Pancreatic Adenocarcinoma
Conditions
Keywords
MEK inhibitor, cancer, pancreatic Adenocarcinoma, metastatic, chemo-naive, phase II
Brief summary
The research trial is testing the experimental treatment MSC1936369B in combination with Gemcitabine, in subjects with metastatic pancreatic adenocarcinoma. The study will be run in two parts: Safety Run-In: Will determine the Maximum Tolerated Dose (MTD) and the recommended Phase II dose of MSC1936369B, when combined with gemcitabine, in subjects with metastatic pancreatic adenocarcinoma. Phase II: Will assess the anti-tumor activity of MSC1936369B combined with gemcitabine compared to gemcitabine alone as first line treatment in subjects with metastatic pancreatic adenocarcinoma.
Interventions
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject has provided signed informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments. 2. Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas and availability of tumor sample. 3. Evidence of disease (not necessarily measurable disease). Complete tumor assessment including chest X ray, CT scan of abdomen and other scans as necessary to document all sites of disease performed within 28 days prior to trial entry/randomization. 4. Age ≥ 18 years. 5. Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For the purposes of this trial, women of childbearing potential is defined as: All female subjects after puberty unless they are post-menopausal for at least two years, are surgically sterile or are sexually inactive. 6. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to screening, during and four weeks after the last dose of trial medication. Adequate contraception is defined as two barrier methods, or one barrier method with a spermicide, or intrauterine device. The use of hormonal contraceptives should be avoided in female subjects of childbearing potential due to a possible drug-drug interaction.
Exclusion criteria
1. Bone marrow impairment as evidenced by hemoglobin less (\<) 9.0 gram per deciliter (g/dL), neutrophil count \< 1.5 x 10\^9/ liter (L), platelets \< 100 x 10\^9/L. 2. Renal impairment as evidenced by serum creatinine \> 1.5 x upper limit of normal (ULN), and/or calculated creatinine clearance \< 60 mL/min. 3. Liver function abnormality as defined by total bilirubin \> 1.5 x ULN, or aspartate aminotransferase/ alanine aminotransferase (AST/ALT) \> 2.5 x ULN, for subjects with liver involvement AST/ALT \> 5 x ULN. 4. Serum calcium \> 1 x ULN. 5. History of central nervous system (CNS) metastases, unless subject has been previously treated for CNS metastases, is stable by CT scan without evidence of cerebral edema, and has no requirements for corticosteroids or anticonvulsants. 6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) greater than 1. 7. Significant cardiac conduction abnormalities, including QT interval corrected for heart rate (QTc) prolongation of \> 480 milliseconds (ms) and/or pacemaker. 8. Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) | Up to 28 days in Cycle 1 | DLT using the National Cancer Institute Common Terminology Criteria for Adverse Events(CTCAE) v3.0,was defined as any of the following toxicities at any dose level and judged to be possibly or probably related to trial medication by the Investigator and/or the Sponsor and relevant for the combination treatment: Grade 3/more non-hematological toxicity excluding: Subjects with liver involvement: Grade 4 asymptomatic increases in liver function tests and subject without liver involvement: Grade 3 asymptomatic increases in liver function tests reversible within 7 days. Grade 3 vomiting encountered despite adequate therapy. Grade 3 diarrhea encountered despite adequate anti diarrhea therapy. Grade 4 neutropenia greater (\>) 5 days duration or febrile neutropenia lasting for more than 1 day. Grade 4 thrombocytopenia \> 1 day/Grade 3 with bleeding. Grade 4 anemia: Any treatment delay \> 2 weeks due to drug-related adverse effects. |
| Phase II: Progression-Free Survival (PFS) Time | From the time of randomization to every 8 weeks up to end of treatment (EOT) (6 years) | PFS was defined as the time from randomization to the first documentation of objective tumor progression (Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline, Progressive Disease (PD): At least 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started, or the appearance of 1 or more new lesions and stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started) or to death due to any cause, whichever occurred first. PFS calculated as (Months) = Date of first PD or death or censoring date minus date of randomization plus 1) divided by 30.4375. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | — |
| Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | Plasma decay half-life was the time measured for the plasma concentration to decrease by one half. |
| Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1 of Cycle 1 for MSC1936369B, 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 for Gemcitabine | AUC:0 to infinity was a measure of the serum concentration of the drug over time. It was used to characterize drug absorption. |
| Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) was influenced by the fraction of the dose absorbed. |
| Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
| Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. |
| Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | Apparent volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. |
| Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | pre-dose on Day 1, 2, 22 of Cycle 1; post-dose on Day 1, 22 of Cycle 1 | ERK phosphoprotein in peripheral blood monocytes (PBMCs) was analyzed from blood samples of all subjects in the SAF analysis set (safety-run part) only. |
| Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | — |
| Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1 of Cycle 1 for MSC1936369B, 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 for Gemcitabine | AUC:0 to infinity is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. |
| Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | — |
| Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | From the first dose of study drug administration until EOT (6 years) | An adverse event (AE) was any untoward medical occurrence in a subjects who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All AEs (serious and non-serious) except AEs recorded with an onset date prior to the first day of drug administration unless a worsening of the event was recorded after the first dosing date, in which case the event was counted as a TEAE. TEAEs include both SAEs and non-SAEs. |
| Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 2 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
| Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 2 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. |
| Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 2 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. |
| Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | pre-dose on Day 1, 2, 22 of Cycle 1; post-dose on Day 1, 22 of Cycle 1 | ERK phosphoprotein in peripheral blood monocytes (PBMCs) was analyzed from blood samples of all subjects in the SAF analysis set (safety-run part) only. |
| Phase II: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | From the first dose of study drug administration until EOT (6 years) | An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All AEs (serious and non-serious) except AEs recorded with an onset date prior to the first day of drug administration unless a worsening of the event was recorded after the first dosing date, in which case the event was counted as a TEAE. TEAEs include both SAEs and non-SAEs. |
| Phase II: Percentage of Subjects With Best Overall Response (BOR) | Baseline, every 8 weeks up to end of treatment (EOT i.e. 6 years) | Best overall response was defined as the presence of at least one complete response (CR), partial response (PR) or Stable Disease (SD) (using RECIST v1.0) during treatment. CR: Disappearance of all target lesions, PR: At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline and SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started. |
| Phase II: Percentage of Subjects With Clinical Benefit | Baseline, every 8 weeks up to end of treatment (EOT i.e. 6 years) | Clinical Benefit was defined as the presence of at least one CR, PR or Stable Disease (SD) (using RECIST v1.0) during treatment. CR: Disappearance of all target lesions, PR: At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline and SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started. |
| Phase II: Time to Progression (TTP) | From randomization every 8 weeks up to EOT (6 years) | Time to progression (TTP) is defined as the time (in months) from the randomization date to the date of progression prior to the start of any subsequent therapy for the primary disease, as reported and documented by the Investigator (i.e. radiological progression per RECIST). |
| Phase II: Overall Survival (OS) Time | Baseline, every 8 weeks up to EOT (6 years) | Overall survival (OS) time is defined as the time (in months) from randomization to death. |
| Phase II: Absorption Rate Constant (ka) of Pimasertib (MSC1936369B) | Baseline, every 8 weeks up to EOT (6 years) | — |
| Phase II: Clearance From Central Compartment (CL/f) and Intercompartmental Clearance (Q/f) of Pimasertib (MSC1936369B) | Baseline, every 8 weeks up to EOT (6 years) | — |
| Phase II: Volume of Central Compartment (V1/f) and Volume of Peripheral Compartment (V2/f) of Pimasertib (MSC1936369B) | Baseline, every 8 weeks up to EOT (6 years) | — |
| Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 2 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. |
| Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 | — |
Countries
Germany, United States
Participant flow
Recruitment details
First/last subject (informed consent): Nov 2009/Jul 2013. Clinical data cut off: Dec 2013, Study completion date: April 2015
Participants by arm
| Arm | Count |
|---|---|
| Safety Run-in Part: Regimen 1 Subjects received pimasertib capsule orally once daily (qd) doses of 15, 30, 45, 68, 90, and 120 milligram (mg) on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks). | 27 |
| Safety Run-in Part: Regimen 2 Subjects received pimasertib capsule orally twice daily (bid) doses of 60 and 75 mg continuously for a 28-day cycle and gemcitabine 1000 mg/m\^2 intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks). | 26 |
| Phase II: Arm 1 (Gemcitabine + Placebo) Subjects received gemcitabine 1000 mg/m\^2 IV infusion on for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and placebo matched to pimasertib orally bid - continuous regimen. Subjects with disease progression in Arm 1 were allowed crossover to receive pimasertib capsule orally 60 mg bid - continuous regimen. | 44 |
| Phase II: Arm 2 (Gemcitabine + Pimasertib) Subjects received gemcitabine 1000 mg/m\^2 IV infusion on for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and pimasertib capsule orally 60 mg bid - continuous regimen. | 44 |
| Total | 141 |
Baseline characteristics
| Characteristic | Safety Run-in Part: Regimen 1 | Safety Run-in Part: Regimen 2 | Phase II: Arm 1 (Gemcitabine + Placebo) | Phase II: Arm 2 (Gemcitabine + Pimasertib) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 7 Participants | 19 Participants | 16 Participants | 53 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 19 Participants | 25 Participants | 28 Participants | 88 Participants |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 22 Participants | 17 Participants | 56 Participants |
| Sex: Female, Male Male | 18 Participants | 18 Participants | 22 Participants | 27 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 27 | 26 / 26 | 39 / 42 | 44 / 45 |
| serious Total, serious adverse events | 18 / 27 | 20 / 26 | 28 / 42 | 35 / 45 |
Outcome results
Primary
Phase II: Progression-Free Survival (PFS) Time
PFS was defined as the time from randomization to the first documentation of objective tumor progression (Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline, Progressive Disease (PD): At least 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started, or the appearance of 1 or more new lesions and stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started) or to death due to any cause, whichever occurred first. PFS calculated as (Months) = Date of first PD or death or censoring date minus date of randomization plus 1) divided by 30.4375.
Time frame: From the time of randomization to every 8 weeks up to end of treatment (EOT) (6 years)
Population: Intent to Treat (ITT) analysis set included all subjects who had been randomized for the phase II part, as per the interactive voice response system (IVRS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Progression-Free Survival (PFS) Time | 2.83 months |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Progression-Free Survival (PFS) Time | 3.75 months |
Primary
Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs)
DLT using the National Cancer Institute Common Terminology Criteria for Adverse Events(CTCAE) v3.0,was defined as any of the following toxicities at any dose level and judged to be possibly or probably related to trial medication by the Investigator and/or the Sponsor and relevant for the combination treatment: Grade 3/more non-hematological toxicity excluding: Subjects with liver involvement: Grade 4 asymptomatic increases in liver function tests and subject without liver involvement: Grade 3 asymptomatic increases in liver function tests reversible within 7 days. Grade 3 vomiting encountered despite adequate therapy. Grade 3 diarrhea encountered despite adequate anti diarrhea therapy. Grade 4 neutropenia greater (\>) 5 days duration or febrile neutropenia lasting for more than 1 day. Grade 4 thrombocytopenia \> 1 day/Grade 3 with bleeding. Grade 4 anemia: Any treatment delay \> 2 weeks due to drug-related adverse effects.
