Advanced Solid Tumor
Conditions
Keywords
MEK inhibitor, Solid Tumor, Phase I
Brief summary
The main purpose of this study is to test the experimental drug, MSC2015103B at different dose levels and on different treatment schedules, to see whether it is safe and can be tolerated when given to subjects once a day one day per week over a 21-day period or once a day three times per week over a 21-day period. The investigators would also like to find out how MSC2015103B is broken down by the body. Additional purposes of the trial are to assess side effects of MSC2015103B and to find out whether MSC2015103B has anti-cancer effects. In addition, the investigators would like to explore pharmacokinetics.
Interventions
DRUGMSC2015103B
Schedule 1: MSC2015103B will be administered orally once weekly on Days 1, 8, and 15 of a 21-day cycle until MTD establishment. Starting dose will be 150 microgram (mcg), which will be escalated to 200 mcg, 300 mcg, 450 mcg, 650 mcg, 1000 mcg and 1500 mcg subsequently.
Sponsors
EMD Serono
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed solid tumor preferably, but not exclusively, including pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian carcinoma, or melanoma which is locally advanced or metastatic, and either refractory after standard therapy for the disease or for which no effective standard therapy is available * Eastern Cooperative Oncology Group Performance Status (ECOG PS) of less than or equal to (\<=) 1 * Has read and understands the informed consent form and is willing and able to give informed consent. Fully understands requirements of and willing to comply with all trial visits and assessments * Evidence of measurable disease at trial entry as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. * Willing to provide archival tissue samples for molecular analysis Other inclusion criteria as defined in protocol.
Exclusion criteria
* Bone marrow impairment as evidenced by hemoglobin less than (\<) 9.0 gram per deciliter (g/dL), neutrophil count \< 1.5 x 10\^9 per liter (/L), and/or platelets \<100 x 10\^9/L per liter (/L) * Renal impairment as evidenced by serum creatinine greater than (\>) 1.5 x upper limit of normal (ULN) and/or calculated creatinine clearance \< 50 milliliter per minute (mL/min) (Cockcroft-Gault formula) * Liver function and liver cell integrity abnormality as defined by total bilirubin \> 1.5 x ULN, or aspartate aminotransferase/alanine aminotransferase (AST/ALT) \> 2.5 x ULN, for subjects with liver involvement AST/ALT \> 5 x ULN. Subjects with albumin \< 2.5 g/dL are also excluded * History of central nervous system (CNS) metastases. * History of difficulty of swallowing, malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the tested product. * Chronic diarrhea that is \>= Grade 2 in severity * Clinically significant cardiac conduction abnormalities * A left ventricular ejection fraction of \< 45% * A history of stroke or myocardial infarction within the past year * A history of uveitis and scleritis * Retinal pathology beyond normal age-related processes * Evidence of a retinal vein occlusion on fluorescein angiogram or a history of retinal vein occlusion * Subjects are also excluded if their ophthalmologist finds that their optic disc is at risk for a central retinal vein occlusion * History of glaucoma * Subjects requiring daily and/or chronic systemic steroids * Pregnant or nursing females Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Experienced Dose-limiting Toxicities (DLT) | Up to Day 21 of Cycle 1 | DLT was evaluated using the National cancer institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. DLT was defined as any of the following AEs occurring during Cycle 1 that are not related to progressive disease (PD) at any dose level: Any Grade 3 or more non-hematological toxicity excluding: Grade 3 diarrhea or associated electrolyte abnormalities that were controlled with adequate and optimal therapies, Grade 3 liver function abnormalities which resolved within 7 days, vomiting. Grade 4 neutropenia of greater than (\>) 5 days duration or Grade 3 febrile neutropenia, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, any severe or life threatening AE or any AE or abnormality which impairs daily normal physiological functions, any treatment delay for 2 weeks or more due to adverse effects not related to PD. All events judged to be related by the Investigator to PD were excluded from the DLT definition. |
