A Study of EMD525797 in Solid Tumor Patients in Japan

Study Overview
=================
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.

Official Title
-----------------
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

Conditions
-----------------
Solid Tumor

Intervention / Treatment
-----------------
* Biological: EMD525797
* Biological: EMD525797
* Biological: EMD525797
* Biological: EMD525797


Participation Criteria
=================
Eligibility Criteria
-----------------
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 exclusion criteria could also apply

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EMD525797 250 milligram (mg)<br> | Biological: EMD525797<br>* Subjects will receive 250 milligram (mg) of EMD525797 intravenously every 2 weeks, until progressive disease (PD), unacceptable toxicity or withdrawal of consent.<br>|
| Experimental: EMD525797 500 mg<br> | Biological: EMD525797<br>* Subjects will receive 500 mg of EMD525797 intravenously every 2 weeks, until PD or unacceptable toxicity or withdrawal of consent.<br>|
| Experimental: EMD525797 1000 mg<br> | Biological: EMD525797<br>* Subjects will receive 1000 mg of EMD525797 intravenously every 2 weeks, until PD or unacceptable toxicity or withdrawal of consent.<br>|
| Experimental: EMD525797 1500 mg<br> | Biological: EMD525797<br>* Subjects will receive 1500 mg of EMD525797 intravenously every 2 weeks, until PD or unacceptable toxicity, or withdrawal of consent.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to Week 4 | 
| 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 | 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). | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | 
| 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. | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 
| 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). | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | 
| 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. | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 
| 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. | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | 
| 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). | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 
| 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. | Pre-dose, hour 1 (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to Week 36 | 
| 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. | Baseline up to Week 36 | 
| 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. | From first dosing date until disease progression or death, maximum up to Week 36 | 
| 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 | The elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data. | Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | 
| 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. | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 
| Minimum Observed Serum Concentration (Cmin) After Multiple Doses | The observed minimum serum concentration determined directly from the serum concentration-time profile of each subject. | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 
| 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) | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 
| 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). | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 
| 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 | 
| 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. | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 
| 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). | Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 | 
| 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. | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 
| 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. | Pre-dose, EOI, 4, 8, 24, 48, and 96 hours after start of infusion at Week 5 | 
| 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. | Pre-dose, end of infusion (EOI), 4, 8, 24, 48, and 96 hours after start of infusion at Week 1 and Week 5 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
alpha v integrin, antibody, solid tumor, Japanese, EMD525797