Hematologic Neoplasms, Leukemia, Myeloid, Acute
Conditions
Keywords
MEK Inhibitor, Pimasertib, Acute Myeloid Leukemia, Hematological Malignancies, Elderly Patients, Phase II
Brief summary
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.
Interventions
DRUGPimasertib
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.
Sponsors
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Part 1: 1. Subjects with one of the following conditions: * Primary or secondary AML, pathologically confirmed according to World Health Organization (WHO) classification who meet at least one of the following conditions: 1. Subjects with second or subsequent relapse after standard therapy, for whom no established treatment options are available 2. Subjects refractory to available therapies, for example, who failed to achieve complete response (CR) after 2 induction chemotherapy treatments 3. Newly-diagnosed older subjects (greater than or equal to 75 years of age), not candidates for intensive chemotherapy * Subjects with myelodysplastic syndrome (MDS), International Prognostic Scoring System (IPSS) Int-2 or high risk who are resistant or intolerant to standard treatment and not candidates for transplantation * Subjects with relapsed or refractory multiple myeloma (MM), who have failed or are intolerant to at least two prior therapies including thalidomide, lenalidomide and bortezomib * Subjects with advanced myeloproliferative disorders (MPD) for whom no established treatment options are available * Subjects with acute lymphocytic leukemia (ALL), relapsed, refractory or intolerant to standard treatment and for whom no effective treatment options are available 2. Age greater than or equal to 18 years 3. Subjects have read and understood the Informed Consent Form and are willing and able to give informed consent. They fully understand requirements of the trial and are willing to comply with all trial visits and assessments 4. Subjects and their partners must be willing to avoid pregnancy during the trial and until 1 month after the last trial drug administration. Subjects must therefore be willing to use adequate contraception as approved by the Investigator, two barrier methods or one barrier method with spermicide or intrauterine device, 2 weeks before, during the trial and 1 month after. The use of hormonal contraceptives should be avoided due to a possible drug-drug interaction in female subjects of childbearing age Part 2: 1. Subjects (male and female) with newly diagnosed primary or secondary AML pathologically confirmed according to WHO classification who have not been exposed to any prior therapy for AML with the exception of: * Emergency leukapheresis and * Emergency treatment for hyperleukocytosis with hydroxyurea that is allowed until 24 hours before the start of the trial treatment. Prior therapy for pre-existing hematological conditions, for example, MDS or MPD, including but not limited to hypomethylating agents, is also allowed until at least 2 weeks or 5 half-lives of that agent before the first dose of pimasertib 2. Subjects meet at least one of the following conditions: * Age greater than or equal to 75 years OR * Age greater than or equal to 60 and less than 75 years with at least one of the following poor prognostic factors: * Secondary AML, as determined by known and documented exposure to leukemogenic therapy or environmental toxin or antecedent history of MDS or MPD according to WHO criteria for at least 3 months prior to trial entry, with prior bone marrow aspirate, biopsy and peripheral blood smear documenting the diagnosis * At least one of the following unfavorable cytogenetic abnormalities: del(5q), -5, -7, del(7q), abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) or complex karyotypes (greater than or equal to 3 unrelated abnormalities) * Eastern Cooperative Oncology Group (ECOG) status 2 3. Subjects have read and understood the Informed Consent Form and are willing and able to give informed consent. They fully understand requirements of the trial and are willing to comply with all trial visits and assessments 4. Subjects and their partners must be willing to avoid pregnancy during the trial and until 1 month after the last trial drug administration. Subjects must therefore be willing to use adequate contraception as approved by the Investigator such as two barrier methods or one barrier method with spermicide or intrauterine device, 2 weeks before, during the trial and 1 month after. The use of hormonal contraceptives should be avoided due to a possible drug-drug interaction in female subjects of childbearing age
Exclusion criteria
Part 1 and Part 2: 1. ECOG performance status 3 or greater 2. Hyperleukocytosis with greater than 30 x 10 to the ninth power per liter leukemia blasts in peripheral blood 3. Acute promyelocytic leukemia \[t(15;17)\] 4. Administration of any antineoplastic therapy within at least 2 weeks or 5 half lives of that therapy of the first pimasertib dose; except the use of hydroxyurea as permitted in inclusion criteria 5. Participation in other clinical trials within at least 2 weeks of the first pimasertib dose 6. Clinical evidence of active central nervous system leukemia 7. Active and uncontrolled infection including but not limited to known infection with human immunodeficiency virus (HIV), active hepatitis B or hepatitis C. Subjects with an infection receiving treatment with antibiotics may be entered into the trial if they are afebrile and hemodynamically stable for 48 hours prior to trial entry 8. Major surgery within two weeks prior to trial entry 9. Liver function tests above the following limits at screening: total bilirubin \>1.5 x upper limit of normal (ULN) unless related to Gilbert's syndrome or hemolysis, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \>2.5 