Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

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All Drugs and Chemicals

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Niacinamide

Niacin

Nicotinic Acids

Folic Acid

Vitamin B Complex

Trace Elements

Nicotinamide

Nicotinic Acid

Vitamin B3

Folate

Vitamin B9

Subjects with solid tumor will be administered with Pimasertib 30 mg twice a day (BID) in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Pimasertib

Subjects with solid tumor will be administered with Pimasertib 45 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Subjects with solid tumor will be administered with Pimasertib 60 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Subjects with HCC will be administered with Pimasertib 30 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Subjects with HCC will be administered with Pimasertib 45 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Medical Responsible

This is a two-part trial. "Solid tumor" in this protocol means solid tumor excluding hepatocellular carcinoma (HCC).

Part 1: Dose Escalation Phase in subjects with solid tumor (Cohort A) and HCC (Cohort B). The dose will be increased from 45 mg twice a day (BID) with 3+3 cohort method up to the recommended phase 2 dose (RP2D) of pimasertib established as single agent in the global studies for each arm independently.

Part 2: The Maximum Tolerated Dose (MTD) defined in Part 1 will be confirmed in more subjects in Cohort A (N=18) and Cohort B (N=6) separately.

Following the recommendation by the Safety Monitoring Committee, Cohort B was discontinued due to hepatocellular carcinoma (HCC) and there will be no further enrollment of subjects to this cohort. This decision is based upon review of safety and efficacy information.

A Multicentre, Open Label, Phase 1 Trial in Japan of the Mitogen Activated Protein Extracellular Signal Regulated Kinase (MEK) Inhibitor Pimasertib Given Orally to Subjects With Solid Tumors as Monotherapy

A Multicentre, Open Label, Phase I Trial in Japan of the MEK Inhibitor Pimasertib Given Orally to Subjects With Solid Tumors as Monotherapy

DLT defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0): any of following toxicities possibly/probably related to study drug: Any non-hematological toxicity of Grade 3 or higher (excluding Grade 3 asymptomatic rise in liver function tests (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], alkaline phosphatase \[ALP\], gamma-glutamyl transferase \[GGT\] reversible in 7 days for subjects with solid tumor and without liver involvement, or Grade 4 for subjects with HCC or with liver involvement; Grade 3 or 4 asymptomatic rise in creatinine phosphokinase (CPK) reversible in 7 days, deniable for myocardial infarction and rhabdomyolysis; Grade 3 vomiting/diarrhea encountered without optimal therapy). Any Grade 4 neutropenia \>5 days duration, any Grade 3 or above febrile neutropenia. Grade 4 thrombocytopenia \>1 day or Grade 3 with bleeding. Any treatment delay \>2 weeks due to drug-related adverse effects.

An adverse event (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 unfavorable 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 or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) 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 30 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs.

The summarized data was not available for this arm therefore individual data was presented.

Data were not reported for "Part 1: Pimasertib 45 mg in HCC" arm as there were no PK samples collected for this arm.

Data were not reported for "Part 1: Pimasertib 45 mg In HCC" arm as there were no PK samples collected for this arm.

Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours).

Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours). The summarized data was not available for this arm therefore individual data was presented.

Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (12 hours). Data were not reported for "Part 1: Pimasertib 45 mg In HCC" arm as there were no PK samples collected for this arm.

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.

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. The summarized data was not available for this arm therefore individual data was presented.

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. Data were not reported for "Part 1: Pimasertib 45 mg In HCC" arm as there were no PK samples collected for this arm.

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. The summarized data was not available for this arm therefore individual data was presented.

Apparent clearance at steady state was reported. Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Data were not reported for "Part 1: Pimasertib 45 mg In HCC" arm as there were no PK samples collected for this arm.

Apparent clearance at steady state was reported. Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The summarized data was not available for this arm therefore individual data was presented.

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.

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. The summarized data was not available for this arm therefore individual data was presented.

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. Data were not reported for "Part 1: Pimasertib 45 mg In HCC" arm as there were no PK samples collected for this arm.

Racc (AUC) was calculated as, area under the curve from time zero to end of dosing interval on Day 1 divided by area under the curve from time zero to end of dosing interval on Day 15. Data were not reported for "Part 1: Pimasertib 45 mg In HCC" arm as there were no PK samples collected for this arm.

Racc (AUC) was calculated as, area under the curve from time zero to end of dosing interval on Day 1 divided by area under the curve from time zero to end of dosing interval on Day 15.

Racc (Cmax) was calculated as, maximum observed plasma concentration on Day 1 (Cmax) divided by maximum observed plasma concentration on Day 15 (Cmax). Data were not reported for "Part 1: Pimasertib 45 mg In HCC" arm as there were no PK samples collected for this arm.

Racc (Cmax) was calculated as, maximum observed plasma concentration on Day 1 (Cmax) divided by maximum observed plasma concentration on Day 15 (Cmax).

Percentage of subjects with best overall response in each category (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) was reported. CR was 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 was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as at least a 20% increase in the sum of diameters 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 was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Percentage of subjects with objective response (CR plus PR) according to RECIST Version 1.1 was reported. CR was 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 was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters.

Percentage of subjects with disease control (CR plus PR plus greater than 12 weeks SD) according to RECIST Version 1.1 was reported CR was 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 was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD was defined as at least a 20% increase in the sum of diameters 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.

