Solid Tumor
Conditions
Keywords
alpha v integrin, antibody, solid tumor, Japanese, EMD525797
Brief summary
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.
Interventions
BIOLOGICALEMD525797
Subjects will receive 250 milligram (mg) of EMD525797 intravenously every 2 weeks, until progressive disease (PD), unacceptable toxicity or withdrawal of consent.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than or equal to (\>=) 20 years * Histologically or cytologically proven advanced or metastatic solid tumor * Evidence of progressive disease after standard chemotherapy or no standard chemotherapy * Confirmation of availability of formalin-fixed paraffin-embedded (FFPE) tumor block(s) or tissue sections * Presence of at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 complete tumor assessment to be performed within the 30 days prior to the first EMD525797 administration * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 * Estimated life expectancy of at least 3 months * Absolute Neutrophil Count (ANC) \>= 1.5 x 10\^9 per liter (/Liter) * Platelets \>= 100 x 10\^9/Liter * Haemoglobin \>= 9.0 gram per deciliter (g/dL) (without transfusions) * Total bilirubin less than or equal to (\<=) 1.5 x upper limit of normal (ULN) * Aspartate transaminase (AST), alanine transaminase (ALT) less than or equal to (\<=) 3 x ULN * In subjects with hepatic metastasis, total bilirubin \<= 3 x ULN, AST and ALT \<= 5 x ULN * Prothrombin time (PT), prothrombin time/international normalized ratio (PT/INR), and activated partial thromboplastin time (APTT) within normal limits * Creatinine clearance \>= 50 milliliter per minute (mL/min) Other protocol defined inclusion criteria could also apply
Exclusion criteria
* Previous treatment with anti-integrin therapy * Radiotherapy to bone lesions, systemic surgery, orthopedic surgery (all within the 4 week prior to treatment with EMD525797), clinically significant unhealed wound, or unrecovered bone fracture * Chronic doses of oral steroids, defined as \>= 10 milligram of prednisone equivalents per day * Confirmed or clinically suspected brain or leptomeningeal metastases * Known hypersensitivity to EMD525797 or its excipients * History of allergic reactions to other monoclonal antibody therapy * Antibody treatment within the past 8 weeks or chemotherapy within the 4 weeks prior to treatment with EMD525797 * Uncontrolled diabetes * Uncontrolled hypertension defined as systolic blood pressure \>= 160 millimeter of mercury (mmHg) and/or diastolic blood pressure \>= 100 millimeter of mercury (mmHg) under resting conditions * Autoimmune diseases * Current history of chronic daily acetylsalicylic acid (ASS) therapy (ASS at doses \<=100 mg is permitted) * Bleeding disorders; * History of thromboembolic events (history of superficial thrombophlebitis is not an exclusion * Anticoagulants within the past 10 days prior to the first treatment and during treatment period * Severe peripheral vascular disease or ulceration * Unstable angina pectoris, or myocardial infarction or other severe heart diseases within the past 6 months before treatment with EMD 525797 * Clinical significant abnormal ECG at screening * Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent * Known HIV infection, active or chronic carrier of hepatitis B virus (HBV antigen positive or HBV DNA positive) or hepatitis C virus (HCV antibody positive) Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Dose-limiting Toxicities (DLTs) | Baseline up to Week 4 | 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. |
| Maximum Observed Serum Concentration (Cmax): After Single Dose | Pre-dose, hour 1(end of infusion [EOI]), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | — |
| Maximum Observed Serum Concentration (Cmax) of EMD 525797:After Multiple Dose | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | — |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Single Dose | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | 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 Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Multiple Dose | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 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 (CL) of EMD 525797: After Single Dose | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | 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). |
| Total Body Clearance at Steady State (CLss) of EMD 525797 | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 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 (Vz): After Single Dose | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | 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. |
| Pharmacokinetics of EMD 525797 - Trough Values | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 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: After Multiple Dose | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Observed Serum Concentration Immediately Before Next Dosing (Cpre) | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | The observed serum concentration immediately before next dosing determined directly from the serum concentration-time profile of each subject (= trough concentration) |
| Average Serum Concentration at Steady State (Cav) | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 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). |
| Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Single Dose | Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | — |
| Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Multiple Dose | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | — |
| Elimination Rate Constant ( λ z): After Multiple Dose | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | The elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data. |
| Mean Residency Time (MRT0-inf) | Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | 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). |
| Mean Residence Time at Steady State (MRTss) | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 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. |
| Percentage Peak-Trough Fluctuation (PTF) | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | The peak trough fluctuation over one dosing interval at steady state, calculated as PTF (%) = ( \[Cmax - Cmin\] / Cav ) multiplied by 100. |
| Accumulation Ratio (Rac) | Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 and Week 5 | 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. |
| Volume of Distribution at Steady State (Vss) | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 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. |
| Number of Subjects With Overall Tumor Response | Baseline up to Week 36 | 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. |
| Number of Subjects With Clinical Benefit | Baseline up to Week 36 | 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. |
| Progression-free Survival (PFS) | From first dosing date until disease progression or death, maximum up to Week 36 | 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. |
| Apparent Terminal Half Life (t1/2): After Single Dose | Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | — |
| Apparent Terminal Half Life (t1/2): After Multiple Dose | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | — |
| Time to Maximum Observed Serum Concentration (Tmax): After Single Dose | Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | — |
| Time to Maximum Observed Serum Concentration (Tmax): After Multiple Dose | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | — |
| Elimination Rate Constant (λz): After Single Dose | Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | The elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data. |
| Minimum Observed Serum Concentration (Cmin) After Multiple Doses | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | The observed minimum serum concentration determined directly from the serum concentration-time profile of each subject. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| EMD525797 250 mg 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. | 8 |
| EMD525797 500 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. | 6 |
| EMD525797 1000 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. | 6 |
| EMD525797 1500 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. | 7 |
| Total | 27 |
Baseline characteristics
| Characteristic | EMD525797 250 mg | EMD525797 500 mg | EMD525797 1000 mg | EMD525797 1500 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.4 years STANDARD_DEVIATION 11.64 | 60.5 years STANDARD_DEVIATION 4.42 | 54.7 years STANDARD_DEVIATION 14.32 | 57.3 years STANDARD_DEVIATION 10.81 | 56.3 years STANDARD_DEVIATION 10.69 |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 3 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 6 / 6 | 6 / 6 | 7 / 7 |
| serious Total, serious adverse events | 1 / 8 | 1 / 6 | 1 / 6 | 1 / 7 |
Outcome results
Primary
Apparent Volume of Distribution: After Multiple Dose
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.
Time frame: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Apparent Volume of Distribution: After Multiple Dose | 3.505 liter | Geometric Coefficient of Variation 18.2 |
| EMD525797 500 mg | Apparent Volume of Distribution: After Multiple Dose | 3.775 liter | Geometric Coefficient of Variation 22 |
| EMD525797 1000 mg | Apparent Volume of Distribution: After Multiple Dose | 4.224 liter | Geometric Coefficient of Variation 21.5 |
| EMD525797 1500 mg | Apparent Volume of Distribution: After Multiple Dose | 4.565 liter | Geometric Coefficient of Variation 40 |
Primary
Apparent Volume of Distribution (Vz): After Single Dose
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.
Time frame: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Apparent Volume of Distribution (Vz): After Single Dose | 3.285 liter | Geometric Coefficient of Variation 20.5 |
| EMD525797 500 mg | Apparent Volume of Distribution (Vz): After Single Dose | 3.284 liter | Geometric Coefficient of Variation 37.8 |
| EMD525797 1000 mg | Apparent Volume of Distribution (Vz): After Single Dose | 3.506 liter | Geometric Coefficient of Variation 23.7 |
| EMD525797 1500 mg | Apparent Volume of Distribution (Vz): After Single Dose | 3.268 liter | Geometric Coefficient of Variation 17.3 |
Primary
Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Multiple Dose
Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above LLQ.
Time frame: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Multiple Dose | 10674.2 hour*mcg/mL | Geometric Coefficient of Variation 30.2 |
| EMD525797 500 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Multiple Dose | 37344.9 hour*mcg/mL | Geometric Coefficient of Variation 28.2 |
| EMD525797 1000 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Multiple Dose | 159979.5 hour*mcg/mL | Geometric Coefficient of Variation 29.5 |
| EMD525797 1500 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Multiple Dose | 242989.3 hour*mcg/mL | Geometric Coefficient of Variation 35.7 |
Primary
Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Single Dose
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).