| Percentage of Subjects Who Experienced DLT | Up to Day 21 of Cycle 1 | DLT was evaluated using the National cancer institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. DLT was defined as any of the following AEs occurring during Cycle 1 that are not related to PD at any dose level: Any Grade 3 or more non-hematological toxicity excluding: Grade 3 diarrhea or associated electrolyte abnormalities that were controlled with adequate and optimal therapies, Grade 3 liver function abnormalities which resolved within 7 days, vomiting. Grade 4 neutropenia of greater than (\>) 5 days duration or Grade 3 febrile neutropenia, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, any severe or life threatening AE or any AE or abnormality which impairs daily normal physiological functions, any treatment delay for 2 weeks or more due to adverse effects not related to PD. All events judged to be related by the Investigator to PD were excluded from the DLT definition. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | From the initiation of the trial till the data cut-off date 15 July 2013 | Abnormal laboratory findings and other abnormal investigational findings which were associated with clinical signs and symptoms, lead to treatment discontinuation, or considered medically important by the investigator were reported as AEs. |
| Maximum Plasma Concentration (Cmax) | Schedule 1 : 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Days 1 and 17. | — |
| Time to Reach Maximum Plasma Concentration (Tmax) | Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17. | — |
| Apparent Terminal Half Life (T1/2) | Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17. | The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. |
| Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17. | The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. |
| Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | From the initiation of the trial till the data cut-off date 15 July 2013 | An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. SAE (Serious adverse event) is defined as any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.. TEAEs are events between first dose of study drug up to the cut-off date (15 July 2013) and were absent before treatment or that worsened relative to pretreatment state. |
| Apparent Oral Clearance of the Drug From Plasma (CL/f) | Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1. | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/f was influenced by the fraction absorbed. |
| Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1. | 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 after oral dose (Vz/f) was influenced by the fraction absorbed. |
| Extracellular Signal-regulated Kinase (ERK) Phosphorylation Levels | Schedule 1: Day 1: Pre-dose; Post-dose: 2, 4, 8, 24 hour; 48 or 72 hour; 48 or 96 hour, 168 hour; Day 15: Pre-dose; Schedule 2: Day 1: Pre-dose; Post-dose: 2, 8, 24, 48, 96 hour; Day 15: Pre-dose; Day 17: Pre-dose; Post-dose: 2, 8, and 24 hour | ERK phosphorylation levels were to be assessed in peripheral blood mononuclear cells (PBMC) during the dose escalation |
| Percentage of Subjects With Overall Response | Every 6 Weeks until complete response or till data cut-off date 15 July 2013 | Overall response was to be confirmed by complete response (CR) or partial response (PR) using response evaluation criteria in solid tumours Version 1.0 (RECIST) during treatment. CR: The disappearance of all target and non-target lesions and normalization of tumor marker level; PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline. |
| Percentage of Subjects With Clinical Benefit | Every 6 Weeks until complete response or till data cut-off date 15 July 2013 | Clinical benefit was to be confirmed by CR, PR or stable disease (SD) lasting at least 6 weeks (using RECIST v1.0) during treatment. CR: The disappearance of all target and non-target lesions and normalization of tumor marker level; PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started. |
| AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17. | — |
| Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | From the initiation of the trial till the data cut-off date 15 July 2013 | Abnormal laboratory findings and other abnormal investigational findings which were associated with clinical signs and symptoms, lead to treatment discontinuation, or considered medically important by the investigator were reported as AEs. |
Countries
United States
Participant flow
Recruitment details
First/Last subject (informed consent): 09 September 2011/18 April 2013. Study completion date: 15 July 2013, Clinical data cut-off date: 15 July 2013; Subjects were randomized at 3 centers in United States.