Time frame: Up to 28 days in Cycle 1
Population: DLT analysis set included all subjects of safety run-in part who received any dose of pimasertib on at least 18 out of 20/25 out of 28 of the planned days on pimasertib \& least 3 gemcitabine weekly infusions during first 28 days of treatment or experienced DLT during the 28 first days of treatment regardless of the amount of each drug received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) | 0 subjects |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) | 0 subjects |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) | 0 subjects |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) | 0 subjects |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) | 0 subjects |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) | 0 subjects |
| Safety Run-in Part Regimen 2: 60 mg | Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) | 1 subjects |
| Safety Run-in Part Regimen 2: 75 mg | Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) | 2 subjects |
Secondary
Phase II: Absorption Rate Constant (ka) of Pimasertib (MSC1936369B)
Time frame: Baseline, every 8 weeks up to EOT (6 years)
Population: As per change in planned analysis, there was reduction of PK investigations for the phase II part of the trial, removal of PK sampling for gemcitabine and its metabolites and replacement of intense sampling with a sparse sampling scheme for pimasertib, thus the outcome measure was not analyzed.
Secondary
Phase II: Clearance From Central Compartment (CL/f) and Intercompartmental Clearance (Q/f) of Pimasertib (MSC1936369B)
Time frame: Baseline, every 8 weeks up to EOT (6 years)
Population: As per change in planned analysis, there was reduction of PK investigations for the phase II part of the trial, removal of PK sampling for gemcitabine and its metabolites and replacement of intense sampling with a sparse sampling scheme for pimasertib, thus the outcome measure was not analyzed.
Secondary
Phase II: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation
An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All AEs (serious and non-serious) except AEs recorded with an onset date prior to the first day of drug administration unless a worsening of the event was recorded after the first dosing date, in which case the event was counted as a TEAE. TEAEs include both SAEs and non-SAEs.
Time frame: From the first dose of study drug administration until EOT (6 years)
Population: SAF for the Phase II included all subjects who had received at least 1 administration of the trial medication Gemcitabine or Placebo if the subject is in the gemcitabine + Placebo treatment arm (Arm 1) and MSC1936369B or gemcitabine in the MSC1936369B + gemcitabine treatment arm (Arm 2).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs | 40 subjects |
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | Serious TEAEs | 28 subjects |
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs Leading to Treatment Discontinuation | 10 subjects |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs | 45 subjects |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | Serious TEAEs | 35 subjects |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs Leading to Treatment Discontinuation | 21 subjects |
Secondary
Phase II: Overall Survival (OS) Time
Overall survival (OS) time is defined as the time (in months) from randomization to death.
Time frame: Baseline, every 8 weeks up to EOT (6 years)
Population: ITT analysis set included all subjects who had been randomized for the phase II part, as per the interactive voice response system (IVRS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Overall Survival (OS) Time | 6.64 months |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Overall Survival (OS) Time | 9.33 months |
Secondary
Phase II: Percentage of Subjects With Best Overall Response (BOR)
Best overall response was defined as the presence of at least one complete response (CR), partial response (PR) or Stable Disease (SD) (using RECIST v1.0) during treatment. CR: Disappearance of all target lesions, PR: At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline and SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started.
Time frame: Baseline, every 8 weeks up to end of treatment (EOT i.e. 6 years)
Population: ITT analysis set included all subjects who had been randomized for the phase II part, as per the interactive voice response system (IVRS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Percentage of Subjects With Best Overall Response (BOR) | PR | 9.1 percentage of subjects |
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Percentage of Subjects With Best Overall Response (BOR) | PD | 29.5 percentage of subjects |
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Percentage of Subjects With Best Overall Response (BOR) | SD | 36.4 percentage of subjects |
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Percentage of Subjects With Best Overall Response (BOR) | Missing | 25 percentage of subjects |
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Percentage of Subjects With Best Overall Response (BOR) | CR | 0 percentage of subjects |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Percentage of Subjects With Best Overall Response (BOR) | Missing | 20.5 percentage of subjects |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Percentage of Subjects With Best Overall Response (BOR) | CR | 0 percentage of subjects |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Percentage of Subjects With Best Overall Response (BOR) | PR | 9.1 percentage of subjects |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Percentage of Subjects With Best Overall Response (BOR) | SD | 50.0 percentage of subjects |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Percentage of Subjects With Best Overall Response (BOR) | PD | 20.5 percentage of subjects |
Secondary
Phase II: Percentage of Subjects With Clinical Benefit
Clinical Benefit was defined as the presence of at least one CR, PR or Stable Disease (SD) (using RECIST v1.0) during treatment. CR: Disappearance of all target lesions, PR: At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline and SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started.
Time frame: Baseline, every 8 weeks up to end of treatment (EOT i.e. 6 years)
Population: ITT analysis set included all subjects who had been randomized for the phase II part, as per the interactive voice response system (IVRS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Percentage of Subjects With Clinical Benefit | 45.5 percentage of subjects |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Percentage of Subjects With Clinical Benefit | 59.1 percentage of subjects |
Secondary
Phase II: Time to Progression (TTP)
Time to progression (TTP) is defined as the time (in months) from the randomization date to the date of progression prior to the start of any subsequent therapy for the primary disease, as reported and documented by the Investigator (i.e. radiological progression per RECIST).