Time frame: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Single Dose | 7942.6 hour*mcg/mL | Geometric Coefficient of Variation 19.6 |
| EMD525797 500 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Single Dose | 21562.3 hour*mcg/mL | Geometric Coefficient of Variation 14 |
| EMD525797 1000 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Single Dose | 67545.6 hour*mcg/mL | Geometric Coefficient of Variation 18.9 |
| EMD525797 1500 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration(AUC0-t) of EMD 525797: After Single Dose | 95369.6 hour*mcg/mL | Geometric Coefficient of Variation 40.9 |
Primary
Maximum Observed Serum Concentration (Cmax): After Single Dose
Time frame: Pre-dose, hour 1(end of infusion [EOI]), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Maximum Observed Serum Concentration (Cmax): After Single Dose | 73.12 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 12.1 |
| EMD525797 500 mg | Maximum Observed Serum Concentration (Cmax): After Single Dose | 162.48 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 15.2 |
| EMD525797 1000 mg | Maximum Observed Serum Concentration (Cmax): After Single Dose | 419.26 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 16.4 |
| EMD525797 1500 mg | Maximum Observed Serum Concentration (Cmax): After Single Dose | 683.46 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 28 |
Primary
Maximum Observed Serum Concentration (Cmax) of EMD 525797:After Multiple Dose
Time frame: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Maximum Observed Serum Concentration (Cmax) of EMD 525797:After Multiple Dose | 89.336 mcg/mL | Geometric Coefficient of Variation 6.6 |
| EMD525797 500 mg | Maximum Observed Serum Concentration (Cmax) of EMD 525797:After Multiple Dose | 198.728 mcg/mL | Geometric Coefficient of Variation 20.1 |
| EMD525797 1000 mg | Maximum Observed Serum Concentration (Cmax) of EMD 525797:After Multiple Dose | 680.022 mcg/mL | Geometric Coefficient of Variation 18.1 |
| EMD525797 1500 mg | Maximum Observed Serum Concentration (Cmax) of EMD 525797:After Multiple Dose | 1170.73 mcg/mL | Geometric Coefficient of Variation 22.2 |
Primary
Number of Subjects With Dose-limiting Toxicities (DLTs)
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.
Time frame: Baseline up to Week 4
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EMD525797 250 mg | Number of Subjects With Dose-limiting Toxicities (DLTs) | 0 subjects |
| EMD525797 500 mg | Number of Subjects With Dose-limiting Toxicities (DLTs) | 0 subjects |
| EMD525797 1000 mg | Number of Subjects With Dose-limiting Toxicities (DLTs) | 0 subjects |
| EMD525797 1500 mg | Number of Subjects With Dose-limiting Toxicities (DLTs) | 0 subjects |
Primary
Pharmacokinetics of EMD 525797 - Trough Values
The observed serum concentration immediately before next dosing determined directly from the serum concentration-time profile of each subject (= trough concentration).
Time frame: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Pharmacokinetics of EMD 525797 - Trough Values | 5.73 mcg/mL | Geometric Coefficient of Variation 150.7 |
| EMD525797 500 mg | Pharmacokinetics of EMD 525797 - Trough Values | 44.28 mcg/mL | Geometric Coefficient of Variation 40.1 |
| EMD525797 1000 mg | Pharmacokinetics of EMD 525797 - Trough Values | 200.05 mcg/mL | Geometric Coefficient of Variation 30.3 |
| EMD525797 1500 mg | Pharmacokinetics of EMD 525797 - Trough Values | 286.11 mcg/mL | Geometric Coefficient of Variation 30.5 |
Primary
Total Body Clearance at Steady State (CLss) of EMD 525797
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.
Time frame: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Total Body Clearance at Steady State (CLss) of EMD 525797 | 0.0224 liter per hour | Geometric Coefficient of Variation 26.4 |
| EMD525797 500 mg | Total Body Clearance at Steady State (CLss) of EMD 525797 | 0.0154 liter per hour | Geometric Coefficient of Variation 26.9 |
| EMD525797 1000 mg | Total Body Clearance at Steady State (CLss) of EMD 525797 | 0.0075 liter per hour | Geometric Coefficient of Variation 19.1 |
| EMD525797 1500 mg | Total Body Clearance at Steady State (CLss) of EMD 525797 | 0.0078 liter per hour | Geometric Coefficient of Variation 25.1 |
Primary
Total Body Clearance (CL) of EMD 525797: After Single Dose
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).