Pre-assignment details
Enrolled: 28 subjects were screened for eligibility and all were randomized in to the trial.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 - MSC2015103B (Schedule 1) MSC2015103B was administered orally once weekly on Days 1, 8, and 15 of a 21-day cycle until maximum tolerated dose (MTD) was established. Starting dose was 150 microgram (mcg), which was escalated to 200 mcg, 300 mcg, 450 mcg, 650 mcg, 1000 mcg and 1500 mcg subsequently. | 21 |
| Part 1 - MSC2015103B (Schedule 2) MSC2015103B was administered orally thrice weekly on Days 1, 3, 5, 8, 10, 12, 15, 17 and 19 of a 21-day cycle until MTD was established. Starting dose was 150 mcg, and was escalated to 200 mcg subsequently. | 7 |
| Total | 28 |
Baseline characteristics
| Characteristic | Total | Part 1 - MSC2015103B (Schedule 1) | Part 1 - MSC2015103B (Schedule 2) |
|---|---|---|---|
| Age, Customized 18 to less than (<) 45 years | 2 Subjects | 2 Subjects | 0 Subjects |
| Age, Customized >=65 years | 11 Subjects | 9 Subjects | 2 Subjects |
| Age, Customized Greater than equal to (>=) 45 to <65 years | 15 Subjects | 10 Subjects | 5 Subjects |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 20 Participants | 17 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 21 | 7 / 7 |
| serious Total, serious adverse events | 4 / 21 | 3 / 7 |
Outcome results
Primary
Number of Subjects Who Experienced Dose-limiting Toxicities (DLT)
DLT was evaluated using the National cancer institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. DLT was defined as any of the following AEs occurring during Cycle 1 that are not related to progressive disease (PD) at any dose level: Any Grade 3 or more non-hematological toxicity excluding: Grade 3 diarrhea or associated electrolyte abnormalities that were controlled with adequate and optimal therapies, Grade 3 liver function abnormalities which resolved within 7 days, vomiting. Grade 4 neutropenia of greater than (\>) 5 days duration or Grade 3 febrile neutropenia, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, any severe or life threatening AE or any AE or abnormality which impairs daily normal physiological functions, any treatment delay for 2 weeks or more due to adverse effects not related to PD. All events judged to be related by the Investigator to PD were excluded from the DLT definition.
Time frame: Up to Day 21 of Cycle 1
Population: Safety analysis set included all the subjects who received at least one administration of the trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Dose-limiting Toxicities (DLT) | 0 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Dose-limiting Toxicities (DLT) | 0 Subjects |
Primary
Percentage of Subjects Who Experienced DLT
DLT was evaluated using the National cancer institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. DLT was defined as any of the following AEs occurring during Cycle 1 that are not related to PD at any dose level: Any Grade 3 or more non-hematological toxicity excluding: Grade 3 diarrhea or associated electrolyte abnormalities that were controlled with adequate and optimal therapies, Grade 3 liver function abnormalities which resolved within 7 days, vomiting. Grade 4 neutropenia of greater than (\>) 5 days duration or Grade 3 febrile neutropenia, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, any severe or life threatening AE or any AE or abnormality which impairs daily normal physiological functions, any treatment delay for 2 weeks or more due to adverse effects not related to PD. All events judged to be related by the Investigator to PD were excluded from the DLT definition.
Time frame: Up to Day 21 of Cycle 1
Population: Safety analysis set included all subjects who received at least one administration of the trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced DLT | 0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced DLT | 0 Percentage of subjects |
Secondary
Apparent Oral Clearance of the Drug From Plasma (CL/f)
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/f was influenced by the fraction absorbed.
Time frame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1.