Time frame: From randomization every 8 weeks up to EOT (6 years)
Population: ITT analysis set included all subjects who had been randomized for the phase II part, as per the interactive voice response system (IVRS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Phase II: Time to Progression (TTP) | 3.78 months |
| Safety Run-in Part Regimen 1: 30 mg | Phase II: Time to Progression (TTP) | 5.09 months |
Secondary
Phase II: Volume of Central Compartment (V1/f) and Volume of Peripheral Compartment (V2/f) of Pimasertib (MSC1936369B)
Time frame: Baseline, every 8 weeks up to EOT (6 years)
Population: As per change in planned analysis, there was reduction of PK investigations for the phase II part of the trial, removal of PK sampling for gemcitabine and its metabolites and replacement of intense sampling with a sparse sampling scheme for pimasertib, thus the outcome measure was not analyzed.
Secondary
Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) was influenced by the fraction of the dose absorbed.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 22 (n=2,2,3,2,3,9) | 74.143 Liter per hour (L/h) | Geometric Coefficient of Variation 43.6 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 92.152 Liter per hour (L/h) | Geometric Coefficient of Variation 25.3 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 22 (n=2,2,3,2,3,9) | 42.484 Liter per hour (L/h) | Geometric Coefficient of Variation 31.2 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 58.104 Liter per hour (L/h) | Geometric Coefficient of Variation 32.9 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 51.072 Liter per hour (L/h) | Geometric Coefficient of Variation 37.1 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 22 (n=2,2,3,2,3,9) | 44.579 Liter per hour (L/h) | Geometric Coefficient of Variation 23.1 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 22 (n=2,2,3,2,3,9) | 56.502 Liter per hour (L/h) | Geometric Coefficient of Variation 7.5 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 87.765 Liter per hour (L/h) | Geometric Coefficient of Variation 58.9 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 52.025 Liter per hour (L/h) | Geometric Coefficient of Variation 32.3 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 22 (n=2,2,3,2,3,9) | 50.873 Liter per hour (L/h) | Geometric Coefficient of Variation 59.6 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 22 (n=2,2,3,2,3,9) | 55.723 Liter per hour (L/h) | Geometric Coefficient of Variation 57.8 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1 | CL/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 55.171 Liter per hour (L/h) | Geometric Coefficient of Variation 53 |
Secondary
Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 2
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 2 | CL/f: MSC1936369B on Day 1 (n=10,11) | 85.186 Liter per hour (L/H) | Geometric Coefficient of Variation 69.4 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 2 | CL/f: MSC1936369B on Day 22 (n=8,5) | 70.163 Liter per hour (L/H) | Geometric Coefficient of Variation 63.2 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 2 | CL/f: MSC1936369B on Day 1 (n=10,11) | 52.558 Liter per hour (L/H) | Geometric Coefficient of Variation 30 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 2 | CL/f: MSC1936369B on Day 22 (n=8,5) | 68.312 Liter per hour (L/H) | Geometric Coefficient of Variation 24.9 |
Secondary
Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1
Apparent volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 1 (n= 4,3,3,3,3,11) | 359.55 liter | Geometric Coefficient of Variation 635.6 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 1723.6 liter | Geometric Coefficient of Variation 55.9 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 1 (n= 4,3,3,3,3,11) | 531.23 liter | Geometric Coefficient of Variation 64.7 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 908.50 liter | Geometric Coefficient of Variation 56.5 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 1 (n= 4,3,3,3,3,11) | 587.64 liter | Geometric Coefficient of Variation 206.3 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 251.79 liter | — |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 1 (n= 4,3,3,3,3,11) | 729.65 liter | Geometric Coefficient of Variation 46.3 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 149.65 liter | Geometric Coefficient of Variation 1453.7 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 1 (n= 4,3,3,3,3,11) | 2402.1 liter | Geometric Coefficient of Variation 59.5 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 2140.8 liter | Geometric Coefficient of Variation 15.5 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 1 (n= 4,3,3,3,3,11) | 1270.1 liter | Geometric Coefficient of Variation 82 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1 | V: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 805.15 liter | Geometric Coefficient of Variation 138 |
Secondary
Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 2
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 2 | V: Gemcitabine on Day 1 (n=11,14) | 716.12 liter | Geometric Coefficient of Variation 343.3 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 2 | V: Gemcitabine on Day 22 (n=9,4) | 1590.8 liter | Geometric Coefficient of Variation 120.5 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 2 | V: Gemcitabine on Day 1 (n=11,14) | 1059.0 liter | Geometric Coefficient of Variation 196.6 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 2 | V: Gemcitabine on Day 22 (n=9,4) | 801.90 liter | Geometric Coefficient of Variation 130.3 |
Secondary
Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1
AUC:0 to infinity was a measure of the serum concentration of the drug over time. It was used to characterize drug absorption.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1 of Cycle 1 for MSC1936369B, 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 for Gemcitabine
Population: PKS of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: MSC1936369B on Day 1 (n=4,3,3,3,3,11) | 162.8 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 25.3 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 245795.5 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 10.8 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 22(n=2,2,1,2,2,9) | 10828.0 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 93.8 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 1(n=4,3,3,3,3,11) | 29536.1 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 473.4 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 22 (n=2,2,2,2,2,10) | 190952.6 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 9.3 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 228032.9 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 27.6 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 1(n=4,3,3,3,3,11) | 13536.5 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 40.4 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: MSC1936369B on Day 1 (n=4,3,3,3,3,11) | 516.3 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 32.9 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 22(n=2,2,1,2,2,9) | 12019.6 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 29.5 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 22 (n=2,2,2,2,2,10) | 376280.5 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 13 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 1(n=4,3,3,3,3,11) | 10053.3 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 24.6 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: MSC1936369B on Day 1 (n=4,3,3,3,3,11) | 881.1 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 37.1 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 22 (n=2,2,2,2,2,10) | 217930.8 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 70.4 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 276968.3 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 28.9 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 22(n=2,2,1,2,2,9) | 9093.2 hour*nanogram per milliliter (h*ng/mL) | — |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 1(n=4,3,3,3,3,11) | 18956.0 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 37.2 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 22 (n=2,2,2,2,2,10) | 327424.8 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 2 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: MSC1936369B on Day 1 (n=4,3,3,3,3,11) | 