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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00982865




Registration number
NCT00982865
Ethics application status
Date submitted
22/09/2009
Date registered
22/09/2009
Date last updated
9/02/2018

Titles & IDs
Public title
Trial of MSC1936369B in Subjects With Solid Tumors
Scientific title
A Multicenter, Open Label, Phase I Trial of the MEK Inhibitor MSC1936369B Given Orally to Subjects With Solid Tumours
Secondary ID [1] 0 0
2007-004665-18
Secondary ID [2] 0 0
28062
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid Tumors 0 0
Cancer 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - MSC1936369B
Treatment: Drugs - MSC1936369B
Treatment: Drugs - MSC1936369B
Treatment: Drugs - MSC1936369B

Experimental: MSC1936369B Regimen 1 - Subjects will be administered MSC1936369B (pimasertib) capsules 1 to 120 milligram (mg) orally, once daily (QD) on Days 1 to 5, 8 to 12, 15 to 19 of each 21-day treatment cycle until progressive disease (PD) or intolerable toxicity or investigator/subject decision.

Experimental: MSC1936369B Regimen 2 - MSC1936369B Regimen 2 (Without Food Effect): Subjects will be administered MSC1936369B capsules 1 to 255 mg orally QD on Days 1 to 15 of each 21-day treatment cycle until PD or intolerable toxicity or investigator/subject decision.
MSC1936369B Regimen 2 (With Food Effect): : Subjects will be administered MSC1936369B capsules 90 or 150 mg orally QD on Day 1 to 15 of each 21-day treatment cycle until PD or intolerable toxicity or investigator/subject decision. Subjects in the Regimen 2 FE cohort were assigned in a 1:1 ratio to either the fed/fasted sequence or fasted/fed sequence for Day 1 of Cycle 1 and Day 1 of Cycle 2.

Experimental: MSC1936369B Regimen 3 once daily - Subjects will be administered MSC1936369B capsules 60 to 90 mg orally QD in each 21-day treatment cycle until PD or intolerable toxicity or investigator/subject decision.

Experimental: MSC1936369B Regimen 3 twice daily (BID) - Subjects will be administered MSC1936369B capsules 45 to 75 mg orally BID in each 21-day treatment cycle until PD or intolerable toxicity or investigator/subject decision.