Population: Pharmacokinetic analysis set included all the subjects who have received at least one dose of MSC2015103B and who have provided sufficient plasma concentrations of MSC2015103B measurement after the first dose. N signifies the total number of subjects evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Apparent Oral Clearance of the Drug From Plasma (CL/f) | 41.156 Liter/hour |
| Part 1 - MSC2015103B (Schedule 2) | Apparent Oral Clearance of the Drug From Plasma (CL/f) | 50.924 Liter/hour |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | Apparent Oral Clearance of the Drug From Plasma (CL/f) | 133.34 Liter/hour |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | Apparent Oral Clearance of the Drug From Plasma (CL/f) | 57.033 Liter/hour |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | Apparent Oral Clearance of the Drug From Plasma (CL/f) | 52.192 Liter/hour |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | Apparent Oral Clearance of the Drug From Plasma (CL/f) | 75.968 Liter/hour |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | Apparent Oral Clearance of the Drug From Plasma (CL/f) | 63.673 Liter/hour |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | Apparent Oral Clearance of the Drug From Plasma (CL/f) | 73.813 Liter/hour |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | Apparent Oral Clearance of the Drug From Plasma (CL/f) | 145.44 Liter/hour |
Secondary
Apparent Terminal Half Life (T1/2)
The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination.
Time frame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17.
Population: Pharmacokinetic analysis set included all the subjects who received at least 1 dose of MSC2015103B and provided sufficient plasma concentrations of MSC2015103B measurement after the first dose.n signifies the number of subjects evaluable for the particular timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 134.88 Hour |
| Part 1 - MSC2015103B (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 102.30 Hour |
| Part 1 - MSC2015103B (Schedule 2) | Apparent Terminal Half Life (T1/2) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 102.53 Hour |
| Part 1 - MSC2015103B (Schedule 2) | Apparent Terminal Half Life (T1/2) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 115.41 Hour |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 138.47 Hour |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 55.023 Hour |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 53.072 Hour |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 55.43 Hour |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 37.16 Hour |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 115.34 Hour |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 52.852 Hour |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 103.77 Hour |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 100.91 Hour |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | Apparent Terminal Half Life (T1/2) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 81.124 Hour |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | Apparent Terminal Half Life (T1/2) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 30.850 Hour |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | Apparent Terminal Half Life (T1/2) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 121.58 Hour |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | Apparent Terminal Half Life (T1/2) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 145.70 Hour |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | Apparent Terminal Half Life (T1/2) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 33.007 Hour |
Secondary
Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f)
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 after oral dose (Vz/f) was influenced by the fraction absorbed.
Time frame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1.
Population: Pharmacokinetic analysis set included all the subjects who received at least 1 dose of MSC2015103B and who provided sufficient plasma concentrations of MSC2015103B measurement after the first dose. n signifies the number of subjects evaluable for the particular timepoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | 8008.6 Liter |
| Part 1 - MSC2015103B (Schedule 2) | Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | 8478.7 Liter |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | 10584 Liter |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | 4366.9 Liter |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | 8684.7 Liter |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | 5792.4 Liter |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | 7452.2 Liter |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | 3285.2 Liter |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | 6925.6 Liter |
Secondary
Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf])
The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.
Time frame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17.
Population: Pharmacokinetic analysis set included all the subjects who have received at least 1 dose of MSC2015103B and provided sufficient plasma concentrations of MSC2015103B measurement after the first dose. n signifies the number of subjects evaluable for the particular timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 3644.7 Hour*picogram/milliliter |
| Part 1 - MSC2015103B (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 3 (n=,3,3,3,3,1,3,2,2,3) | 4715.2 Hour*picogram/milliliter |
| Part 1 - MSC2015103B (Schedule 2) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 3927.4 Hour*picogram/milliliter |
| Part 1 - MSC2015103B (Schedule 2) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 3 (n=,3,3,3,3,1,3,2,2,3) | 4377.2 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 2249.9 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 3 (n=,3,3,3,3,1,3,2,2,3) | 16465 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 7890.1 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 3 (n=,3,3,3,3,1,3,2,2,3) | 12397 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 12454 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 3 (n=,3,3,3,3,1,3,2,2,3) | 24580 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 3 (n=,3,3,3,3,1,3,2,2,3) | 35423 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 13164 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 3 (n=,3,3,3,3,1,3,2,2,3) | 66081 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 23558 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 2032.2 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 3 (n=,3,3,3,3,1,3,2,2,3) | 21735 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 1375.2 Hour*picogram/milliliter |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | Week 3 (n=,3,3,3,3,1,3,2,2,3) | 14870 Hour*picogram/milliliter |
Secondary
AUC Versus Time Curve Within One Dosing Interval (AUC0-tau)
Time frame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17.