x ULN, or for subjects with liver involvement AST and/or ALT \>5 x ULN 10. Serum creatinine \>1.5 x ULN and /or creatinine clearance \<30 milliliter per minute (mL/min) at screening 11. International normalized ratio (INR) greater than 1.5 x ULN unless on treatment with warfarin 12. For female subjects: pregnant or breast-feeding 13. History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product 14. Has significant cardiac conduction abnormalities and/or pacemaker 15. Has retinal degenerative disease (heredity retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion and/or any medically relevant abnormal findings at the initial ophthalmologic examination 16. Subjects with solid tumors, for whom the Investigator has clinical suspicion of active disease at the time of enrolment. Subjects with adequately treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are eligible for this study 17. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such 18. Other significant disease that in the Investigator's opinion would exclude the subject from the trial 19. Legal incapacity or limited legal capacity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs) | Baseline Up to Day 29 of Cycle 1 | 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. |
| Part 2: Percentage of Subjects With Best Overall Response | Day 29 of every 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3). | — |
| Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 | — |
| Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3) | — |
| Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 | 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. |
| Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3). | 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. |
| 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 | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 | — |
| 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 | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3). | — |
| Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 | 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. |
| Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | Baseline up to 3 years | 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. |
| Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 | 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. |
| Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 | 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. |
| Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3) | 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. |
| Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 | 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. |
| Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3) | 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. |
| Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 | 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. |
| Part 1: Percentage of Subjects With Best Overall Response | Day 29 of every alternate 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012 | 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. |
| Part 2: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | Up to 3 years | 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. |
| Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3) | 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. |
| Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 | — |
Countries
France, United States
Participant flow
Recruitment details
First/last subject (informed consent): September 2009/12 April 2012. Last subject completed : December 2012; Clinical data cut-off: December 2012.
Pre-assignment details
Enrolled: 116 screened for eligibility; 35 were excluded (mainly non-fulfillment of inclusion or exclusion). 81 subjects were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Regimen 1 (Part 1) 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. | 33 |
| Regimen 2 (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. | 32 |
| Regimen 3 (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. | 15 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Enrolled but not treated | 0 | 1 | 0 |
| Overall Study | Ongoing at data cut-off | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Regimen 1 (Part 1) | Regimen 2 (Part 1) | Regimen 3 (Part 1) | Total |
|---|---|---|---|---|
| Age, Customized 18 to less than (<) 60 | 14 Subjects | 12 Subjects | 6 Subjects | 32 Subjects |
| Age, Customized 60 to <75 | 13 Subjects | 16 Subjects | 6 Subjects | 35 Subjects |
| Age, Customized Greater than or equal to (>=) 75 | 6 Subjects | 4 Subjects | 3 Subjects | 13 Subjects |
| Sex: Female, Male Female | 9 Participants | 13 Participants | 7 Participants | 29 Participants |
| Sex: Female, Male Male | 24 Participants | 19 Participants | 8 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 32 / 33 | 30 / 32 | 15 / 15 |
| serious Total, serious adverse events | 24 / 33 | 28 / 32 | 12 / 15 |
Outcome results
Primary
Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs)
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.
Time frame: Baseline Up to Day 29 of Cycle 1
Population: The DLT analysis set included all subjects who received over 90 percent (%) administration of trial medication in Cycle 1 or showed a DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen 1 (Part 1) | Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs) | 1 subjects |
| Regimen 2 (Part 1) | Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs) | 0 subjects |
| Regimen 3 (Part 1) | Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs) | 5 subjects |
Primary
Part 2: Percentage of Subjects With Best Overall Response
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.