Time frame: Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Total Body Clearance (CL) of EMD 525797: After Single Dose | 0.0294 liter per hour | Geometric Coefficient of Variation 24.5 |
| EMD525797 500 mg | Total Body Clearance (CL) of EMD 525797: After Single Dose | 0.0188 liter per hour | Geometric Coefficient of Variation 29.9 |
| EMD525797 1000 mg | Total Body Clearance (CL) of EMD 525797: After Single Dose | 0.0083 liter per hour | Geometric Coefficient of Variation 23 |
| EMD525797 1500 mg | Total Body Clearance (CL) of EMD 525797: After Single Dose | 0.0089 liter per hour | Geometric Coefficient of Variation 52.9 |
Secondary
Accumulation Ratio (Rac)
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.
Time frame: Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 and Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Accumulation Ratio (Rac) | 1.371 ratio | Geometric Coefficient of Variation 23.5 |
| EMD525797 500 mg | Accumulation Ratio (Rac) | 1.510 ratio | Geometric Coefficient of Variation 18.4 |
| EMD525797 1000 mg | Accumulation Ratio (Rac) | 1.967 ratio | Geometric Coefficient of Variation 13 |
| EMD525797 1500 mg | Accumulation Ratio (Rac) | 1.762 ratio | Geometric Coefficient of Variation 12 |
Secondary
Apparent Terminal Half Life (t1/2): After Multiple Dose
Time frame: Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EMD525797 250 mg | Apparent Terminal Half Life (t1/2): After Multiple Dose | 119.58 hour |
| EMD525797 500 mg | Apparent Terminal Half Life (t1/2): After Multiple Dose | 195.75 hour |
| EMD525797 1000 mg | Apparent Terminal Half Life (t1/2): After Multiple Dose | 345.92 hour |
| EMD525797 1500 mg | Apparent Terminal Half Life (t1/2): After Multiple Dose | 448.45 hour |
Secondary
Apparent Terminal Half Life (t1/2): After Single Dose
Time frame: Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EMD525797 250 mg | Apparent Terminal Half Life (t1/2): After Single Dose | 83.95 hour |
| EMD525797 500 mg | Apparent Terminal Half Life (t1/2): After Single Dose | 114.45 hour |
| EMD525797 1000 mg | Apparent Terminal Half Life (t1/2): After Single Dose | 298.99 hour |
| EMD525797 1500 mg | Apparent Terminal Half Life (t1/2): After Single Dose | 240.76 hour |
Secondary
Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Multiple Dose
Time frame: Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Multiple Dose | 11164.0 hour*mcg/mL | Geometric Coefficient of Variation 26.4 |
| EMD525797 500 mg | Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Multiple Dose | 32561.0 hour*mcg/mL | Geometric Coefficient of Variation 26.9 |
| EMD525797 1000 mg | Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Multiple Dose | 132877.8 hour*mcg/mL | Geometric Coefficient of Variation 19.1 |
| EMD525797 1500 mg | Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Multiple Dose | 192894.5 hour*mcg/mL | Geometric Coefficient of Variation 25.1 |
Secondary
Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Single Dose
Time frame: Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Single Dose | 7970.1 hour*mcg/mL | Geometric Coefficient of Variation 20.3 |
| EMD525797 500 mg | Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Single Dose | 21563.6 hour*mcg/mL | Geometric Coefficient of Variation 14 |
| EMD525797 1000 mg | Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Single Dose | 67555.4 hour*mcg/mL | Geometric Coefficient of Variation 19 |
| EMD525797 1500 mg | Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval( AUCtau): After Single Dose | 100861.0 hour*mcg/mL | Geometric Coefficient of Variation 26.5 |
Secondary
Average Serum Concentration at Steady State (Cav)
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).
Time frame: Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Average Serum Concentration at Steady State (Cav) | 33.23 mcg/mL | Geometric Coefficient of Variation 26.4 |
| EMD525797 500 mg | Average Serum Concentration at Steady State (Cav) | 96.91 mcg/mL | Geometric Coefficient of Variation 26.9 |
| EMD525797 1000 mg | Average Serum Concentration at Steady State (Cav) | 395.47 mcg/mL | Geometric Coefficient of Variation 19.1 |
| EMD525797 1500 mg | Average Serum Concentration at Steady State (Cav) | 574.09 mcg/mL | Geometric Coefficient of Variation 25.1 |
Secondary
Elimination Rate Constant ( λ z): After Multiple Dose
The elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data.
