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Pimasertib will be administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose will be escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib

Pimasertib will be administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose will be escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib will be administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose escalation will proceed to 75 mg BID until MTD is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib will be administered orally twice daily on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. Dose will be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib will be administered orally twice daily on Days 1 to 21 of a 28-day cycle. Dose will be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Medical responsible

This is an open-label, multi-center, dose-escalation trial of pimasertib (MSC1936369B) in blood and bone marrow cancers. The trial will be conducted in two parts:

Part 1 (safety run-in period): Will determine the maximum tolerated dose (MTD) of the study drug in subjects with advanced hematological malignancies.

Part 2: Will assess the anti-leukemic activity of the study drug in older subjects with newly diagnosed poor prognosis acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy.

Trial of Pimasertib in Hematological Malignancies

Phase II Trial With Safety-Run-In of MEK Inhibitor MSC1936369B in Subjects With Poor Prognosis Acute Myeloid Leukemia and Other Hematological Malignancies

The DLT was any toxicity that resulted in treatment delay for more than (\>) 2 weeks due to treatment-related adverse effects, or any Grade greater than or equal to (\>=) 3 non-hematological toxicity excluding Grade 4 asymptomatic increases in liver function tests reversible within 7 days in subjects with liver involvement, and Grade 3 asymptomatic increases in liver function tests reversible within 7 days for subjects without liver involvement, Grade 3 vomiting unless encountered and persistent for more than 3 days despite adequate and optimal therapy, and Grade 3 diarrhea unless encountered and persistent for more than 3 days despite adequate and optimal anti-diarrhea therapy at any DL and judged to be possibly or probably related to the trial treatment by the Investigator and/or the Sponsor.

The best overall response was to be reported as either of the following: (1) Morphologic complete remission (CR) = normalization of the peripheral blood absolute neutrophil count (PBANC) \>1.0x10\^9 per liter (/L), platelets \>100x10\^9 /L, bone marrow aspirate with less than or equal to (\<=) 5 percent (%) blasts, no blasts with Auer rods (AML only). (2) Complete remission with incomplete blood count recovery (CRi) = Same as CR without normalization of PBANC and platelet count. (3) Partial remission (PR) = normalization of PBANC \>1.0x10\^9/L, platelets \>100x10\^9/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts less than (\<) 5%. (4) Progressive disease (PD) = \>50% increase in peripheral blood or bone marrow blasts. (5) Stable disease (SD) = subjects who failed to achieve CR, CRi or PR and without criteria for PD.

An adverse event (AE) was defined as any new untoward medical occurrences/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. TEAEs include both SAEs and non-SAEs.

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 AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. It is obtained from AUC0-t plus AUCt-infinity.

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. Data for Pimasertib 75 mg arm was not available for all the regimens combined, thus reported as separate outcome measure and not included in this outcome.

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.

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 for Pimasertib 75 mg arm was not available for all the regimens combined, thus reported as separate outcome measure and not included in this outcome.

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.

The best overall response was reported as either of the following: (1) Morphologic complete remission (CR) = normalization of the peripheral blood absolute neutrophil count (PBANC) \>1.0x10\^9 per liter (/L), platelets \>100x10\^9 /L, bone marrow aspirate with less than or equal to (\<=) 5 percent (%) blasts, no blasts with Auer rods (AML only). (2) Complete remission with incomplete blood count recovery (CRi) = Same as CR without normalization of PBANC and platelet count. (3) Partial remission (PR) = normalization of PBANC \>1.0x10\^9/L, platelets \>100x10\^9/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts less than (\<) 5%. (4) Progressive disease (PD) = \>50% increase in peripheral blood or bone marrow blasts. (5) Stable disease (SD) = Subjects who failed to achieve CR, CRi or PR and without criteria for PD.

An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that results in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.

EMD Serono

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. SAEs and Other AEs (non-SAEs) were reported.

Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Regimen 1 (Part 1)

Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Regimen 2 (Part 1)

Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Regimen 3 (Part 1)

Total

18 to less than (<) 60

60 to <75

Greater than or equal to (>=) 75

Age, Customized

Sex: Female, Male

Baseline analysis population included all the subjects who were treated with at least one administration of pimasertib.

The trial has been terminated due to an estimated low probability of clinical benefit based on limited anti-leukemic effects observed in safety run-in (Part 1).

Merck KGaA Communication Center

The DLT analysis set included all subjects who received over 90 percent (%) administration of trial medication in Cycle 1 or showed a DLT.

Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs)

Pimasertib was to be administered orally twice daily on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. Dose was to be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment was to be continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Regimen 1 (Part 2)

Pimasertib was to be administered orally twice daily on Days 1 to 21 of a 28-day cycle. Dose was to be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment was to be continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Regimen 2 (Part 2)

Due to limited anti-leukemic effects observed in the safety run-in part decision was made not to conduct part 2 hence this outcome measure was not assessed. Effects observed in the safety run-in part decision was made not to conduct part 2 hence this outcome measure was not assessed.

Part 2: Percentage of Subjects With Best Overall Response

TEAEs

Serious TEAEs

TEAEs Leading to Death

TEAEs Leading to Treatment Discontinuation

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

Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation

Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib 8 mg (All Regimens [Part 1])

Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib 15 mg (All Regimens [Part 1])

Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib 23 mg (All Regimens [Part 1])

Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib 30 mg (All Regimens [Part 1])

Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib 42 mg (All Regimens [Part 1])

Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib 45 mg (All Regimens [Part 1])

Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib 60 mg (All Regimens [Part 1])

Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib 75 mg (All Regimens [Part 1])

Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Pimasertib 90 mg (All Regimens [Part 1])

Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided adequate PK samples per protocol. N (number of subject analyzed) signifies subjects evaluable for this outcome measure.

Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose

Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose

Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples per protocol. N (number of subject analyzed) signifies subjects evaluable for this outcome measure.

Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose

Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples per protocol. Number of subjects analysed refer to the subjects evaluable for this outcome measure.

Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose

Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. N (number of subject analyzed) signifies subjects evaluable for this outcome measure.

Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose

Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose

Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) of Pimasertib: Single Dose

Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. '"n" =Subjects evaluable for this outcome measure for specified categories for each reporting group, respectively.

Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) of Pimasertib: Multiple Dose

Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. 'N'(number of subjects analyzed)=subjects evaluable for this measure.

Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose

Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose

Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose

Regimen 1 (n=0)

Regimen 2 (n=3)

Regimen 3 (n=1)

Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. 'N'(number of subjects analyzed)=subjects evaluable for this measure and "n" = subjects evaluable for the specified regimen.

Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose

Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose

Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose

Regimen 1 (n = 0)

Regimen 2 (n = 3)

Regimen 3 (n = 1)

Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose

Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose

The efficacy analysis set included all subjects who received at least 1 administration of planned dose of pimasertib and had at least 1 efficacy assessment after the first dose. 'N' (number of subjects analyzed)=subjects evaluable for this outcome measure.

Part 1: Percentage of Subjects With Best Overall Response

This outcome measure was not analyzed as the trial was terminated during safety run-in (Part 1).

Spots Global Cancer Trial Database for Trial of Pimasertib in Hematological Malignancies

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