Metastatic Colorectal Cancer
Conditions
Keywords
Mek Inhibitor, Metastatic Colorectal Cancer, K-Ras Mutation, Phase II, Second line K-Ras mutated metastatic colorectal cancer
Brief summary
The research trial is testing the experimental treatment pimasertib (MSC1936369B) in combination with FOLFIRI, as second-line treatment in metastatic K Ras mutated colorectal cancer subjects. The study will be run in two parts: Part 1, or Safety Run-in Part: Will determine the maximum tolerated dose and the recommended Phase 2 dose (RP2D) of pimasertib combined with FOLFIRI as second-line treatment in subjects with metastatic K Ras mutated colorectal cancer. Part 2 or Phase 2 Randomised Part: Will assess the anti-tumor activity of pimasertib combined with FOLFIRI compared to FOLFIRI with placebo as second-line treatment in metastatic K Ras mutated colorectal cancer subjects. Phase I which Is an open label dose escalation 3+3 cohort, non-randomized, safety Phase II which is a double blind randomized safety/efficacy
Interventions
DRUGPimasertib
Subjects will be administered with pimasertib orally once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle.
DRUGPlacebo
Subjects will be administered with placebo orally once daily on days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle.
DRUGFOLFIRI
Subjects will be administered with FOLFIRI (laevoleucovorin 200 milligram per square meter \[mg/m\^2\] intravenous \[i.v\] infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 milliliter \[mL\] dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Sponsors
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For Safety Run-in and Part 2 or Phase 2 Randomised Part * Histologically confirmed K-Ras mutated colon/rectum cancer * Subject's disease must have progressed during or after a first-line treatment for metastatic disease with oxaliplatin and fluoropyrimidines based chemotherapy with or without bevacizumab * Evidence of metastatic measurable disease at trial entry as per Response Evaluation Criteria in Solid Tumors. Complete tumor assessment performed within 14 days prior to first trial drug administration * Male/female subjects aged greater than or equal to (\>=) 18 years * Subject has read and understood the informed consent form * Women of childbearing potential must have a negative blood pregnancy test at the screening visit. Subjects and their partners must be willing to avoid pregnancy during the trial
Exclusion criteria
For Safety Run-in and Part 2 or Phase 2 Randomised Part * Bone marrow impairment * Renal impairment * Liver function and liver cell integrity abnormality * History of central nervous system (CNS) metastases * History of difficulty of swallowing, malabsorption or other chronic gastrointestinal disease * Eastern Cooperative Oncology Group Performance Status (ECOG PS) greater than (\>)1 * Known human immunodeficiency virus (HIV) positivity, active hepatitis C, or active hepatitis B * Has received extensive prior radiotherapy on more than 30 percent (%) of bone marrow reserves, or prior bone marrow/stem cell transplantation * Has received chemotherapy, any investigational drug, or having participated in another clinical trial within the past 4 weeks prior to trial first drug administration * Has a history of any other significant medical disease * Past or current history (within the last 2 years prior to inclusion) of malignancies except for the indication under this study * Has significant cardiac conduction abnormalities and/or pacemaker * Is a pregnant or nursing female * Has retinal degenerative disease, history of uveitis, or history of retinal vein occlusion * Other significant disease that in the Investigator's opinion would exclude the subject from the trial * Known hypersensitivity to the trial treatment(s) or diluents (when applicable), including placebo or other comparator drug(s) * Legal incapacity or limited legal capacity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 or Safety Run-in Part: Maximum Tolerated Dose (MTD) | Baseline up to Day 28 (Part 1) | MTD was defined as the dose level, at which the treatment-related dose limiting toxicity (DLT) occurred in \>1 of 3 subjects or in \>1 of 6 subjects. DLT was defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Any Grade \>=3 non-hematological toxicity except for Grade 4 asymptomatic increases in liver function tests (LFTs) reversible within 7 days in subjects with liver involvement, Grade 3 asymptomatic increases in LFTs reversible within 7 days in subjects without liver involvement, Grade 3 vomiting controlled with adequate and optimal therapy and prophylaxis, and Grade 3 diarrhea controlled with adequate and optimal anti-diarrhea therapy; any Grade 4 neutropenia lasing \>5 days/ febrile neutropenia lasting \>1 day; any Grade 4 thrombocytopenia/Grade 3 with bleeding; any treatment delay \>2 weeks due to trial treatment-related adverse effects at any dose level and judged to be possibly or probably related to the trial treatment. |
| Part 2 or Phase 2 Randomised Part: Progression Free Survival (PFS) | From randomization up to first documented disease progression maximum up to 2 years | PFS was defined as time (in months) from the date of randomization to the first documentation of disease progression as reported and documented by the Investigator (i.e. radiological progression per RECIST v1.0) or death for any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | — |
| Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | — |
| Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | Area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) at which the concentration is at or above the lower limit of quantification. |
| Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | The AUC(0-inf) of pimasertib and irinotecan was estimated by determining the total area under the concentration time curve extrapolated to infinity. |
| Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | The t1/2 was defined as the time required for the plasma concentration of pimasertib and irinotecan to decrease 50% in the final stage of elimination. |
| Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. |
| Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | Clearance of a drug was a measure of the rate at which drug was metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. |
| Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan | The AUC(0-inf) was estimated by determining the total area under the concentration time curve extrapolated to infinity. |
| Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | Up to 2 years | BOR was defined based on Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST V1.0) as following: Complete response (CR) was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. Partial response (PR) was defined as at least a 30 percent (%) decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks (28 days). Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease (PD) being demonstrated during the first 4 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started. |
| Part 1 or Safety Run-in Part: Circulating Biomarkers in Serum | Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years | — |
| Part 2 or Phase 2 Randomized Part: Circulating Biomarkers | Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years | — |
| Part 2 or Phase 2 Randomized Part: Best Overall Response | Up to 2 years | BOR was defined based on Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST V1.0) as following: Complete response (CR) was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. Partial response (PR) was defined as at least a 30 percent (%) decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks (28 days). Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease (PD) being demonstrated during the first 4 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started. |
| Part 2 or Phase 2 Randomized Part: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | From the first dose of study drug administration up to 28 days after the last dose of study drug administration | An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAES between first dose of study drug administration and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
| Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 | — |
| Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | From the first dose of study drug administration up to 28 days after the last dose of study drug administration | An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
Countries
Belgium, Italy, Spain
Participant flow
Recruitment details
First/last subject (informed consent): March 2010/September 2011. Last subject completed:May 2012.
Pre-assignment details
Enrolled: 22 screened for eligibility; 6 were excluded (mainly non-fulfillment of inclusion or exclusion). 16 subjects were treated in a total of 4 centers (2 in Spain and 1 each in Belgium and Italy).
Participants by arm
| Arm | Count |
|---|---|
| Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle. | 10 |
| Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle. | 6 |
| Total | 16 |
Baseline characteristics
| Characteristic | Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI | Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI | Total |
|---|---|---|---|
| Age, Continuous | 62.3 Years STANDARD_DEVIATION 12 | 60.4 Years STANDARD_DEVIATION 17.2 | 61.6 Years STANDARD_DEVIATION 13.7 |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 6 / 6 |
| serious Total, serious adverse events | 4 / 10 | 4 / 6 |
Outcome results
Primary
Part 1 or Safety Run-in Part: Maximum Tolerated Dose (MTD)
MTD was defined as the dose level, at which the treatment-related dose limiting toxicity (DLT) occurred in \>1 of 3 subjects or in \>1 of 6 subjects. DLT was defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Any Grade \>=3 non-hematological toxicity except for Grade 4 asymptomatic increases in liver function tests (LFTs) reversible within 7 days in subjects with liver involvement, Grade 3 asymptomatic increases in LFTs reversible within 7 days in subjects without liver involvement, Grade 3 vomiting controlled with adequate and optimal therapy and prophylaxis, and Grade 3 diarrhea controlled with adequate and optimal anti-diarrhea therapy; any Grade 4 neutropenia lasing \>5 days/ febrile neutropenia lasting \>1 day; any Grade 4 thrombocytopenia/Grade 3 with bleeding; any treatment delay \>2 weeks due to trial treatment-related adverse effects at any dose level and judged to be possibly or probably related to the trial treatment.
Time frame: Baseline up to Day 28 (Part 1)
Population: The safety analysis set included all subjects who received at least one (non-zero) administration of the trial medication (any of the 3 FOLFIRI drugs and pimasertib).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Maximum Tolerated Dose (MTD) | 45 mg |
Primary
Part 2 or Phase 2 Randomised Part: Progression Free Survival (PFS)
PFS was defined as time (in months) from the date of randomization to the first documentation of disease progression as reported and documented by the Investigator (i.e. radiological progression per RECIST v1.0) or death for any cause.
Time frame: From randomization up to first documented disease progression maximum up to 2 years
Population: Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, PFS was not evaluated for this study.
Secondary
Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38
Clearance of a drug was a measure of the rate at which drug was metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.