Merck Serono Co., Ltd., Japan

Merck KGaA, Darmstadt, Germany

Subjects with solid tumor were administered with Pimasertib 30 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Part 1: Pimasertib 30 mg in Solid Tumor

Subjects with solid tumor were administered with Pimasertib 45 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Part 1: Pimasertib 45 mg in Solid Tumor

Subjects with solid tumor were administered with Pimasertib 60 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Part 1: Pimasertib 60 mg in Solid Tumor

Subjects with HCC were administered with Pimasertib 30 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Part 1: Pimasertib 30 mg in HCC

Subjects with HCC were administered with Pimasertib 45 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Part 1: Pimasertib 45 mg in HCC

Subjects with solid tumor were administered with Pimasertib 30 mg BID in 21- day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Total

Age, Continuous

Sex: Female, Male

Safety analysis set included all subjects who received at least one administration of pimasertib.

Due to the Sponsor's decision not to pursue the study drug as monotherapy, the Expansion Phase (Part 2) of the study was not conducted.

Merck KGaA Communication Center

Subjects with solid tumor were administered with Pimasertib 60 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject, whichever comes first.

Subjects with HCC were administered with Pimasertib 30 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject, whichever comes first.

Subjects with HCC were administered with Pimasertib 45 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject, whichever comes first.

DLT analysis set included all subjects who experienced any DLT during Cycle 1 and who received above 85% of all planned doses of pimasertib during Cycle 1.

Number of Subjects Who Experienced at Least One Dose Limiting Toxicity (DLT)

TEAEs

Serious TEAEs

Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs) or Serious TEAEs

Pharmacokinetic (PK) analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.

Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 1

Subject 1

Subject 2

PK analysis set included all subjects who received at least 1 planned dose of pimasertib and who had at least 1 measurable post-dose concentration. Subjects with important protocol deviations or events, which may impact the quality of the PK data were excluded from the PK analysis set.

Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1

PK analysis set. Here "Overall Number of Participants Analyzed" signifies the overall number of subjects who were evaluable for this outcome measure for each arm, respectively.

Maximum Observed Concentration (Cmax) of Pimasertib on Cycle 1 Day 15

Maximum Observed Concentration (Cmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15

Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 1

Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1

Time to Reach Maximum Concentration (Tmax) on Cycle 1 Day 15

Time to Reach Maximum Concentration (Tmax) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15

Area Under the Concentration Over Time (AUCt) at Cycle 1 Day 1

Area Under the Concentration Over Time (AUCt) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1

Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 1

Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib of 1 Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1

Subjects with solid tumor were administered with Pimasertib 30 milligram (mg) twice a day (BID) in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Pimasertib at Cycle 1 Day 15

Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUC0-tau) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15

Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 1

Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1

Subjects with solid tumor were administered with Pimasertib 30 mg BID until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Subjects with solid tumor were administered with Pimasertib 45 mg BID until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Subjects with solid tumor were administered with Pimasertib 60 mg BID until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Apparent Terminal Half-life (t1/2) of Pimasertib on Cycle 1 Day 15

Apparent Terminal Half-life (t1/2) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15

Subjects with HCC were administered with Pimasertib 60 mg BID in 21-day cycles until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Subjects with HCC were administered with Pimasertib 30 mg BID until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Apparent Clearance (CL/f) of Pimasertib on Cycle 1 Day 1

Apparent Clearance (CL/f) of Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1

Apparent Clearance at Steady-state (CLss/f) of Pimasertib on Cycle 1 Day 15

Apparent Clearance at Steady-state (CLss/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15

Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 1

Apparent Volume of Distribution at Terminal Phase (Vz/f) Part 1: Pimasertib 45 mg in HCC Arm on Cycle 1 Day 1

Apparent Volume of Distribution at Terminal Phase (Vz/f) of Pimasertib on Cycle 1 Day 15

Apparent Volume of Distribution at Terminal Phase (Vz/f) of Part 1: Pimasertib 30 mg in HCC Arm on Cycle 1 Day 15

Accumulation Ratio for AUC Racc(AUC) of Pimasertib

Accumulation Ratio for AUC Racc(AUC) of Part 1: Pimasertib 30 mg In HCC Arm

Accumulation Ratio for Cmax Racc(Cmax) of Pimasertib

Accumulation Ratio for Cmax Racc(Cmax) of Part 1: Pimasertib 30 mg In HCC Arm

Not evaluable

Subjects with HCC were administered with Pimasertib 45 mg BID until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Efficacy analysis set included all subjects who received at least one administration of planned dose of pimasertib and who have had at least one efficacy assessment after the first dose.

Percentage of Subjects With Best Overall Response

Subjects with solid tumor were administered with Pimasertib 30 mg twice a day (BID) until disease progression, intolerable toxicity, investigators decision to discontinue treatment or withdrawal of consent by the subject.

Efficacy analysis set' included all subjects who received at least one administration of planned dose of pimasertib and who have had at least one efficacy assessment after the first dose.

Spots Global Cancer Trial Database for A Multicentre, Open Label, Phase 1 Trial in Japan of the Mitogen Activated Protein Extracellular Signal Regulated Kinase (MEK) Inhibitor Pimasertib Given Orally to Subjects With Solid Tumors as Monotherapy

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