Treatment: Drugs: MSC1936369B


Treatment: Drugs: MSC1936369B


Treatment: Drugs: MSC1936369B


Treatment: Drugs: MSC1936369B


Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Subjects Experienced Any Dose-Limiting Toxicity (DLT) Over the First Cycle - Day 1 to 21 - DLT was defined as any of following toxicities at any dose level according to using National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) v3.0(CTCAE), probably or possibly related to trial medication by investigator or sponsor: a)Any Grade 3 or more non-haematological toxicity excluding: (i)Grade 3 asymptomatic increase in liver function tests (Aspartate Aminotransferase, Alanine transaminase, Alkaline Phosphatase reversible within 7 days for subjects without liver involvement, or grade 4 for subjects with liver involvement; (ii)Grade 3 vomiting if it is encountered despite adequate and optimal therapy (e.g. serotonin [5HT3] antagonists and corticosteroids); (iii)Grade 3 diarrhoea if it is encountered despite adequate and optimal anti diarrhoea therapy; b)Grade 4 neutropenia of >5 days duration or febrile neutropenia lasting for more than 1 day; c)Grade 4 thrombocytopenia >1 day or grade 3 with bleeding; d)Any treatment delay >2 weeks due to drug-related AEs.
Timepoint [1] 0 0
Day 1 up to Day 21 of Cycle 1
Secondary outcome [1] 0 0
Number of Subjects With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Discontinuation - AE was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 253 weeks. TEAEs include both Serious TEAEs and non-serious TEAEs.
Timepoint [1] 0 0
Baseline up to 253 weeks
Secondary outcome [2] 0 0
Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Death
Timepoint [2] 0 0
Baseline up to 253 weeks
Secondary outcome [3] 0 0
Number of Subjects With Clinical Significant Laboratory Abnormalities and Vital Signs Reported as Treatment Emergent Adverse Events - Any clinically significant changes in laboratory evaluations and vital signs were recorded as treatment emergent adverse events. The clinical laboratory parameters that were assessed included: Hematological parameters, Blood chemistry parameters, Urinalysis and the vital signs that were assessed included: Blood pressure, Heart rate, Temperature and Weight. SAF analysis was used.
Timepoint [3] 0 0
Baseline up to 253 weeks
Secondary outcome [4] 0 0
Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 1 - Pharmacokinetic (PK) parameter Cmax was obtained directly from the concentration versus time curve.
Timepoint [4] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours (h) post-dose on Cycle 1(C1) Day 1 (D1), Cycle 1 Day 12 (D12) and Cycle 3 (C3) Day 1
Secondary outcome [5] 0 0
Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (Without Food Effect) - Cmax was obtained directly from the concentration versus time curve.
Timepoint [5] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [6] 0 0
Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (With Food Effect) - Cmax was obtained directly from the concentration versus time curve. Summarized data over Day 1 and Day 2 was reported.
Timepoint [6] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
Secondary outcome [7] 0 0
Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 3 Once Daily - Cmax was obtained directly from the concentration versus time curve.
Timepoint [7] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [8] 0 0
Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 3 Twice Daily - Cmax was obtained directly from the concentration versus time curve.
Timepoint [8] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
Secondary outcome [9] 0 0
Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 1 - Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Timepoint [9] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
Secondary outcome [10] 0 0
Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (Without Food Effect) - Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Timepoint [10] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [11] 0 0
Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (With Food Effect) - Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve. Summarized data over Day 1 and Day 2 was reported.
Timepoint [11] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
Secondary outcome [12] 0 0
Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 3 Once Daily - Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Timepoint [12] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [13] 0 0
Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 3 Twice Daily - Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Timepoint [13] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
Secondary outcome [14] 0 0
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: Regimen 1 - Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.
Timepoint [14] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
Secondary outcome [15] 0 0
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: : Regimen 2 (Without Food Effect) - Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.
Timepoint [15] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [16] 0 0
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: Regimen 2 (With Food Effect) - Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. Summarized data over Day 1 and Day 2 was reported.
Timepoint [16] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
Secondary outcome [17] 0 0
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: Regimen 3 Once Daily - Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.
Timepoint [17] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [18] 0 0
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of MSC1936369B: Regimen 3 Twice Daily - Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.
Timepoint [18] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
Secondary outcome [19] 0 0
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B : Regimen 1 - AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ ?z, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and ?z is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Timepoint [19] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
Secondary outcome [20] 0 0
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (Without Food Effect) - AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ ?z, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the Lower Limit of quantification (LLQ) and ?z is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Timepoint [20] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [21] 0 0
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (With Food Effect) - AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ ?z, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and ?z is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. Summarized data over Day 1 and Day 2 was reported.
Timepoint [21] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
Secondary outcome [22] 0 0
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 3 Twice Daily - AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ ?z, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and ?z is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Timepoint [22] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
Secondary outcome [23] 0 0
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 3 Once Daily - AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ ?z, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and ?z is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Timepoint [23] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [24] 0 0
Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 1 - Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by ?z. As AUCextra was >20% of AUC0-inf, t1/2 derived from ?z was regarded as implausible & not calculated for arms MSC1936369B 1mg, 1.5mg, 2.5 mg.
Timepoint [24] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
Secondary outcome [25] 0 0
Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (Without Food Effect) - Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by ?z. As AUCextra was >20% of AUC0-inf, t1/2 derived from ?z was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg.
Timepoint [25] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [26] 0 0
Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (With Food Effect) - Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by ?z. Summarized data over Day 1 and Day 2 was reported.
Timepoint [26] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
Secondary outcome [27] 0 0
Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 3 Once Daily - Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by ?z.
Timepoint [27] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [28] 0 0
Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 3 Twice Daily - Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by ?z.
Timepoint [28] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
Secondary outcome [29] 0 0
Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 1 - Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf. As AUCextra was >20% of AUC0-inf, CL/f derived from ?z was regarded as implausible & not calculated for arms MSC1936369B 1mg, 1.5mg, 2.5 mg.
Timepoint [29] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
Secondary outcome [30] 0 0
Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (Without Food Effect) - Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf. As AUCextra was >20% of AUC0-inf, CL/f derived from ?z was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg.
Timepoint [30] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [31] 0 0
Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (With Food Effect) - Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf. Summarized data over Day 1 and Day 2 was reported.
Timepoint [31] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
Secondary outcome [32] 0 0
Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 3 Once Daily - Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf.
Timepoint [32] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [33] 0 0
Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 3 Twice Daily - Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from plasma, CL= Dose/AUC0-inf.
Timepoint [33] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
Secondary outcome [34] 0 0
Apparent Volume of Distribution Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 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 plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by ?z. As AUCextra was >20% of AUC0-inf, Vz/F derived from ?z was regarded as implausible & not calculated for arms MSC1936369B 1mg, 1.5mg, 2.5 mg.
Timepoint [34] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
Secondary outcome [35] 0 0
Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (Without Food Effect) - 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 plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by ?z. As AUCextra was >20% of AUC0-inf, Vz/F derived from ?z was regarded as implausible & not calculated for arms MSC1936369B 1mg, 2mg, 3.5 mg.
Timepoint [35] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [36] 0 0
Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (With Food Effect) - 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 plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by ?z. Summarized data over Day 1 and Day 2 was reported.
Timepoint [36] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
Secondary outcome [37] 0 0
Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 3 Once Daily - 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 plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by ?z
Timepoint [37] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [38] 0 0
Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 3 Twice Daily - 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 plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by ?z
Timepoint [38] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
Secondary outcome [39] 0 0
Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-8 (AUC Extra): Regimen 1 - AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: %AUCextra = (1- [AUC0-t / AUC0-inf])*100. %AUCextra was reported in terms of percentage of AUC0-inf.
Timepoint [39] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
Secondary outcome [40] 0 0
Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-8 (AUC Extra): Regimen 2 (Without Food Effect) - AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: %AUCextra = (1- [AUC0-t / AUC0-inf])*100. %AUCextra was reported in terms of percentage of AUC0-inf.
Timepoint [40] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [41] 0 0
Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-8 (AUC Extra): Regimen 2 (With Food Effect) - AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: AUCextra = (1- [AUC0-t / AUC0-inf])*100. AUCextra was reported in terms of percentage of AUC0-inf. Summarized data over Day 1 and Day 2 was reported.
Timepoint [41] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
Secondary outcome [42] 0 0
Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-8 (AUC Extra): Regimen 3 Once Daily - AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: AUCextra = (1- [AUC0-t / AUC0-inf])*100. AUCextra was reported in terms of percentage of AUC0-inf.
Timepoint [42] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
Secondary outcome [43] 0 0
Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-8 (AUC Extra): Regimen 3 Twice Daily - AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: AUCextra = (1- [AUC0-t / AUC0-inf])*100. AUCextra was reported in terms of percentage of AUC0-inf.
Timepoint [43] 0 0
Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
Secondary outcome [44] 0 0
Phosphorylated Extra-Cellular Signal-Regulated Kinase (pERK) Fold Change in Peripheral Blood Monocyte Cells (PBMC) and Tot ERK Fold Change in Peripheral Blood Monocyte Cells (PBMC)
Timepoint [44] 0 0
Pre-dose on C1D1, C1D2, C1D5, C1D8; 2, 4, 8 h post-dose on C1D1; pre-dose, 2, 8, 24 h post-dose on C1D12-15; pre-dose, 2, 4 h post-dose on C1D3
Secondary outcome [45] 0 0
Number of Subjects With Clinical Benefit (Complete Response [CR], Partial Response [PR] or Stable Disease [SD}) and Progressive Disease (PD) Based on the Best Overall Response (BOR) - Number of subjects with clinical benefit (CR, PR, or SD) and PD according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) was reported. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: defined as at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. PD:defined as at least a 20% increase in sum of longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of longest diameter while on study.
Timepoint [45] 0 0
Baseline until disease progression (assessed up to end of treatment [253 weeks])