774.8 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 58.9 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 259816.2 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 9.2 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 22(n=2,2,1,2,2,9) | 76448.7 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 466.6 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 22 (n=2,2,2,2,2,10) | 248496.4 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 5.2 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: MSC1936369B on Day 1 (n=4,3,3,3,3,11) | 1729.9 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 32.3 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 1(n=4,3,3,3,3,11) | 8178.4 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 28.7 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 22(n=2,2,1,2,2,9) | 9604.8 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 11.9 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 239902.9 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 27.1 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 240293.8 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 15 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 22(n=2,2,1,2,2,9) | 10598.0 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 66.7 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Gemcitabine (dFdC) on Day 1(n=4,3,3,3,3,11) | 11680.1 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 59 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: MSC1936369B on Day 1 (n=4,3,3,3,3,11) | 2175.1 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 53 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | AUC: Metabolite (dFdU) on Day 22 (n=2,2,2,2,2,10) | 247430.7 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 29.2 |
Secondary
Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2
AUC:0 to infinity is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1 of Cycle 1 for MSC1936369B, 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1 for Gemcitabine
Population: PKS of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | AUC: Gemcitabine (dFdC) on Day 1 (n= 11, 14) | 11932.0 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 343 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | AUC: Metabolite (dFdU) on Day 1 (n= 11, 13) | 189007.0 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 40.6 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | AUC: Gemcitabine (dFdC) on Day 22 (n= 9, 4) | 10719.1 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 84.9 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | AUC: Metabolite (dFdU) on Day 22 (n= 10, 5) | 177504.5 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 171.5 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | AUC: MSC1936369B on Day 1 (n= 10, 11) | 704.3 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 69.4 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | AUC: Metabolite (dFdU) on Day 22 (n= 10, 5) | 256714.9 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 37.3 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | AUC: MSC1936369B on Day 1 (n= 10, 11) | 1427.0 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 30 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | AUC: Gemcitabine (dFdC) on Day 1 (n= 11, 14) | 8065.5 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 176.2 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | AUC: Gemcitabine (dFdC) on Day 22 (n= 9, 4) | 10102.3 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 72 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2 | AUC: Metabolite (dFdU) on Day 1 (n= 11, 13) | 234934.8 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 29.9 |
Secondary
Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1
ERK phosphoprotein in peripheral blood monocytes (PBMCs) was analyzed from blood samples of all subjects in the SAF analysis set (safety-run part) only.
Time frame: pre-dose on Day 1, 2, 22 of Cycle 1; post-dose on Day 1, 22 of Cycle 1
Population: Pharmacodynamic population included SAF analysis set for the safety run-in part include all subjects who received at least 1 (non-zero) administration of the trial medication (pimasertib or gemcitabine). Here n signifies those subjects who were evaluable at the specified time point for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Pre-dose (n=2,1,2,1,3,5) | 5.242 Fluorescence Intensity | Standard Deviation 0.21 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Post-dose (n=3,2,2,3,2,6) | 1.611 Fluorescence Intensity | Standard Deviation 0.537 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Pre-dose (n=3,2,2,3,3,7) | 5.389 Fluorescence Intensity | Standard Deviation 0.797 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Post-dose (n=0,0,0,0,2) | NA Fluorescence Intensity | — |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 2 Pre-dose (n=3,2,1,2,2,6) | 4.818 Fluorescence Intensity | Standard Deviation 0.808 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Post-dose (n=3,2,2,3,2,6) | 2.061 Fluorescence Intensity | Standard Deviation 0.825 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Pre-dose (n=2,1,2,1,3,5) | 6.000 Fluorescence Intensity | — |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Pre-dose (n=3,2,2,3,3,7) | 6.476 Fluorescence Intensity | Standard Deviation 0.997 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Post-dose (n=0,0,0,0,2) | NA Fluorescence Intensity | — |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 2 Pre-dose (n=3,2,1,2,2,6) | 6.719 Fluorescence Intensity | Standard Deviation 2.835 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Post-dose (n=3,2,2,3,2,6) | 0.837 Fluorescence Intensity | Standard Deviation 0.149 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Pre-dose (n=2,1,2,1,3,5) | 1.978 Fluorescence Intensity | Standard Deviation 2.539 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Post-dose (n=0,0,0,0,2) | NA Fluorescence Intensity | — |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 2 Pre-dose (n=3,2,1,2,2,6) | 3.902 Fluorescence Intensity | — |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Pre-dose (n=3,2,2,3,3,7) | 4.767 Fluorescence Intensity | Standard Deviation 0.114 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 2 Pre-dose (n=3,2,1,2,2,6) | 2.768 Fluorescence Intensity | Standard Deviation 0.33 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Pre-dose (n=3,2,2,3,3,7) | 6.509 Fluorescence Intensity | Standard Deviation 2.24 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Post-dose (n=3,2,2,3,2,6) | 3.881 Fluorescence Intensity | Standard Deviation 5.387 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Pre-dose (n=2,1,2,1,3,5) | 8.653 Fluorescence Intensity | — |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Post-dose (n=0,0,0,0,2) | NA Fluorescence Intensity | — |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Pre-dose (n=2,1,2,1,3,5) | 4.252 Fluorescence Intensity | Standard Deviation 1.259 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Pre-dose (n=3,2,2,3,3,7) | 4.608 Fluorescence Intensity | Standard Deviation 0.197 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Post-dose (n=0,0,0,0,2) | NA Fluorescence Intensity | — |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Post-dose (n=3,2,2,3,2,6) | 1.059 Fluorescence Intensity | Standard Deviation 0.042 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 2 Pre-dose (n=3,2,1,2,2,6) | 4.874 Fluorescence Intensity | Standard Deviation 2.119 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Pre-dose (n=3,2,2,3,3,7) | 4.229 Fluorescence Intensity | Standard Deviation 1.719 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Pre-dose (n=2,1,2,1,3,5) | 3.453 Fluorescence Intensity | Standard Deviation 0.86 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 1 Post-dose (n=3,2,2,3,2,6) | 0.946 Fluorescence Intensity | Standard Deviation 0.248 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 22 Post-dose (n=0,0,0,0,2) | 4.130 Fluorescence Intensity | Standard Deviation 1.772 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1 | Cycle 1 Day 2 Pre-dose (n=3,2,1,2,2,6) | 3.636 Fluorescence Intensity | Standard Deviation 1.755 |
Secondary
Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2
ERK phosphoprotein in peripheral blood monocytes (PBMCs) was analyzed from blood samples of all subjects in the SAF analysis set (safety-run part) only.
