol and who provided sufficient data for a concentration time profile for EMD 525797. Here "Number of Participants analyzed" signifies those subjects who were evaluable for this outcome measure for each arm, respectively.

Observed Maximum Serum Concentration (Cmax) of EMD 525797 After Third Infusion

Area Under the Serum Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) After First Infusion

Total Body Clearance of Drug From Serum (CL) After First Infusion

Apparent Volume of Distribution During Terminal Phase (Vz) of EMD 525797 After First Infusion

Trough Serum Concentration (Ctrough) Of EMD 525797 at Week 1

Trough Serum Concentration (Ctrough) Of EMD 525797 at Week 3

Trough Serum Concentration (Ctrough) Of EMD 525797 at Week 5

Time to Reach Observed Serum Concentration (Tmax) After First Infusion

Time to Reach Observed Serum Concentration (Tmax) After Third Infusion

Week 1

Week 3

Week 5

Week 8

Week 9

Number of Subjects With Positive Anti-EMD 525797 Antibodies

Subjects were administered with 250 milligram (mg) mg of EMD 525797 intravenously over 1 hour every 2 weeks for 6 weeks. Subjects who will be clinically benefitted at the end of Week 6 will continue at the same dose-level until disease progression, intolerance to treatment, withdrawal of consent or if the subject was no longer benefitted from the treatment as per Investigator's discretion.

Subjects were administered with 500 mg of EMD 525797 intravenously over 1 hour every 2 weeks for 6 weeks. Subjects who will be clinically benefitted at the end of Week 6 will continue at the same dose-level until disease progression, intolerance to treatment, withdrawal of consent or if the subject was no longer benefitted from the treatment as per Investigator's discretion.

Subjects were administered with 1000 mg of EMD 525797 intravenously over 1 hour every 2 weeks for 6 weeks. Subjects who will be clinically benefitted at the end of Week 6 will continue at the same dose-level until disease progression, intolerance to treatment, withdrawal of consent or if the subject was no longer benefitted from the treatment as per Investigator's discretion.

Subjects were administered with 1500 mg of EMD 525797 intravenously over 1 hour every 2 weeks for 6 weeks. Subjects who will be clinically benefitted at the end of Week 6 will continue at the same dose-level until disease progression, intolerance to treatment, withdrawal of consent or if the subject was no longer benefitted from the treatment as per Investigator's discretion.

As per change in planned analysis, it was decided that that the biomarker analysis were not significantly associated with compound administration and thus the data was not collected for this outcome.

Serum Levels of Interleukin 6 (IL-6) and Interleukin 8 (IL-8)

C-Reactive Protein Levels

Apparent Terminal Half-life (t1/2) of EMD 525797 After First Infusion

PK analysis set included all subjects who received at least first dose of the study drug according to the protocol and who provided sufficient data for a concentration time profile for EMD 525797. Here "Number of Participants analyzed" signifies those subjects who were evaluable for this outcome measure for each arm, respectively.

Elimination Rate Constant (λz) of EMD 525797 After First Infusion

Observed Minimum Serum Concentration (Cmin) of EMD 525797 After Third Infusion

Average Serum Concentration at Steady State (Cav) of EMD 525797 After Third Infusion

Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval (AUCtau) of EMD 525797 After First Infusion

Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval (AUCtau) of EMD 525797 After Third Infusion

Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of EMD 525797 After First Infusion

Peak Trough Fluctuation Over One Dosing Interval at Steady State (%PTF) of EMD 525797 After Third Infusion

Mean Residence Time of Drug in the Body (MRT) of EMD 525797 After First Infusion

Apparent Volume of Distribution at Steady State (Vss) of EMD 525797 After Third Infusion

Accumulation Ratio Of Cmax (R_Cmax)

Accumulation Ratio of AUC (R_AUC)

Week 6: CR

Week 6: PR

Week 6: SD

Week 6: PD

Week 19: CR

Week 19: PR

Week 19: SD

Week 19: PD

Overall: CR

Overall: PR

Overall: SD

Overall: PD

Efficacy analysis set included all subjects who received at least 1 dose of the study drug.

Number of Subjects With Best Overall Response (BOR)

PCWG1

PCWG2

Progression-free Survival (PFS) as Per Prostate Cancer Clinical Trials Working Group 1 (PCWG1) and Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Criteria

Subject 1

Subject 2

Subject 3

Efficacy analysis set included all subjects who received at least 1 dose of the study drug. Here "Number of Participants" analyzed signifies those subjects who were evaluable for this outcome measure.

Time to Progression (TTP)

Baseline score 0, worst post-baseline score 0

Baseline score 0, worst post-baseline score 1

Baseline score 0, worst post-baseline score 2

Baseline score 0, worst post-baseline score 3

Baseline score 0, worst post-baseline score 4

Baseline score 1, worst post-baseline score 0

Baseline score 1, worst post-baseline score 1

Baseline score 1, worst post-baseline score 2

Baseline score 1, worst post-baseline score 3

Baseline score 1, worst post-baseline score 4

Baseline score 2, worst post-baseline score 0

Baseline score 2, worst post-baseline score 1

Baseline score 2, worst post-baseline score 2

Baseline score 2, worst post-baseline score 3

Baseline score 2, worst post-baseline score 4

Baseline score 3, worst post-baseline score 0

Baseline score 3, worst post-baseline score 1

Baseline score 3, worst post-baseline score 2

Baseline score 3, worst post-baseline score 3

Baseline score 3, worst post-baseline score 4

Baseline score 4, worst post-baseline score 0

Baseline score 4, worst post-baseline score 1

Baseline score 4, worst post-baseline score 2

Baseline score 4, worst post-baseline score 3

Baseline score 4, worst post-baseline score 4

Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score vs. Worst Post-baseline Score

Baseline score 0, best post-baseline score 0

Baseline score 0, best post-baseline score 1

Baseline score 0, best post-baseline score 2

Baseline score 0, best post-baseline score 3

Baseline score 0, best post-baseline score 4

Baseline score 1, best post-baseline score 0

Baseline score 1, best post-baseline score 1

Baseline score 1, best post-baseline score 2

Baseline score 1, best post-baseline score 3

Baseline score 1, best post-baseline score 4

Baseline score 2, best post-baseline score 0

Baseline score 2, best post-baseline score 1

Baseline score 2, best post-baseline score 2

Baseline score 2, best post-baseline score 3

Baseline score 2, best post-baseline score 4

Baseline score 3, best post-baseline score 0

Baseline score 3, best post-baseline score 1

Baseline score 3, best post-baseline score 2

Baseline score 3, best post-baseline score 3

Baseline score 3, best post-baseline score 4

Baseline score 4, best post-baseline score 0

Baseline score 4, best post-baseline score 1

Baseline score 4, best post-baseline score 2

Baseline score 4, best post-baseline score 3

Baseline score 4, best post-baseline score 4

Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score vs. Best Post-baseline Score

Screening

Baseline

Week 7

FUP Week 11

FUP Week 15

FUP Week 19

FUP Week 23

FUP Week 27

FUP Week 31

FUP Week 35

FUP Week 39

FUP Week 43

FUP Week 47

FUP Week 51

FUP Week 55

FUP Week 59

FUP Week 63

FUP Week 67

FUP Week 71

FUP Week 75

Efficacy analysis set included all subjects who received at least 1 dose of the study drug. Here "n" signifies those subjects who were evaluable for this outciome measure at the specified time points.

Spots Global Cancer Trial Database for pharmacodynamics of emd 525797