Time frame: Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Elimination Rate Constant ( λ z): After Multiple Dose | 0.00639 per hour | Geometric Coefficient of Variation 35.5 |
| EMD525797 500 mg | Elimination Rate Constant ( λ z): After Multiple Dose | 0.00407 per hour | Geometric Coefficient of Variation 36.7 |
| EMD525797 1000 mg | Elimination Rate Constant ( λ z): After Multiple Dose | 0.00178 per hour | Geometric Coefficient of Variation 35.2 |
| EMD525797 1500 mg | Elimination Rate Constant ( λ z): After Multiple Dose | 0.00170 per hour | Geometric Coefficient of Variation 53.3 |
Secondary
Elimination Rate Constant (λz): After Single Dose
The elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data.
Time frame: Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Elimination Rate Constant (λz): After Single Dose | 0.00895 per hour | Geometric Coefficient of Variation 31.5 |
| EMD525797 500 mg | Elimination Rate Constant (λz): After Single Dose | 0.00573 per hour | Geometric Coefficient of Variation 66.7 |
| EMD525797 1000 mg | Elimination Rate Constant (λz): After Single Dose | 0.00237 per hour | Geometric Coefficient of Variation 25.6 |
| EMD525797 1500 mg | Elimination Rate Constant (λz): After Single Dose | 0.00272 per hour | Geometric Coefficient of Variation 49.6 |
Secondary
Mean Residence Time at Steady State (MRTss)
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.
Time frame: Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Mean Residence Time at Steady State (MRTss) | 160.05 hour | Geometric Coefficient of Variation 28 |
| EMD525797 500 mg | Mean Residence Time at Steady State (MRTss) | 260.73 hour | Geometric Coefficient of Variation 29.5 |
| EMD525797 1000 mg | Mean Residence Time at Steady State (MRTss) | 548.88 hour | Geometric Coefficient of Variation 35.5 |
| EMD525797 1500 mg | Mean Residence Time at Steady State (MRTss) | 564.86 hour | Geometric Coefficient of Variation 53.1 |
Secondary
Mean Residency Time (MRT0-inf)
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).
Time frame: Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Mean Residency Time (MRT0-inf) | 118.46 hour | Geometric Coefficient of Variation 25 |
| EMD525797 500 mg | Mean Residency Time (MRT0-inf) | 187.29 hour | Geometric Coefficient of Variation 48.7 |
| EMD525797 1000 mg | Mean Residency Time (MRT0-inf) | 408.34 hour | Geometric Coefficient of Variation 23.3 |
| EMD525797 1500 mg | Mean Residency Time (MRT0-inf) | 357.21 hour | Geometric Coefficient of Variation 48.8 |
Secondary
Minimum Observed Serum Concentration (Cmin) After Multiple Doses
The observed minimum serum concentration determined directly from the serum concentration-time profile of each subject.
Time frame: Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Minimum Observed Serum Concentration (Cmin) After Multiple Doses | 5.64 mcg/mL | Geometric Coefficient of Variation 154.6 |
| EMD525797 500 mg | Minimum Observed Serum Concentration (Cmin) After Multiple Doses | 44.22 mcg/mL | Geometric Coefficient of Variation 40.2 |
| EMD525797 1000 mg | Minimum Observed Serum Concentration (Cmin) After Multiple Doses | 200.5 mcg/mL | Geometric Coefficient of Variation 30.3 |
| EMD525797 1500 mg | Minimum Observed Serum Concentration (Cmin) After Multiple Doses | 286.11 mcg/mL | Geometric Coefficient of Variation 30.5 |
Secondary
Number of Subjects With Clinical Benefit
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.
Time frame: Baseline up to Week 36
Population: Full analysis set included all subjects who received at least one (non-zero) administration of the trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EMD525797 250 mg | Number of Subjects With Clinical Benefit | 0 subjects |
| EMD525797 500 mg | Number of Subjects With Clinical Benefit | 0 subjects |
| EMD525797 1000 mg | Number of Subjects With Clinical Benefit | 0 subjects |
| EMD525797 1500 mg | Number of Subjects With Clinical Benefit | 0 subjects |
Secondary
Number of Subjects With Overall Tumor Response
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.