Time frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. n signifies number of subjects evaluable per each category, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | Pimasertib: Day 8 (n=8, 5) | 34.2 Liter per hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 23.5 Liter per hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | Pimasertib: Day 1 (n=7, 5) | 38.7 Liter per hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | SN-38: Day 1 (n=9, 6) | 29.4 Liter per hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 23.5 Liter per hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | Irinotecan: Day 1 (n=9, 6) | 29.4 Liter per hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 26.2 Liter per hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | Pimasertib: Day 1 (n=7, 5) | 42.1 Liter per hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | Pimasertib: Day 8 (n=8, 5) | 44.6 Liter per hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | Irinotecan: Day 1 (n=9, 6) | 29.7 Liter per hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 26.2 Liter per hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 | SN-38: Day 1 (n=9, 6) | 29.7 Liter per hour |
Secondary
Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed.
Time frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. n signifies number of subjects evaluable per each category, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | Pimasertib: Day 8 (n=8, 5) | 265 Liter |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 212 Liter |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | Pimasertib: Day 1 (n=7, 5) | 276 Liter |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | Irinotecan: Day 1 (n=9, 6) | 297 Liter |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 212 Liter |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | SN-38: Day 1 (n=9, 6) | 297 Liter |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 253 Liter |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | Pimasertib: Day 1 (n=7, 5) | 348 Liter |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | Pimasertib: Day 8 (n=8, 5) | 395 Liter |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | Irinotecan: Day 1 (n=9, 6) | 313 Liter |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 253 Liter |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 | SN-38: Day 1 (n=9, 6) | 313 Liter |
Secondary
Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38
The t1/2 was defined as the time required for the plasma concentration of pimasertib and irinotecan to decrease 50% in the final stage of elimination.
Time frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. n signifies number of subjects evaluable per each category, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 1 (n=7, 5) | 5.31 hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 8 (n=8, 5) | 5.12 hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 1 (n=9, 6) | 6.43 hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 6.21 hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 1 (n=9, 6) | 6.43 hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 6.21 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 1 (n=9, 6) | 6.83 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 1 (n=7, 5) | 5.56 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 6.45 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 8 (n=8, 5) | 5.08 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 6.45 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 1 (n=9, 6) | 6.83 hour |
Secondary
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38
The AUC(0-inf) of pimasertib and irinotecan was estimated by determining the total area under the concentration time curve extrapolated to infinity.
Time frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. n signifies number of subjects evaluable per each category, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 1 (n=7, 5) | 1160 ng/mL*hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 8 (n=8, 5) | 1340 ng/mL*hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 1 (n=9, 6) | 10600 ng/mL*hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 13600 ng/mL*hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 1 (n=9, 6) | 10600 ng/mL*hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 13600 ng/mL*hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 1 (n=9, 6) | 11200 ng/mL*hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 1 (n=7, 5) | 1430 ng/mL*hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 12300 ng/mL*hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 8 (n=8, 5) | 1340 ng/mL*hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 12300 ng/mL*hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 1 (n=9, 6) | 11200 ng/mL*hour |
Secondary
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38
Area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) at which the concentration is at or above the lower limit of quantification.
Time frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
Population: The pharmacokinetic (PK) evaluation set included subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). n signifies number of subjects evaluable in each category, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 1 (n=9, 5) | 1120 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 8 (n=8, 5) | 1270 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 1 (n=10, 6) | 10500 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 12700 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 1 (n=10, 6) | 10500 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 12700 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 1 (n=10, 6) | 10200 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 1 (n=9, 5) | 1390 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 11400 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 8 (n=8, 5) | 1260 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 11400 (nanogram/milliliter)*hour([ng/mL]*hour) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 1 (n=10, 6) | 10200 (nanogram/milliliter)*hour([ng/mL]*hour) |
Secondary
Part 1 or Safety Run-in Part: Circulating Biomarkers in Serum
Time frame: Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years
Population: Number of subjects enrolled in the safety run-in part of the trial was less and it would not provide sufficient statistical power to perform any analysis. Hence, the biomarker samples were not analyzed as part of the trial.