Time frame: Day 29 of every 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012
Population: 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.
Secondary
Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose
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.
Time frame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose | Regimen 1 (n=0) | NA liter/hour | — |
| Regimen 1 (Part 1) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose | Regimen 2 (n=3) | 93 liter/hour | Standard Deviation 103.367 |
| Regimen 1 (Part 1) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose | Regimen 3 (n=1) | 45 liter/hour | — |
Secondary
Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose
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.
Time frame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose | 60.90 liter/hour | Geometric Coefficient of Variation 45.51 |
| Regimen 2 (Part 1) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose | 46.74 liter/hour | Geometric Coefficient of Variation 78.85 |
| Regimen 3 (Part 1) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose | 66.52 liter/hour | Geometric Coefficient of Variation 33.4 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose | 37.95 liter/hour | Geometric Coefficient of Variation 47.59 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose | 55.80 liter/hour | Geometric Coefficient of Variation 35.9 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose | 69.23 liter/hour | Geometric Coefficient of Variation 33.4 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose | 65.11 liter/hour | Geometric Coefficient of Variation 65.69 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose | 34.44 liter/hour | Geometric Coefficient of Variation 119.51 |
| Pimasertib 90 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose | 41.96 liter/hour | — |
Secondary
Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose
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.
Time frame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose | 99.43 liter/hour | Geometric Coefficient of Variation 52.86 |
| Regimen 2 (Part 1) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose | 103.29 liter/hour | Geometric Coefficient of Variation 42.07 |
| Regimen 3 (Part 1) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose | 72.88 liter/hour | Geometric Coefficient of Variation 76.28 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose | 53.37 liter/hour | Geometric Coefficient of Variation 33.26 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose | 57.15 liter/hour | Geometric Coefficient of Variation 49.72 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose | 52.42 liter/hour | Geometric Coefficient of Variation 49.59 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose | 58.40 liter/hour | Geometric Coefficient of Variation 49.21 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose | 48.03 liter/hour | Geometric Coefficient of Variation 68.78 |
Secondary
Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose
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: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose | Regimen 1 (n = 0) | NA liter | — |
| Regimen 1 (Part 1) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose | Regimen 2 (n = 3) | 442.2 liter | Standard Deviation 214.6 |
| Regimen 1 (Part 1) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose | Regimen 3 (n = 1) | 196.0 liter | — |
Secondary
Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose
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: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose | 601.7 liter | Geometric Coefficient of Variation 79.2 |
| Regimen 2 (Part 1) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose | 863.7 liter | Geometric Coefficient of Variation 193.5 |
| Regimen 3 (Part 1) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose | 332.8 liter | Geometric Coefficient of Variation 14.5 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose | 207.8 liter | Geometric Coefficient of Variation 46.8 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose | 293.1 liter | Geometric Coefficient of Variation 27.6 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose | 395.1 liter | Geometric Coefficient of Variation 52.9 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose | 422.0 liter | Geometric Coefficient of Variation 79.2 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose | 689.9 liter | Geometric Coefficient of Variation 16 |
| Pimasertib 90 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose | 305.2 liter | — |
Secondary
Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose
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.