Population: Pharmacokinetic analysis set included all the subjects who received at least 1 dose of MSC2015103B and provided sufficient plasma concentrations of MSC2015103B measurement after the first dose. n signifies the number of subjects evaluable for the particular timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 2072.8 hours*picogram/milliliter |
| Part 1 - MSC2015103B (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 2946.9 hours*picogram/milliliter |
| Part 1 - MSC2015103B (Schedule 2) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 2381.6 hours*picogram/milliliter |
| Part 1 - MSC2015103B (Schedule 2) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 3002.0 hours*picogram/milliliter |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 1752.7 hours*picogram/milliliter |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 8865.3 hours*picogram/milliliter |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 6824.4 hours*picogram/milliliter |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 10696 hours*picogram/milliliter |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 8434.6 hours*picogram/milliliter |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 23670 hours*picogram/milliliter |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 25150 hours*picogram/milliliter |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 11533 hours*picogram/milliliter |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 47114 hours*picogram/milliliter |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 17698 hours*picogram/milliliter |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 1345.3 hours*picogram/milliliter |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 4993.3 hours*picogram/milliliter |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 865.76 hours*picogram/milliliter |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 3070.5 hours*picogram/milliliter |
Secondary
Extracellular Signal-regulated Kinase (ERK) Phosphorylation Levels
ERK phosphorylation levels were to be assessed in peripheral blood mononuclear cells (PBMC) during the dose escalation
Time frame: Schedule 1: Day 1: Pre-dose; Post-dose: 2, 4, 8, 24 hour; 48 or 72 hour; 48 or 96 hour, 168 hour; Day 15: Pre-dose; Schedule 2: Day 1: Pre-dose; Post-dose: 2, 8, 24, 48, 96 hour; Day 15: Pre-dose; Day 17: Pre-dose; Post-dose: 2, 8, and 24 hour
Population: As the trial was terminated early due to administrative reason, it was decided as per Statistical Analysis Plan not to evaluate the biomarker data for this study.
Secondary
Maximum Plasma Concentration (Cmax)
Time frame: Schedule 1 : 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Days 1 and 17.
Population: Pharmacokinetic analysis set included all the subjects who received at least 1 dose of MSC2015103B and provided sufficient plasma concentrations of MSC2015103B measurement after the first dose. n signifies the number of subjects evaluable for the particular timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 1 (n=3, 4, 3, 3, 3, 3, 2, 3, 4) | 38.750 Picogram per milliliter |
| Part 1 - MSC2015103B (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 2 (n= 3,3,3,3,1,3,2,2,3) | 48.952 Picogram per milliliter |
| Part 1 - MSC2015103B (Schedule 2) | Maximum Plasma Concentration (Cmax) | Week 1 (n=3, 4, 3, 3, 3, 3, 2, 3, 4) | 38.110 Picogram per milliliter |
| Part 1 - MSC2015103B (Schedule 2) | Maximum Plasma Concentration (Cmax) | Week 2 (n= 3,3,3,3,1,3,2,2,3) | 63.732 Picogram per milliliter |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 1 (n=3, 4, 3, 3, 3, 3, 2, 3, 4) | 97.293 Picogram per milliliter |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 2 (n= 3,3,3,3,1,3,2,2,3) | 219.71 Picogram per milliliter |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 1 (n=3, 4, 3, 3, 3, 3, 2, 3, 4) | 290.98 Picogram per milliliter |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 2 (n= 3,3,3,3,1,3,2,2,3) | 329.62 Picogram per milliliter |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 1 (n=3, 4, 3, 3, 3, 3, 2, 3, 4) | 396.45 Picogram per milliliter |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 2 (n= 3,3,3,3,1,3,2,2,3) | 2471.0 Picogram per milliliter |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 2 (n= 3,3,3,3,1,3,2,2,3) | 1728.1 Picogram per milliliter |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 1 (n=3, 4, 3, 3, 3, 3, 2, 3, 4) | 888.15 Picogram per milliliter |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 2 (n= 3,3,3,3,1,3,2,2,3) | 5636.8 Picogram per milliliter |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | Maximum