Eligibility
Key inclusion criteria
- Pathologically-confirmed solid tumor which is locally advanced or metastatic, and
either refractory after standard therapy for the disease or for which no effective
standard therapy is available. In the regimen 3, regimen 2 food-effect, and BID
cohorts, the tumor type will be restricted to melanoma.

- Age greater than or equal to (>=) 18 years

- Has read and understands the informed consent form and is willing and able to give
informed consent. Fully understands requirements of the trial and willing to comply
with all trial visits and assessments
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Bone marrow impairment as evidenced by Haemoglobin less than (<) 9.0 gram per
deciliter (g/dL), Neutrophil count < 1.0*10^9/Liter, platelets < 100*10^9/Liter

- Renal impairment as evidenced by serum creatinine > 1.5*upper limit normal (ULN),
and/or calculated creatinine clearance < 60 milliliter per minute (mL/min)

- Liver function abnormality as defined by total bilirubin > 1.5*ULN, or aspartate
aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5*ULN, for subjects with
liver involvement AST/ALT > 5*ULN

- INR > 1.5*ULN

- Serum calcium > 1*ULN

- History of central nervous system (CNS) metastases, unless subject has been previously
treated for CNS metastases, is stable by computer tomography (CT) scan without
evidence of cerebral oedema, and has no requirements for corticosteroids or
anticonvulsants

- History of difficulty swallowing, malabsorption or other chronic gastro-intestinal
disease or conditions that may hamper compliance and/or absorption of the tested
product

- Eastern Cooperative Oncology Group Performance status (ECOG PS) greater than (>) 1

- Known human immunodeficiency virus (HIV) positivity, active hepatitis C, or active
hepatitis B

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 0 0
- Westmead
Recruitment outside Australia
Country [1] 0 0
Belgium
State/province [1] 0 0
Brussels
Country [2] 0 0
Belgium
State/province [2] 0 0
Ghent
Country [3] 0 0
France
State/province [3] 0 0
Bordeaux
Country [4] 0 0
France
State/province [4] 0 0
Paris
Country [5] 0 0
France
State/province [5] 0 0
Rennes
Country [6] 0 0
France
State/province [6] 0 0
Toulouse
Country [7] 0 0
Netherlands
State/province [7] 0 0
Amsterdam

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck KGaA, Darmstadt, Germany
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Merck Serono S.A., Geneva
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This is a first in man trial with a primary objective being the determination of the Maximum
Tolerated dose (MTD) and the dose-limiting toxicity (DLT) in several regimens of MEK
inhibitor MSC1936369B administered orally once a day, in subjects with malignant solid tumors
to see how safe is treatment with MSC1936369B.
Trial website
https://clinicaltrials.gov/show/NCT00982865
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Responsible
Address 0 0
Merck KGaA, Darmstadt, Germany
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No data has been provided for results reporting
Summary results
Other publications