Time frame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose | 757.5 liter | Geometric Coefficient of Variation 48.3 |
| Regimen 2 (Part 1) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose | 524.8 liter | Geometric Coefficient of Variation 51.5 |
| Regimen 3 (Part 1) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose | 320.8 liter | Geometric Coefficient of Variation 60.1 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose | 308.8 liter | Geometric Coefficient of Variation 27.1 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose | 320.2 liter | Geometric Coefficient of Variation 40.4 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose | 260.8 liter | Geometric Coefficient of Variation 46.9 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose | 250.3 liter | Geometric Coefficient of Variation 48.5 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose | 235.2 liter | Geometric Coefficient of Variation 24.2 |
Secondary
Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose
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: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose | 6.97 hour | Geometric Coefficient of Variation 75.47 |
| Regimen 2 (Part 1) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose | 10.91 hour | Geometric Coefficient of Variation 590.54 |
| Regimen 3 (Part 1) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose | 3.69 hour | Geometric Coefficient of Variation 22.69 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose | 3.93 hour | Geometric Coefficient of Variation 32.17 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose | 3.71 hour | Geometric Coefficient of Variation 21.38 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose | 3.96 hour | Geometric Coefficient of Variation 17.24 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose | 4.52 hour | Geometric Coefficient of Variation 66.99 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose | 8.44 hour | Geometric Coefficient of Variation 175.1 |
| Pimasertib 90 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose | 5.04 hour | — |
Secondary
Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose
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: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose | 5.28 hour | Geometric Coefficient of Variation 41.55 |
| Regimen 2 (Part 1) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose | 3.52 hour | Geometric Coefficient of Variation 19.75 |
| Regimen 3 (Part 1) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose | 3.05 hour | Geometric Coefficient of Variation 13.96 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose | 4.01 hour | Geometric Coefficient of Variation 36.61 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose | 3.88 hour | Geometric Coefficient of Variation 42.26 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose | 3.45 hour | Geometric Coefficient of Variation 23.8 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose | 2.97 hour | Geometric Coefficient of Variation 21.92 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose | 4.21 hour | Geometric Coefficient of Variation 92.04 |
| Pimasertib 90 mg (All Regimens [Part 1]) | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose | 3.39 hour | Geometric Coefficient of Variation 49.59 |
Secondary
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
Time frame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | 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 | 131.4 hour*nanogram/milliliter | Geometric Coefficient of Variation 45.5 |
| Regimen 2 (Part 1) | 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 | 307.2 hour*nanogram/milliliter | Geometric Coefficient of Variation 75.4 |
| Regimen 3 (Part 1) | 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 | 321.9 hour*nanogram/milliliter | Geometric Coefficient of Variation 29.9 |
| Pimasertib 30 mg (All Regimens [Part 1]) | 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 | 679.4 hour*nanogram/milliliter | Geometric Coefficient of Variation 53.7 |
| Pimasertib 42 mg (All Regimens [Part 1]) | 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 | 761.2 hour*nanogram/milliliter | Geometric Coefficient of Variation 35.5 |
| Pimasertib 45 mg (All Regimens [Part 1]) | 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 | 628.0 hour*nanogram/milliliter | Geometric Coefficient of Variation 28.2 |
| Pimasertib 60 mg (All Regimens [Part 1]) | 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 | 991.6 hour*nanogram/milliliter | Geometric Coefficient of Variation 66.1 |
| Pimasertib 75 mg (All Regimens [Part 1]) | 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 | 2195.2 hour*nanogram/milliliter | Geometric Coefficient of Variation 97.3 |
| Pimasertib 90 mg (All Regimens [Part 1]) | 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 | 2144.7 hour*nanogram/milliliter | — |
Secondary
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
Time frame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | 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 | 54.0 hour*nanogram/milliliter | Geometric Coefficient of Variation 57.2 |
| Regimen 2 (Part 1) | 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 | 125.4 hour*nanogram/milliliter | Geometric Coefficient of Variation 42.4 |
| Regimen 3 (Part 1) | 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 | 230.9 hour*nanogram/milliliter | Geometric Coefficient of Variation 60.9 |
| Pimasertib 30 mg (All Regimens [Part 1]) | 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 | 456.2 hour*nanogram/milliliter | Geometric Coefficient of Variation 25.5 |
| Pimasertib 42 mg (All Regimens [Part 1]) | 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 | 581.8 hour*nanogram/milliliter | Geometric Coefficient of Variation 45.4 |
| Pimasertib 45 mg (All Regimens [Part 1]) | 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 | 735.2 hour*nanogram/milliliter | Geometric Coefficient of Variation 47.2 |
| Pimasertib 60 mg (All Regimens [Part 1]) | 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 | 863.8 hour*nanogram/milliliter | Geometric Coefficient of Variation 52.8 |
| Pimasertib 75 mg (All Regimens [Part 1]) | 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 | 905.0 hour*nanogram/milliliter | Geometric Coefficient of Variation 92.8 |
| Pimasertib 90 mg (All Regimens [Part 1]) | 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 | 1268.2 hour*nanogram/milliliter | Geometric Coefficient of Variation 31.9 |
Secondary
Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose
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.