Time frame: pre-dose on Day 1, 2, 22 of Cycle 1; post-dose on Day 1, 22 of Cycle 1
Population: Pharmacodynamic population included SAF analysis set for the safety run-in part include all subjects who received at least 1 (non-zero) administration of the trial medication (pimasertib or gemcitabine). Here n signifies those subjects who were evaluable at the specified time point for each arm respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | Cycle 1 Day 1 Post-dose (n=5,3) | 1.520 Fluorescence Intensity | Standard Deviation 0.109 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | Cycle 1 Day 22 Pre-dose (n=6,2) | 2.728 Fluorescence Intensity | Standard Deviation 0.818 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | Cycle 1 Day 2 Pre-dose (n=7,3) | 3.877 Fluorescence Intensity | Standard Deviation 2.099 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | Cycle 1 Day 22 Post-dose (n=3,1) | 1.443 Fluorescence Intensity | Standard Deviation 0.458 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | Cycle 1 Day 1 Pre-dose (n=7,4) | 6.081 Fluorescence Intensity | Standard Deviation 0.827 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | Cycle 1 Day 22 Post-dose (n=3,1) | 1.111 Fluorescence Intensity | — |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | Cycle 1 Day 1 Pre-dose (n=7,4) | 5.874 Fluorescence Intensity | Standard Deviation 2.239 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | Cycle 1 Day 1 Post-dose (n=5,3) | 1.048 Fluorescence Intensity | Standard Deviation 0.155 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | Cycle 1 Day 2 Pre-dose (n=7,3) | 2.263 Fluorescence Intensity | Standard Deviation 0.593 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2 | Cycle 1 Day 22 Pre-dose (n=6,2) | 2.295 Fluorescence Intensity | Standard Deviation 0.51 |
Secondary
Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: Pharmacokinetic set (PKS) of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 1 (n=4,3,3,3,3,11) | 32.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 107.5 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 22 (n= 3,3,3,2,3,10) | 29.6 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 39.8 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 69540.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 1729.4 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 22 (n= 2,3,3,2,3,9) | 24115.8 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 71.9 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 1 (n= 4,3,3,3,3,11) | 29359.8 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 8.5 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 22 (n= 2,3,3,2,3,10) | 29677.6 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 3 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 22 (n= 3,3,3,2,3,10) | 174.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 29.6 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 22 (n= 2,3,3,2,3,9) | 11799.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 167.7 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 22 (n= 2,3,3,2,3,10) | 38265.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 54.3 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 1 (n=4,3,3,3,3,11) | 131.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 32.9 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 21207.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 21 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 1 (n= 4,3,3,3,3,11) | 33171.6 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 21.2 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 22 (n= 2,3,3,2,3,10) | 10569.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 449.2 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 1 (n= 4,3,3,3,3,11) | 34868.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 12.8 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 22 (n= 2,3,3,2,3,9) | 181.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 39158542.7 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 17759.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 34.1 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 1 (n=4,3,3,3,3,11) | 205.8 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 30 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 22 (n= 3,3,3,2,3,10) | 261.8 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 52 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 22 (n= 2,3,3,2,3,9) | 163196.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 3183.3 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 22 (n= 3,3,3,2,3,10) | 212.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 16.9 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 29762.1 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 76.7 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 22 (n= 2,3,3,2,3,10) | 32869.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 8.7 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 1 (n= 4,3,3,3,3,11) | 33804.4 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 16.7 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 1 (n=4,3,3,3,3,11) | 151.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 40.1 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 1 (n=4,3,3,3,3,11) | 485.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 58.7 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 1 (n= 4,3,3,3,3,11) | 37786.4 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 13.6 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 22 (n= 3,3,3,2,3,10) | 409.1 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 44.1 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 15606.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 23.1 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 22 (n= 2,3,3,2,3,9) | 669.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 3278825923 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 22 (n= 2,3,3,2,3,10) | 17135.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 227.5 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 22 (n= 2,3,3,2,3,9) | 23207.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 99.5 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 23880.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 83.8 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 1 (n= 4,3,3,3,3,11) | 34038.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 29.7 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | Metabolite (dFdU) on Day 22 (n= 2,3,3,2,3,10) | 21077.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 179.5 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 22 (n= 3,3,3,2,3,10) | 252.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 477 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1 | MSC1936369B on Days 1 (n=4,3,3,3,3,11) | 484.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 39.8 |
Secondary
Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | MSC1936369B on Day 1 (n= 12,13) | 175.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 65 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | MSC1936369B on Day 22 (n=10,9) | 228.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 59 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Gemcitabine (dFdC) on Day 1 (n=11,14) | 27849.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 344 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Gemcitabine (dFdC) on Day 22 (n=9,4) | 21589.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 118.8 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Gemcitabine Metabolite (dFdU) on Day 1 (n=11, 10) | 33033.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 11.8 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Gemcitabine Metabolite (dFdU) on Day 22 (n=10,5) | 13455.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 546 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Gemcitabine Metabolite (dFdU) on Day 1 (n=11, 10) | 31623.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 25.4 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | MSC1936369B on Day 1 (n= 12,13) | 345.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 52.8 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Gemcitabine (dFdC) on Day 22 (n=9,4) | 18733.4 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 88.6 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | MSC1936369B on Day 22 (n=10,9) | 244.8 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 31.9 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Gemcitabine Metabolite (dFdU) on Day 22 (n=10,5) | 18298.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 247.7 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Gemcitabine (dFdC) on Day 1 (n=11,14) | 17663.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 173.3 |
Secondary
Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation
An adverse event (AE) was any untoward medical occurrence in a subjects who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All AEs (serious and non-serious) except AEs recorded with an onset date prior to the first day of drug administration unless a worsening of the event was recorded after the first dosing date, in which case the event was counted as a TEAE. TEAEs include both SAEs and non-SAEs.
