Back to resultsTrial of Gemcitabine With or Without MSC1936369B in Pancreatic Cancer
Primary Purpose
Pancreatic Adenocarcinoma
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Pimasertib
Gemcitabine
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Pancreatic Adenocarcinoma focused on measuring MEK inhibitor, cancer, pancreatic Adenocarcinoma, metastatic, chemo-naive, phase II
Eligibility Criteria
Inclusion Criteria:
- Subject has provided signed informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments.
- Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas and availability of tumor sample.
- 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.
- Age ≥ 18 years.
- 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."
- 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:
- 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.
- Renal impairment as evidenced by serum creatinine > 1.5 x upper limit of normal (ULN), and/or calculated creatinine clearance < 60 mL/min.
- 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.
- Serum calcium > 1 x ULN.
- 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.
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) greater than 1.
- Significant cardiac conduction abnormalities, including QT interval corrected for heart rate (QTc) prolongation of > 480 milliseconds (ms) and/or pacemaker.
- Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion.
Sites / Locations
- For Recruiting Locations in the United States, please Contact U.S. Medical Information
- For Recruiting Locations outside the United States, Please contact the Merck KGaA Communication Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Active Comparator
Experimental
Arm Label
Safety Run-in Part: Regimen 1
Safety Run-in Part: Regimen 2
Phase II: Arm 1 (Gemcitabine + Placebo)
Phase II: Arm 2 (Gemcitabine + Pimasertib)
Arm Description
Subjects will receive 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).
Subjects will receive 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) (bid - continuous regimen).
Subjects will receive 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 will receive gemcitabine 1000 mg/m^2 IV infusion 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 bid - continuous regimen.
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1
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
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.
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.
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.
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.
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.
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.
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.
Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
Phase II: Overall Survival (OS) Time
Overall survival (OS) time is defined as the time (in months) from randomization to death.
Phase II: Absorption Rate Constant (ka) of Pimasertib (MSC1936369B)
Phase II: Clearance From Central Compartment (CL/f) and Intercompartmental Clearance (Q/f) of Pimasertib (MSC1936369B)
Phase II: Volume of Central Compartment (V1/f) and Volume of Peripheral Compartment (V2/f) of Pimasertib (MSC1936369B)
Full Information
NCT ID
NCT01016483
First Posted
November 18, 2009
Last Updated
July 12, 2017
Sponsor
EMD Serono
Collaborators
Merck KGaA, Darmstadt, Germany
1. Study Identification
Unique Protocol Identification Number
NCT01016483
Brief Title
Trial of Gemcitabine With or Without MSC1936369B in Pancreatic Cancer
Official Title
Phase II Randomized Trial of MEK Inhibitor MSC1936369B or Placebo Combined With Gemcitabine in Metastatic Pancreas Cancer Subjects
Study Type
Interventional
2. Study Status
Record Verification Date
July 2017
Overall Recruitment Status
Completed
Study Start Date
November 30, 2009 (Actual)
Primary Completion Date
December 31, 2013 (Actual)
Study Completion Date
April 30, 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
EMD Serono
Collaborators
Merck KGaA, Darmstadt, Germany
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pancreatic Adenocarcinoma
Keywords
MEK inhibitor, cancer, pancreatic Adenocarcinoma, metastatic, chemo-naive, phase II
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
141 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Safety Run-in Part: Regimen 1
Arm Type
Experimental
Arm Description
Subjects will receive 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).
Arm Title
Safety Run-in Part: Regimen 2
Arm Type
Experimental
Arm Description
Subjects will receive 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) (bid - continuous regimen).
Arm Title
Phase II: Arm 1 (Gemcitabine + Placebo)
Arm Type
Active Comparator
Arm Description
Subjects will receive 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.
Arm Title
Phase II: Arm 2 (Gemcitabine + Pimasertib)
Arm Type
Experimental
Arm Description
Subjects will receive gemcitabine 1000 mg/m^2 IV infusion 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 bid - continuous regimen.
Intervention Type
Drug
Intervention Name(s)
Pimasertib
Other Intervention Name(s)
MSC1936369B (MEK Inhibitor)
Intervention Type
Drug
Intervention Name(s)
Gemcitabine
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs)
Description
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
Title
Phase II: Progression-Free Survival (PFS) Time
Description
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)
Secondary Outcome Measure Information:
Title
Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation
Description
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)
Title
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
Title
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
Title
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
Description
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
Title
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
Description
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
Title
Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1
Description
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
Title
Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1
Description
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
Title
Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1
Description
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
Title
Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1
Description
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
Title
Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1
Description
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
Title
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
Title
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
Description
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
Title
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
Title
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
Description
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
Title
Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 2
Description
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
Title
Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 2
Description
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
Title
Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 2
Description
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
Title
Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 2
Description
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
Title
Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 2
Description
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
Title
Phase II: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation
Description
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)
Title
Phase II: Percentage of Subjects With Best Overall Response (BOR)
Description
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)
Title
Phase II: Percentage of Subjects With Clinical Benefit
Description
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)
Title
Phase II: Time to Progression (TTP)
Description
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)
Title
Phase II: Overall Survival (OS) Time
Description
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)
Title
Phase II: Absorption Rate Constant (ka) of Pimasertib (MSC1936369B)
Time Frame
Baseline, every 8 weeks up to EOT (6 years)
Title
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)
Title
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Subject has provided signed informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments.
Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas and availability of tumor sample.
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.
Age ≥ 18 years.
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."
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:
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.
Renal impairment as evidenced by serum creatinine > 1.5 x upper limit of normal (ULN), and/or calculated creatinine clearance < 60 mL/min.
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.
Serum calcium > 1 x ULN.
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.
Eastern Cooperative Oncology Group Performance Status (ECOG PS) greater than 1.
Significant cardiac conduction abnormalities, including QT interval corrected for heart rate (QTc) prolongation of > 480 milliseconds (ms) and/or pacemaker.
Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Responsible
Organizational Affiliation
Merck KGaA, Darmstadt, Germany
Official's Role
Study Director
Facility Information:
Facility Name
For Recruiting Locations in the United States, please Contact U.S. Medical Information
City
Rockland
State/Province
Massachusetts
Country
United States
Facility Name
For Recruiting Locations outside the United States, Please contact the Merck KGaA Communication Center
City
Darmstadt
Country
Germany
12. IPD Sharing Statement
Citations:
PubMed Identifier
29756206
Citation
Van Cutsem E, Hidalgo M, Canon JL, Macarulla T, Bazin I, Poddubskaya E, Manojlovic N, Radenkovic D, Verslype C, Raymond E, Cubillo A, Schueler A, Zhao C, Hammel P. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int J Cancer. 2018 Oct 15;143(8):2053-2064. doi: 10.1002/ijc.31603. Epub 2018 Aug 9.
Results Reference
derived
Learn more about this trial
Trial of Gemcitabine With or Without MSC1936369B in Pancreatic Cancer
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