Time frame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose | 226.2 hour*nanogram/milliliter | Geometric Coefficient of Variation 91 |
| Regimen 2 (Part 1) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose | 789.3 hour*nanogram/milliliter | Geometric Coefficient of Variation 1038 |
| Regimen 3 (Part 1) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose | 451.2 hour*nanogram/milliliter | Geometric Coefficient of Variation 39.4 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose | 1030.2 hour*nanogram/milliliter | Geometric Coefficient of Variation 51.6 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose | 938.0 hour*nanogram/milliliter | Geometric Coefficient of Variation 46.6 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose | 786.7 hour*nanogram/milliliter | Geometric Coefficient of Variation 21.2 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose | 1270.8 hour*nanogram/milliliter | Geometric Coefficient of Variation 104.3 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose | 2712.6 hour*nanogram/milliliter | Geometric Coefficient of Variation 456.7 |
| Pimasertib 90 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose | 2830.7 hour*nanogram/milliliter | — |
Secondary
Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose
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.
Time frame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose | 80.5 hour*nanogram/milliliter | Geometric Coefficient of Variation 52.9 |
| Regimen 2 (Part 1) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose | 145.2 hour*nanogram/milliliter | Geometric Coefficient of Variation 42.1 |
| Regimen 3 (Part 1) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose | 315.6 hour*nanogram/milliliter | Geometric Coefficient of Variation 76.3 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose | 562.1 hour*nanogram/milliliter | Geometric Coefficient of Variation 33.3 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose | 734.9 hour*nanogram/milliliter | Geometric Coefficient of Variation 49.7 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose | 858.4 hour*nanogram/milliliter | Geometric Coefficient of Variation 49.6 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose | 1027.4 hour*nanogram/milliliter | Geometric Coefficient of Variation 49.2 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose | 1530.7 hour*nanogram/milliliter | Geometric Coefficient of Variation 135.3 |
| Pimasertib 90 mg (All Regimens [Part 1]) | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose | 1873.9 hour*nanogram/milliliter | Geometric Coefficient of Variation 68.8 |
Secondary
Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose
Time frame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose | 23.6 nanogram/milliliter | Geometric Coefficient of Variation 40.1 |
| Regimen 2 (Part 1) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose | 59.3 nanogram/milliliter | Geometric Coefficient of Variation 53.1 |
| Regimen 3 (Part 1) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose | 69.6 nanogram/milliliter | Geometric Coefficient of Variation 39.2 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose | 150.1 nanogram/milliliter | Geometric Coefficient of Variation 63.7 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose | 187.8 nanogram/milliliter | Geometric Coefficient of Variation 25.3 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose | 123.2 nanogram/milliliter | Geometric Coefficient of Variation 63.4 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose | 231.4 nanogram/milliliter | Geometric Coefficient of Variation 48.2 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose | 383.2 nanogram/milliliter | Geometric Coefficient of Variation 57.6 |
| Pimasertib 90 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose | 486.3 nanogram/milliliter | — |
Secondary
Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose
Time frame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose | 14.8 nanogram/milliliter | Geometric Coefficient of Variation 43 |
| Regimen 2 (Part 1) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose | 29.3 nanogram/milliliter | Geometric Coefficient of Variation 32 |
| Regimen 3 (Part 1) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose | 59.1 nanogram/milliliter | Geometric Coefficient of Variation 86.2 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose | 132.8 nanogram/milliliter | Geometric Coefficient of Variation 29.6 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose | 151.6 nanogram/milliliter | Geometric Coefficient of Variation 38.8 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose | 207.0 nanogram/milliliter | Geometric Coefficient of Variation 27.8 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose | 269.9 nanogram/milliliter | Geometric Coefficient of Variation 46.1 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose | 241.9 nanogram/milliliter | Geometric Coefficient of Variation 81 |
| Pimasertib 90 mg (All Regimens [Part 1]) | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose | 342.6 nanogram/milliliter | Geometric Coefficient of Variation 18.5 |
Secondary
Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation
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.