Time frame: From the first dose of study drug administration until EOT (6 years)
Population: Safety analysis set (SAF) for the safety run-in part included all subjects who had received at least 1 administration of the trial medication (pimasertib or gemcitabine).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs | 27 subjects |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | Serious TEAEs | 18 subjects |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | Permanent treatment discontinuation of pimasertib | 12 subjects |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | Permanent treatment discontinuation of gemcitabine | 14 subjects |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | Permanent treatment discontinuation of gemcitabine | 15 subjects |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | TEAEs | 26 subjects |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | Permanent treatment discontinuation of pimasertib | 16 subjects |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation | Serious TEAEs | 20 subjects |
Secondary
Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 528.62 liter | Geometric Coefficient of Variation 63.1 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 824.33 liter | Geometric Coefficient of Variation 156.8 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 369.12 liter | Geometric Coefficient of Variation 5 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 366.30 liter | Geometric Coefficient of Variation 1.8 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 329.80 liter | Geometric Coefficient of Variation 28.4 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 264.31 liter | Geometric Coefficient of Variation 43.8 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 524.96 liter | Geometric Coefficient of Variation 26.2 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 441.40 liter | Geometric Coefficient of Variation 43.4 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 362.29 liter | Geometric Coefficient of Variation 34 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 284.42 liter | Geometric Coefficient of Variation 35.1 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 367.25 liter | Geometric Coefficient of Variation 50.5 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1 | V/f: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 414.38 liter | Geometric Coefficient of Variation 66.8 |
Secondary
Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 2
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e. gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 2 | V/f: MSC1936369B on Day 1 (n= 10,11) | 335.56 liter | Geometric Coefficient of Variation 66.3 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 2 | V/f: MSC1936369B on Day 22 (n=8,5) | 389.56 liter | Geometric Coefficient of Variation 47.1 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 2 | V/f: MSC1936369B on Day 1 (n= 10,11) | 213.24 liter | Geometric Coefficient of Variation 37.7 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 2 | V/f: MSC1936369B on Day 22 (n=8,5) | 319.02 liter | Geometric Coefficient of Variation 35.5 |
Secondary
Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1
Plasma decay half-life was the time measured for the plasma concentration to decrease by one half.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 4.008 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 8.660 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 4.274 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 7.449 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 8.956 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 22(n=2,2,2,2,2,10) | 7.731 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 6.100 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 4.553 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 22(n=2,2,2,2,2,10) | 8.925 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 3.807 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 2.461 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 10.49 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 22(n=2,2,2,2,2,10) | 8.843 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 9.836 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 0.9152 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 2.421 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 3.833 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 3.254 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 4.493 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 5.744 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 5.327 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 22(n=2,2,2,2,2,10) | 11.14 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 11.52 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 4.232 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 5.036 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 8.349 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 3.162 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 8.940 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 8.213 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 22(n=2,2,2,2,2,10) | 10.21 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9) | 4.680 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 6.242 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 10.93 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: Metabolite (dFdU) on Day 22(n=2,2,2,2,2,10) | 12.17 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 22 (n=2,2,3,2,3,8) | 4.825 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | t1/2: MSC1936369B on Day 1 (n=4,3,3,2,3,11) | 4.580 hours |
Secondary
Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: MSC1936369B on Day 1 (n=10,11) | 2.757 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: MSC1936369B on Day 22 (n=8,5) | 3.425 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: Gemcitabine (dFdC) on Day 1 (n=11,14) | 5.258 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: Gemcitabine (dFdC) on Day 22 (n=9,4) | 5.522 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: Metabolite (dFdU) on Day 1 (n=11,13) | 9.471 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: Metabolite (dFdU) on Day 22 (n=10,5) | 10.68 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: Metabolite (dFdU) on Day 1 (n=11,13) | 10.26 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: MSC1936369B on Day 1 (n=10,11) | 2.603 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: Gemcitabine (dFdC) on Day 22 (n=9,4) | 5.249 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: MSC1936369B on Day 22 (n=8,5) | 3.188 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: Metabolite (dFdU) on Day 22 (n=10,5) | 13.58 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | t1/2: Gemcitabine (dFdC) on Day 1 (n=11,14) | 5.376 hours |