Secondary
Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38
Time frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
Population: The pharmacokinetic (PK) evaluation set included subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). n signifies number of subjects evaluable in each category, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 1 (n=9, 6) | 145 nanogram per milliliter (ng/mL) |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 8 (n=9, 6) | 196 nanogram per milliliter (ng/mL) |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 1 (n=10, 6) | 2070 nanogram per milliliter (ng/mL) |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 2120 nanogram per milliliter (ng/mL) |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 1 (n=10, 6) | 20.4 nanogram per milliliter (ng/mL) |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 15.1 nanogram per milliliter (ng/mL) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 1 (n=10, 6) | 21.9 nanogram per milliliter (ng/mL) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 1 (n=9, 6) | 386 nanogram per milliliter (ng/mL) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 1540 nanogram per milliliter (ng/mL) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 8 (n=9, 6) | 332 nanogram per milliliter (ng/mL) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 27 nanogram per milliliter (ng/mL) |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 1 (n=10, 6) | 1850 nanogram per milliliter (ng/mL) |
Secondary
Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR)
BOR was defined based on Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST V1.0) as following: Complete response (CR) was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. Partial response (PR) was defined as at least a 30 percent (%) decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks (28 days). Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease (PD) being demonstrated during the first 4 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started.
Time frame: Up to 2 years
Population: The efficacy analysis set included all subjects who received at least 1 trial drug dose (any of the three FOLFIRI drugs and pimasertib) and had a baseline tumor assessment and at least 1 post-baseline efficacy assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | SD | 6 Subjects |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | PD | 1 Subjects |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | PR | 1 Subjects |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | Not evaluable | 1 Subjects |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | CR | 0 Subjects |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | Not evaluable | 0 Subjects |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | CR | 0 Subjects |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | PR | 1 Subjects |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | PD | 2 Subjects |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) | SD | 3 Subjects |
Secondary
Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death
An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: From the first dose of study drug administration up to 28 days after the last dose of study drug administration
Population: The safety analysis set included all subjects who received at least one (non-zero) administration of the trial medication (any of the 3 FOLFIRI drugs and pimasertib).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAE | 10 Subjects |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | Serious TEAE | 4 Subjects |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs leading to discontinuation | 6 Subjects |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs leading to death | 0 Subjects |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs leading to death | 0 Subjects |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAE | 6 Subjects |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs leading to discontinuation | 4 Subjects |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | Serious TEAE | 4 Subjects |
Secondary
Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15)
The AUC(0-inf) was estimated by determining the total area under the concentration time curve extrapolated to infinity.
Time frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan
Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. n signifies number of subjects evaluable per each category, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | Pimasertib (n=7, 4) | 0.917 Ratio |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | Irinotecan (n=8, 6) | 0.911 Ratio |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | SN-38 (n=8, 6) | 0.911 Ratio |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | Pimasertib (n=7, 4) | 0.825 Ratio |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | Irinotecan (n=8, 6) | 0.844 Ratio |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | SN-38 (n=8, 6) | 0.844 Ratio |
Secondary
Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15)
Time frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. n signifies number of subjects evaluable per each category, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | Pimasertib (n=8, 5) | 0.837 Ratio of Cmax |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | Irinotecan (n=8, 6) | 0.973 Ratio of Cmax |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | SN-38 (n=8, 6) | 0.973 Ratio of Cmax |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | Pimasertib (n=8, 5) | 0.751 Ratio of Cmax |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | Irinotecan (n=8, 6) | 1.09 Ratio of Cmax |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) | SN-38 (n=8, 6) | 1.09 Ratio of Cmax |
Secondary
Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38
Time frame: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38
Population: The pharmacokinetic (PK) evaluation set included subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). n signifies number of subjects evaluable in each category, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 1 (n=9, 6) | 2 hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 8 (n=9, 6) | 1.5 hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 1 (n=10, 6) | 1.5 hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 1.54 hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 1 (n=10, 6) | 1.5 hour |
| Pimasertib+FOLFIRI (Overall) | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 1.6 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 1 (n=10, 6) | 1.5 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 1 (n=9, 6) | 0.79 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 15 (n=8, 6) | 1.56 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | Pimasertib: Day 8 (n=9, 6) | 1.25 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | SN-38: Day 15 (n=8, 6) | 2.5 hour |
| Part 2 or Phase 2 Randomized Part: Placebo +FOLFIRI | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | Irinotecan: Day 1 (n=10, 6) | 1.5 hour |
Secondary
Part 2 or Phase 2 Randomized Part: Best Overall Response
BOR was defined based on Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST V1.0) as following: Complete response (CR) was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. Partial response (PR) was defined as at least a 30 percent (%) decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks (28 days). Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease (PD) being demonstrated during the first 4 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started.
Time frame: Up to 2 years
Population: Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, Best overall response was not evaluated.
Secondary
Part 2 or Phase 2 Randomized Part: Circulating Biomarkers
Time frame: Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years
Population: Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, circulating biomarkers were not evaluated.
Secondary
Part 2 or Phase 2 Randomized Part: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death
An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAES between first dose of study drug administration and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: From the first dose of study drug administration up to 28 days after the last dose of study drug administration
Population: Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, safety outcome measure could not be performed.