Time frame: Baseline up to 3 years
Population: The safety analysis set included all the subjects who received at least one administration of the trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs | 33 Subjects |
| Regimen 1 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | Serious TEAEs | 24 Subjects |
| Regimen 1 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs Leading to Death | 6 Subjects |
| Regimen 1 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs Leading to Treatment Discontinuation | 7 Subjects |
| Regimen 2 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs Leading to Treatment Discontinuation | 7 Subjects |
| Regimen 2 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs | 32 Subjects |
| Regimen 2 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs Leading to Death | 6 Subjects |
| Regimen 2 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | Serious TEAEs | 28 Subjects |
| Regimen 3 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs Leading to Treatment Discontinuation | 7 Subjects |
| Regimen 3 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | Serious TEAEs | 12 Subjects |
| Regimen 3 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs Leading to Death | 5 Subjects |
| Regimen 3 (Part 1) | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs | 15 Subjects |
Secondary
Part 1: Percentage of Subjects With Best Overall Response
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.
Time frame: Day 29 of every alternate 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | SD | 60.0 Percentage of Subjects |
| Regimen 1 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | PR | 0.0 Percentage of Subjects |
| Regimen 1 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | CR | 0.0 Percentage of Subjects |
| Regimen 1 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | CRi | 0.0 Percentage of Subjects |
| Regimen 1 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | PD | 40.0 Percentage of Subjects |
| Regimen 2 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | PR | 0.0 Percentage of Subjects |
| Regimen 2 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | CR | 0.0 Percentage of Subjects |
| Regimen 2 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | CRi | 0.0 Percentage of Subjects |
| Regimen 2 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | SD | 77.3 Percentage of Subjects |
| Regimen 2 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | PD | 22.7 Percentage of Subjects |
| Regimen 3 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | PD | 28.6 Percentage of Subjects |
| Regimen 3 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | SD | 71.4 Percentage of Subjects |
| Regimen 3 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | CR | 0.0 Percentage of Subjects |
| Regimen 3 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | PR | 0.0 Percentage of Subjects |
| Regimen 3 (Part 1) | Part 1: Percentage of Subjects With Best Overall Response | CRi | 0.0 Percentage of Subjects |
Secondary
Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose
Time frame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose | 1.44 hour | Geometric Coefficient of Variation 78.61 |
| Regimen 2 (Part 1) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose | 1.75 hour | Geometric Coefficient of Variation 83.12 |
| Regimen 3 (Part 1) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose | 2.03 hour | Geometric Coefficient of Variation 59.04 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose | 1.99 hour | Geometric Coefficient of Variation 70.4 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose | 1.64 hour | Geometric Coefficient of Variation 73.93 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose | 1.41 hour | Geometric Coefficient of Variation 52.11 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose | 1.78 hour | Geometric Coefficient of Variation 112.59 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose | 2.75 hour | Geometric Coefficient of Variation 21.83 |
| Pimasertib 90 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose | 2.00 hour | — |
Secondary
Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose
Time frame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen 1 (Part 1) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose | 0.94 hour | Geometric Coefficient of Variation 41.18 |
| Regimen 2 (Part 1) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose | 2.25 hour | Geometric Coefficient of Variation 53.2 |
| Regimen 3 (Part 1) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose | 1.56 hour | Geometric Coefficient of Variation 151.73 |
| Pimasertib 30 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose | 1.09 hour | Geometric Coefficient of Variation 38.74 |
| Pimasertib 42 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose | 1.11 hour | Geometric Coefficient of Variation 78.05 |
| Pimasertib 45 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose | 1.12 hour | Geometric Coefficient of Variation 19.62 |
| Pimasertib 60 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose | 1.03 hour | Geometric Coefficient of Variation 40.27 |
| Pimasertib 75 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose | 2.70 hour | Geometric Coefficient of Variation 96.84 |
| Pimasertib 90 mg (All Regimens [Part 1]) | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose | 1.17 hour | Geometric Coefficient of Variation 76.62 |
Secondary
Part 2: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation
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.
Time frame: Up to 3 years
Population: This outcome measure was not analyzed as the trial was terminated during safety run-in (Part 1).