Plasma Concentration (Cmax) | Week 1 (n=3, 4, 3, 3, 3, 3, 2, 3, 4) | 2215.9 Picogram per milliliter |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | Maximum Plasma Concentration (Cmax) | Week 1 (n=3, 4, 3, 3, 3, 3, 2, 3, 4) | 75.313 Picogram per milliliter |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | Maximum Plasma Concentration (Cmax) | Week 2 (n= 3,3,3,3,1,3,2,2,3) | 190.59 Picogram per milliliter |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | Maximum Plasma Concentration (Cmax) | Week 1 (n=3, 4, 3, 3, 3, 3, 2, 3, 4) | 52.331 Picogram per milliliter |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | Maximum Plasma Concentration (Cmax) | Week 2 (n= 3,3,3,3,1,3,2,2,3) | 157.62 Picogram per milliliter |
Secondary
Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication
Abnormal laboratory findings and other abnormal investigational findings which were associated with clinical signs and symptoms, lead to treatment discontinuation, or considered medically important by the investigator were reported as AEs.
Time frame: From the initiation of the trial till the data cut-off date 15 July 2013
Population: The safety analysis set included all the subjects who received at least one administration of the trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Aspartate aminotransferase increased | 3 Subjects |
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Blood glucose increased | 0 Subjects |
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Blood alkaline phosphatase increased | 0 Subjects |
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypokalemia | 0 Subjects |
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Gamma-glutamyl transferase increased | 0 Subjects |
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hyponatraemia | 0 Subjects |
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Ejection fraction decreased | 0 Subjects |
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypoalbuminaemia | 0 Subjects |
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypophosphatemia | 0 Subjects |
| Part 1 - MSC2015103B (Schedule 1) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Decreased appetite | 3 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypophosphatemia | 1 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Decreased appetite | 1 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypoalbuminaemia | 1 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Aspartate aminotransferase increased | 0 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Gamma-glutamyl transferase increased | 1 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Blood alkaline phosphatase increased | 1 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Ejection fraction decreased | 1 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Blood glucose increased | 1 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypokalemia | 2 Subjects |
| Part 1 - MSC2015103B (Schedule 2) | Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hyponatraemia | 2 Subjects |
Secondary
Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation
An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. SAE (Serious adverse event) is defined as any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.. TEAEs are events between first dose of study drug up to the cut-off date (15 July 2013) and were absent before treatment or that worsened relative to pretreatment state.
Time frame: From the initiation of the trial till the data cut-off date 15 July 2013
Population: The safety analysis set included all the subjects who received at least one administration of the trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | TEAEs | 100.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | Serious TEAEs | 19.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | TEAEs leading to death | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | TEAEs leading to discontinuation | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | TEAEs leading to discontinuation | 14.3 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | TEAEs | 100.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | TEAEs leading to death | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | Serious TEAEs | 42.9 Percentage of subjects |
Secondary
Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication
Abnormal laboratory findings and other abnormal investigational findings which were associated with clinical signs and symptoms, lead to treatment discontinuation, or considered medically important by the investigator were reported as AEs.
