Symptoms and General Pathology

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All Drugs and Chemicals

Antibodies

Immunoglobulins

Subjects will receive 250 milligram (mg) of EMD525797 intravenously every 2 weeks, until progressive disease (PD), unacceptable toxicity or withdrawal of consent.

EMD525797

Subjects will receive 500 mg of EMD525797 intravenously every 2 weeks, until PD or unacceptable toxicity or withdrawal of consent.

Subjects will receive 1000 mg of EMD525797 intravenously every 2 weeks, until PD or unacceptable toxicity or withdrawal of consent.

Subjects will receive 1500 mg of EMD525797 intravenously every 2 weeks, until PD or unacceptable toxicity, or withdrawal of consent.

Medical Responsible

The primary objectives are to assess the safety and tolerability of single and repeated doses of EMD525797, and characterize Pharmacokinetics (PK). The secondary objectives are to investigate the immunogenicity and Progressive disease (PD), and to assess the anti-tumor activity of EMD525797.

A Study of EMD525797 in Solid Tumor Patients in Japan

A Phase I, Open-label Trial to Investigate the Safety, Tolerability, and Pharmacokinetics of EMD525797 After Single Dose and Repeated Dosing at Different Dose Levels in Japanese Patients With Advanced or Metastatic Solid Tumors and Progressive Diseases Following Prior Chemotherapy

DLT was defined as any Grade 3 or 4 haematological or non-haematological toxicity occurring at any dose level until the end of Week 4, and suspected to be reasonably related to the investigational medicinal product by the Investigator and/or Sponsor. Toxicities not considered to be DLTs are as follows- Allergic reactions or anaphylaxis; any Grade 3 or 4 out-of-range laboratory values without any clinical correlate, which were reversible within 7 days, unless the Investigator decided this event is clinically significant. For this reason Grade 3 or 4 out-of-range laboratory values must be re-assessed within 7 days. In case the Investigator provides the subject any treatment(s) due to the out-of-range laboratory values, the event was regarded as a DLT.

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).

Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above LLQ.

Total body clearance of drug in serum was calculated: as CL= Dose divided by Area under the serum concentration-time curve from time zero to infinity (AUC0-inf).

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL of drug in serum was calculated as : CL= Dose/ AUC0-inf. Area under the serum concentration-time curve from time zero to infinity (AUC0-inf), 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 the elimination rate constant.

Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by elimination rate constant \[λz\]) following single dose. Area under the serum concentration-time curve from time zero to infinity, calculated (AUC0-inf) 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 the elimination rate constant. And the elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data. A minimum of three points is required to calculate λz.

The observed serum concentration immediately before next dosing determined directly from the serum concentration-time profile of each subject (= trough concentration).

Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/(Area under the serum concentration-time curve within one complete dosing interval \[AUCtau\]\* λz) following multiple dose.

Overall tumor response was defined as the presence of at least one confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0. Complete response was defined as the disappearance of all target and non-target lesions and normalization of serum levels of tumor markers. PR is at least a 30 percent (%) decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD.

Clinical benefit was defined as presence of at least one confirmed CR, PR, or stable disease (SD) lasting at least 12 weeks according to RECIST v1.0. Per RECIST v1.0: CR was defined as disappearance of all target and non-target lesions and normalization of serum levels of tumor markers . PR was defined as \>=30% decrease in sum of longest diameters of target lesions taking as reference baseline sum longest diameters associated to non-progressive disease response for non-target lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference smallest sum of longest dimensions since treatment started associated to non-progressive disease response for non-target lesions.

PFS time was defined as the time (in months) from the first dosing date to the date of first documentation of disease progression as reported and documented by the Investigator (i.e. radiological progression per RECIST version 1.0) or death for any cause within 12 weeks after last tumor assessment. Subjects without event are censored on the date of last tumor assessment.

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

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

The observed serum concentration immediately before next dosing determined directly from the serum concentration-time profile of each subject (= trough concentration)

The Cav was calculated by dividing the area under the serum concentration-time curve within one complete dosing interval (AUCtau) by the dosing interval (2 weeks or 336 hoursi.e. Cav =AUCtau/tau).

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 blood concentration of a drug. Steady state volume of distribution (Vss) was the apparent volume of distribution at steady-state.

MRT0-inf of drug in the body was calculated by dividing the area under the first moment curve from time zero to infinity with area under the first moment curve from time zero to infinity minus half of infusion of duration (MRT0-inf = AUMC0-inf/AUMC0-inf - T/2).

MRTss = (AUMCtau + tau(AUCinf - AUCtau))/ AUCtau) - T/2, where AUMCtau was the area under the first moment curve within one complete dosing interval and T was the infusion duration. 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 the elimination rate constant.

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

Accumulation ratio for AUC, calculated as area under the serum concentration-time curve within one complete dosing interval at 3rd infusion divided by area under the serum concentration-time curve within one complete dosing interval at 1st infusion.

Merck KGaA, Darmstadt, Germany

The safety analysis set included all subjects who received at least one (non-zero) administration of the trial medication.

250 milligram (mg) of EMD525797 was administered as an intravenous infusion over 1 hour every 2 Weeks until progressive disease (PD), unacceptable toxicity, or withdrawal of consent.

EMD525797 250 mg

500 mg of EMD525797 was administered as an intravenous infusion over 1 hour every 2 Weeks until progressive disease (PD), unacceptable toxicity, or withdrawal of consent.

EMD525797 500 mg

1000 mg of EMD525797 was administered as an intravenous infusion over 1 hour every 2 Weeks until progressive disease (PD), unacceptable toxicity, or withdrawal of consent.

EMD525797 1000 mg

1500 mg of EMD525797 was administered as an intravenous infusion over 1 hour every 2 Weeks until progressive disease (PD), unacceptable toxicity, or withdrawal of consent.

EMD525797 1500 mg

Total

Age, Continuous

Sex: Female, Male

The all-subjects set included all the subjects who signed the informed consent and were treated.

Merck KGaA Communication Center

Dose escalation analysis set/DLT analysis set included all subjects who experienced a DLT or subjects who did not experience a DLT and had a relative dose intensity of \>= 75 percent (%) during the DLT observation period.

Number of Subjects With Dose-limiting Toxicities (DLTs)

The pharmacokinetic (PK) analysis set included all subjects who received at least the first dose of the study drug and who provided sufficient data for a concentration-time profile for EMD 525797.

Maximum Observed Serum Concentration (Cmax): After Single Dose

The PK analysis set included all subjects who received at least the first dose of the study drug and who provided sufficient data for a concentration-time profile for EMD 525797. Here N (number of subjects analyzed) signifies the total number of subjects evaluable for this outcome measure.

Maximum Observed Serum Concentration (Cmax) of EMD 525797:After Multiple Dose

The PK analysis set included all subjects who received at least the first dose of the study drug and who provided sufficient data for a concentration-time profile for EMD 525797.

Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Single Dose

Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Multiple Dose

Total Body Clearance (CL) of EMD 525797: After Single Dose

Full analysis set included all subjects who received at least one (non-zero) administration of the trial medication.

Spots Global Cancer Trial Database for alpha v integrin