Time frame: Baseline up to Week 36
Population: Full analysis set included all subjects who received at least one (non-zero) administration of the trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EMD525797 250 mg | Number of Subjects With Overall Tumor Response | 0 subjects |
| EMD525797 500 mg | Number of Subjects With Overall Tumor Response | 0 subjects |
| EMD525797 1000 mg | Number of Subjects With Overall Tumor Response | 0 subjects |
| EMD525797 1500 mg | Number of Subjects With Overall Tumor Response | 0 subjects |
Secondary
Observed Serum Concentration Immediately Before Next Dosing (Cpre)
The observed serum concentration immediately before next dosing determined directly from the serum concentration-time profile of each subject (= trough concentration)
Time frame: Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Observed Serum Concentration Immediately Before Next Dosing (Cpre) | 5.73 mcg/mL | Geometric Coefficient of Variation 150.7 |
| EMD525797 500 mg | Observed Serum Concentration Immediately Before Next Dosing (Cpre) | 44.28 mcg/mL | Geometric Coefficient of Variation 40.1 |
| EMD525797 1000 mg | Observed Serum Concentration Immediately Before Next Dosing (Cpre) | 200.05 mcg/mL | Geometric Coefficient of Variation 30.3 |
| EMD525797 1500 mg | Observed Serum Concentration Immediately Before Next Dosing (Cpre) | 286.11 mcg/mL | Geometric Coefficient of Variation 30.5 |
Secondary
Percentage Peak-Trough Fluctuation (PTF)
The peak trough fluctuation over one dosing interval at steady state, calculated as PTF (%) = ( \[Cmax - Cmin\] / Cav ) multiplied by 100.
Time frame: Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Percentage Peak-Trough Fluctuation (PTF) | 243.64 percentage fluctuation | Geometric Coefficient of Variation 33.4 |
| EMD525797 500 mg | Percentage Peak-Trough Fluctuation (PTF) | 157.93 percentage fluctuation | Geometric Coefficient of Variation 17 |
| EMD525797 1000 mg | Percentage Peak-Trough Fluctuation (PTF) | 118.69 percentage fluctuation | Geometric Coefficient of Variation 31.8 |
| EMD525797 1500 mg | Percentage Peak-Trough Fluctuation (PTF) | 153.22 percentage fluctuation | Geometric Coefficient of Variation 20.7 |
Secondary
Progression-free Survival (PFS)
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.
Time frame: From first dosing date until disease progression or death, maximum up to Week 36
Population: Full analysis set included all subjects who received at least one (non-zero) administration of the trial medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EMD525797 250 mg | Progression-free Survival (PFS) | 1.18 months |
| EMD525797 500 mg | Progression-free Survival (PFS) | 1.23 months |
| EMD525797 1000 mg | Progression-free Survival (PFS) | 1.31 months |
| EMD525797 1500 mg | Progression-free Survival (PFS) | 1.25 months |
Secondary
Time to Maximum Observed Serum Concentration (Tmax): After Multiple Dose
Time frame: Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EMD525797 250 mg | Time to Maximum Observed Serum Concentration (Tmax): After Multiple Dose | 1.042 hour |
| EMD525797 500 mg | Time to Maximum Observed Serum Concentration (Tmax): After Multiple Dose | 3.00 hour |
| EMD525797 1000 mg | Time to Maximum Observed Serum Concentration (Tmax): After Multiple Dose | 1.025 hour |
| EMD525797 1500 mg | Time to Maximum Observed Serum Concentration (Tmax): After Multiple Dose | 4.000 hour |
Secondary
Time to Maximum Observed Serum Concentration (Tmax): After Single Dose
Time frame: Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EMD525797 250 mg | Time to Maximum Observed Serum Concentration (Tmax): After Single Dose | 1.033 hour |
| EMD525797 500 mg | Time to Maximum Observed Serum Concentration (Tmax): After Single Dose | 1.033 hour |
| EMD525797 1000 mg | Time to Maximum Observed Serum Concentration (Tmax): After Single Dose | 3.967 hour |
| EMD525797 1500 mg | Time to Maximum Observed Serum Concentration (Tmax): After Single Dose | 1.067 hour |
Secondary
Volume of Distribution at Steady State (Vss)
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.
Time frame: Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EMD525797 250 mg | Volume of Distribution at Steady State (Vss) | 3.584 liter | Geometric Coefficient of Variation 9.6 |
| EMD525797 500 mg | Volume of Distribution at Steady State (Vss) | 4.004 liter | Geometric Coefficient of Variation 17.2 |
| EMD525797 1000 mg | Volume of Distribution at Steady State (Vss) | 4.131 liter | Geometric Coefficient of Variation 21.6 |
| EMD525797 1500 mg | Volume of Distribution at Steady State (Vss) | 4.392 liter | Geometric Coefficient of Variation 38.9 |