Secondary
Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 1 (n= 4,3,3,3,3,11) | 1.250 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 22 (n= 3,3,3 2,3,10) | 2.017 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 0.38 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 22 (n=2,3,3,2,3,9) | 0.42 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 0.64 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 22 (n=2,3,3,2,3,10 | 0.54 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 22 (n= 3,3,3 2,3,10) | 1.000 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 22 (n=2,3,3,2,3,9) | 0.50 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 22 (n=2,3,3,2,3,10 | 0.75 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 1 (n= 4,3,3,3,3,11) | 1.000 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 0.50 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 0.50 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 22 (n=2,3,3,2,3,10 | 1.00 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 0.50 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 22 (n=2,3,3,2,3,9) | 0.53 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 0.25 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 1 (n= 4,3,3,3,3,11) | 1.533 hours |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 22 (n= 3,3,3 2,3,10) | 1.000 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 22 (n=2,3,3,2,3,9) | 1.04 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 22 (n= 3,3,3 2,3,10) | 1.750 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 0.25 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 22 (n=2,3,3,2,3,10 | 0.67 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 0.75 hours |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 1 (n= 4,3,3,3,3,11) | 2.000 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 1 (n= 4,3,3,3,3,11) | 1.083 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 0.50 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 22 (n= 3,3,3 2,3,10) | 1.500 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 0.25 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 22 (n=2,3,3,2,3,9) | 0.25 hours |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 22 (n=2,3,3,2,3,10 | 0.75 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 22 (n=2,3,3,2,3,9) | 0.50 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11) | 0.27 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11) | 0.50 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: Metabolite (dFdU) on Day 22 (n=2,3,3,2,3,10 | 0.75 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 22 (n= 3,3,3 2,3,10) | 2.000 hours |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1 | Tmax: MSC1936369B on Day 1 (n= 4,3,3,3,3,11) | 1.500 hours |
Secondary
Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1.Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: MSC1936369B on Day 1 (n=12,13) | 2.000 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: MSC1936369B on Day 22 (n=10,9) | 1.500 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: Gemcitabine (dFdC) on Day 1 (n=11,14) | 0.50 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: Gemcitabine (dFdC) on Day 22 (n=9,4) | 0.25 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: Metabolite (dFdU) on Day 1 (n=11,13) | 0.67 hours |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: Metabolite (dFdU) on Day 22 (n=10,5) | 0.50 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: Metabolite (dFdU) on Day 1 (n=11,13) | 0.67 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: MSC1936369B on Day 1 (n=12,13) | 1.583 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: Gemcitabine (dFdC) on Day 22 (n=9,4) | 0.25 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: MSC1936369B on Day 22 (n=10,9) | 2.000 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: Metabolite (dFdU) on Day 22 (n=10,5) | 0.50 hours |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2 | Tmax: Gemcitabine (dFdC) on Day 1 (n=11,14) | 0.38 hours |
Secondary
Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies those subjects who were evaluable at the specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 1 (n=4,3,3,3,3,11) | 60.537 liter/hour | Geometric Coefficient of Variation 483.4 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 22 (n=2,2,1,2,2,9) | 163.37 liter/hour | Geometric Coefficient of Variation 93.7 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 1 (n=4,3,3,3,3,11) | 133.88 liter/hour | Geometric Coefficient of Variation 45.1 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 22 (n=2,2,1,2,2,9) | 156.93 liter/hour | Geometric Coefficient of Variation 20.1 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 1 (n=4,3,3,3,3,11) | 190.52 liter/hour | Geometric Coefficient of Variation 26 |
| Safety Run-in Part Regimen 1: 45 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 22 (n=2,2,1,2,2,9) | 190.69 liter/hour | — |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 1 (n=4,3,3,3,3,11) | 95.96 liter/hour | Geometric Coefficient of Variation 47.7 |
| Safety Run-in Part Regimen 1: 68 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 22 (n=2,2,1,2,2,9) | 25.123 liter/hour | Geometric Coefficient of Variation 431.2 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 1 (n=4,3,3,3,3,11) | 210.25 liter/hour | Geometric Coefficient of Variation 27.9 |
| Safety Run-in Part Regimen 1: 90 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 22 (n=2,2,1,2,2,9) | 183.97 liter/hour | Geometric Coefficient of Variation 11.6 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 1 (n=4,3,3,3,3,11) | 151.93 liter/hour | Geometric Coefficient of Variation 54.7 |
| Safety Run-in Part Regimen 1: 120 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1 | CL: Gemcitabine on Day 22 (n=2,2,1,2,2,9) | 164.6 liter/hour | Geometric Coefficient of Variation 71.7 |
Secondary
Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 2
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time frame: 0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1
Population: PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here n signifies number of subjects evaluable for each category at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 2 | CL: Gemcitabine on Day 1 (n=11, 14) | 145.65 liter/hour | Geometric Coefficient of Variation 363.2 |
| Safety Run-in Part Regimen 1: 15 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 2 | CL: Gemcitabine on Day 22 (n=9, 4) | 164.68 liter/hour | Geometric Coefficient of Variation 81.4 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 2 | CL: Gemcitabine on Day 1 (n=11, 14) | 221.46 liter/hour | Geometric Coefficient of Variation 186 |
| Safety Run-in Part Regimen 1: 30 mg | Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 2 | CL: Gemcitabine on Day 22 (n=9, 4) | 183.85 liter/hour | Geometric Coefficient of Variation 73.5 |