Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Vasodilator Agents

Lipid Regulating Agents

Hematinics

Vitamins

Sirolimus

Temsirolimus

MTOR Inhibitors

Niacinamide

Niacin

Nicotinic Acids

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Folic Acid

Vitamin B Complex

Trace Elements

Nicotinamide

Nicotinic Acid

Vitamin B3

Folate

Vitamin B9

Pimasertib will be administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.

Pimasertib

Pimasertib will be administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.

Temsirolimus will be administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.

Temsirolimus will be administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.

Medical Responsible

The research trial is testing the experimental drug pimasertib and the drug Torisel, given together, in the treatment of advanced solid tumors. The primary purpose of the study is to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of the drug combination.

Combination Trial of Pimasertib (MSC1936369B) With Temsirolimus

Phase I Dose Escalation Trial of MEK1/2 Inhibitor MSC1936369B Combined With Temsirolimus in Subjects With Advanced Solid Tumors

DLT was defined as any of the following toxicities graded as per National Cancer Institute (NCI) common terminology criteria for adverse events (NCI CTCAE v4.0) encountered within cycle 1 of treatment at any dose level and judged not to be related to the underlying disease or concomitant medications. A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation would expose subjects to unacceptable risk; any Grade \>=3 non-hematological toxicity except Grade 3 asymptomatic increases in liver function tests, diarrhea, nausea or vomiting with duration \<= 48 hours and alopecia; Grade 4 neutropenia of \>5 days duration or febrile neutropenia of \>1 day duration; Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia; any treatment interruption \>2 weeks due to adverse events; any severe, impairing daily functions or life-threatening, complication or abnormality not defined in NCI-CTCAE that is attributable to the therapy.

An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. The TEAEs were those events that occur between first dose of trial treatment and up to 30 days after last dose of the trial treatment that were absent before treatment or that worsened relative to pretreatment state.

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

The AUCtau was defined as the area under the concentration curve divided by the dosing interval. AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Clearance (CL) of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. The CL obtained after oral dose (CL/F) was influenced by the fraction of the dose absorbed (bioavailability). Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

The clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Volume of distribution (Vz) 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 Vz after oral dose (Vz/F) was influenced by the fraction absorbed. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

The Vz 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. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Disease control is defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) \>=12 weeks), based on tumor assessments as determined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. CR: The disappearance of all 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 partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since treatment started.

During the first cycle (either Cycle 1 non-DDI or Cycle 1-DDI) blood samples will be collected for pharmacodynamic marker assessments by flow cytometry such as phospho-ERK and phospho- S6 activities in PBMCs

EMD Serono

Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.

Pimasertib 45 mg+Temsirolimus 12.5 mg

Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.

Pimasertib 45 mg+Temsirolimus 25 mg

Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.

Pimasertib 75 mg+Temsirolimus 25 mg

Total

Age, Continuous

Sex: Female, Male

The safety analysis set included all the subjects who received at least one administration of trial medication.

No formal efficacy evaluation was performed for this trial due to early termination of the trial.

Merck KGaA Communication Center

The dose escalation analysis set included all the subjects who received at least 80% of the planned doses of each treatment (pimasertib and temsirolimus) in the first cycle of treatment or who experienced DLT during the first cycle of treatment regardless of the received amount of drug.

Number of Subjects With Dose Limiting Toxicities (DLTs)

Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

DDI: Day 1

DDI: Day 9

Non-DDI: Day 8

Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were analyzed for drug-drug interaction.

Pimasertib 45 mg+Temsirolimus 12.5 mg (DDI)

Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were analyzed for drug-drug interaction.

Pimasertib 45 mg+Temsirolimus 25 mg (DDI)

Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.

Pimasertib 45 mg+Temsirolimus 25 mg (Non-DDI)

Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.

Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI)

Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. "Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

Maximum Plasma Concentration (Cmax) of Pimasertib

DDI: Day 16

Maximum Plasma Concentration (Cmax) of Temsirolimus

Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib

Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus

DDI: AUCtau: Day 9

Non-DDI: AUCtau: Day 8

DDI: AUC0-inf: Day 1

Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N'=subjects evaluable for this outcome measure; "Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib

Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N'=subjects evaluable for this outcome measure;"Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus

Apparent Terminal Half-life (t1/2) of Pimasertib

Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. N=subjects evaluable for this outcome measure; "Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

Apparent Terminal Half-life (t1/2) of Temsirolimus

Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N' =subjects evaluable for this outcome measure;"Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib

Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N' =subjects evaluable for this outcome measure; "Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus

Pimasertib 75 mg+Temsirolimus (TEM) 25 mg (Non-DDI)

Apparent Volume of Distribution (Vz/F) of Pimasertib

Volume of Distribution (Vz) of Temsirolimus

Data was not evaluated for this outcome as the subjects did not met the minimum criteria duration for the evaluation of the outcome measure due to the early termination of the trial

Number of Subjects With Disease Control Rate

As the trial was terminated early due to toxicities observed with the combination of pimasertib and temsirolimus, it was decided as per plan not to evaluate the biomarker data for this study

Phospho Extracellular Signal Regulated Kinase (pERK ) Levels and Phospho Ribosomal Protein S6 (pS6) Levels in in Peripheral Blood Mononuclear Cells (PBMCs)

Spots Global Cancer Trial Database for Combination Trial of Pimasertib (MSC1936369B) With Temsirolimus

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Study Description

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