Time frame: From the initiation of the trial till the data cut-off date 15 July 2013
Population: The safety analysis set included all the subjects who received at least one administration of the trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Ejection fraction decreased | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Aspartate aminotransferase increased | 14.3 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Decreased appetite | 14.3 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Gamma-glutamyl transferase increased | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Blood alkaline phosphatase increased | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Blood glucose increased | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypokalemia | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hyponatraemia | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypoalbuminaemia | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypophosphatemia | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hyponatraemia | 28.6 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Blood glucose increased | 14.3 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Aspartate aminotransferase increased | 0.0 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypophosphatemia | 14.3 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Decreased appetite | 14.3 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypokalemia | 28.6 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Gamma-glutamyl transferase increased | 14.3 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Hypoalbuminaemia | 14.3 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Blood alkaline phosphatase increased | 14.3 Percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Ejection fraction decreased | 14.3 Percentage of subjects |
Secondary
Percentage of Subjects With Clinical Benefit
Clinical benefit was to be confirmed by CR, PR or stable disease (SD) lasting at least 6 weeks (using RECIST v1.0) during treatment. CR: The disappearance of all target and non-target lesions and normalization of tumor marker level; PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started.
Time frame: Every 6 Weeks until complete response or till data cut-off date 15 July 2013
Population: The efficacy analysis set included all subjects who received at least 1(non-zero) dose of MSC2015103B and had a baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects With Clinical Benefit | 33.3 percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects With Clinical Benefit | 28.6 percentage of subjects |
Secondary
Percentage of Subjects With Overall Response
Overall response was to be confirmed by complete response (CR) or partial response (PR) using response evaluation criteria in solid tumours Version 1.0 (RECIST) during treatment. CR: The disappearance of all target and non-target lesions and normalization of tumor marker level; PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline.
Time frame: Every 6 Weeks until complete response or till data cut-off date 15 July 2013
Population: The efficacy analysis set included all subjects who received at least 1(non-zero) dose of MSC2015103B and had a baseline tumor assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects With Overall Response | PR | 0 percentage of subjects |
| Part 1 - MSC2015103B (Schedule 1) | Percentage of Subjects With Overall Response | CR | 0 percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects With Overall Response | CR | 0 percentage of subjects |
| Part 1 - MSC2015103B (Schedule 2) | Percentage of Subjects With Overall Response | PR | 0 percentage of subjects |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax)
Time frame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17.
Population: Pharmacokinetic analysis set included all the subjects who received at least 1 dose of MSC2015103B and provided sufficient plasma concentrations of MSC2015103B measurement after the first dose. n signifies the number of subjects evaluable for the particular timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Part 1 - MSC2015103B (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 1.1573 Hour |
| Part 1 - MSC2015103B (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 2.4478 Hour |
| Part 1 - MSC2015103B (Schedule 2) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 2.3833 Hour |
| Part 1 - MSC2015103B (Schedule 2) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 5.2643 Hour |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 4.5789 Hour |
| Part 1 - MSC2015103B 300 mcg (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 1.4422 Hour |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 1.1635 Hour |
| Part 1 - MSC2015103B 450 mcg (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 1.4422 Hour |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 1.5874 Hour |
| Part 1 - MSC2015103B 650 mcg (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 0.50000 Hour |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 1.1447 Hour |
| Part 1 - MSC2015103B 1000 mcg (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 2.0110 Hour |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 1.2450 Hour |
| Part 1 - MSC2015103B 1500 mcg (Schedule 1) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 0.70711 Hour |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 2.4248 Hour |
| Part 1 - MSC2015103B 150 mcg (Schedule 2) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 2.8519 Hour |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 3 (n=3,3,3,3,1,3,2,2,3) | 1.6869 Hour |
| Part 1 - MSC2015103B 200 mcg (Schedule 2) | Time to Reach Maximum Plasma Concentration (Tmax) | Week 1 (n=3,4,3,3,3,3,2,3,4) | 1.3161 Hour |