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Conduct the randomized Phase 2 part not recommended due to the achieved MTD for pimasertib (45mg/day) in combination with FOLFIRI
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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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1 or Safety Run-in Part: Pimasertib+FOLFIRI | Experimental |
| |
| Part 2 or Phase 2 Randomized part: Pimasertib+FOLFIRI | Experimental | Planned, not performed |
|
| Part 2 or Phase 2 Randomized part: Placebo+FOLFIRI | Experimental | Planned, not performed |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pimasertib | Drug | 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline up to Day 28 (Part 1) |
| 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. | From randomization up to first documented disease progression maximum up to 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
For Safety Run-in and Part 2 or Phase 2 Randomised Part
Exclusion Criteria:
For Safety Run-in and Part 2 or Phase 2 Randomised Part
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck Serono S.A., Geneva | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Leuven | Belgium | ||||
| Research Site |
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).
First/last subject (informed consent): March 2010/September 2011. Last subject completed:May 2012.
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| ID | Title | Description |
|---|---|---|
| FG000 | Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI | Pimasertib was administered orally at a dose of 45 milligrams per day (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 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. |
| FG001 | 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 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; 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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).
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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). | Posted | Number | mg | Baseline up to Day 28 (Part 1) |
From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Asthenia | General disorders | MedDRA (14.1) | Non-systematic Assessment |
During the trial, the decision was made not to perform the Phase 2 part of the study due to the achieved MTD for pimasertib (45mg/day) in combination with FOLFIRI, so that no further dose escalation was possible as per the protocol.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Merck KGaA Communication Center | Merck Serono, a division of Merck KGaA | +49-6151-72-5200 | service@merckgroup.com |
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| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
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| ID | Term |
|---|---|
| C550600 | N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide |
| C480833 | IFL protocol |
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|
| Placebo | Drug | 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. |
|
| FOLFIRI | Drug | 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. |
|
| From the first dose of study drug administration up to 28 days after the last dose of study drug administration |
| 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 | 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. | 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 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. | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
| 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. | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
| 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. | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
| 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. | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
| 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: 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. | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan |
| 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. | Up to 2 years |
| 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 | 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. | Up to 2 years |
| 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. | From the first dose of study drug administration up to 28 days after the last dose of study drug administration |
| Naples |
| Italy |
| Research Site | Barcelona | Spain |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Pimasertib+FOLFIRI (Overall) | Pimasertib was administered orally once daily 45 mg/day and 60 mg/day 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. |
|
|
| 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. | Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, PFS was not evaluated for this study. | Posted | From randomization up to first documented disease progression maximum up to 2 years |
|
|
| 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. | 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). | Posted | Number | Subjects | From the first dose of study drug administration up to 28 days after the last dose of study drug administration |
|
|
|
| Secondary | Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 | 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. | Posted | Median | Full Range | nanogram per milliliter (ng/mL) | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
|
|
|
| Secondary | Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 | 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. | Posted | Median | Full Range | hour | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
|
|
|
| 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. | 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. | Posted | Median | Full Range | (nanogram/milliliter)*hour([ng/mL]*hour) | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
|
|
|
| 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. | 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. | Posted | Median | Full Range | ng/mL*hour | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
|
|
|
| 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. | 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. | Posted | Median | Full Range | hour | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
|
|
|
| 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. | 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. | Posted | Median | Full Range | Liter per hour | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
|
|
|
| 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. | 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. | Posted | Median | Full Range | Liter | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
|
|
|
| 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) | 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. | Posted | Median | Full Range | Ratio of Cmax | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38 |
|
|
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| 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. | 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. | Posted | Median | Full Range | Ratio | Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan |
|
|
|
| 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. | 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. | Posted | Number | Subjects | Up to 2 years |
|
|
|
| Secondary | Part 1 or Safety Run-in Part: Circulating Biomarkers in Serum | 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. | Posted | Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years |
|
|
| Secondary | Part 2 or Phase 2 Randomized Part: Circulating Biomarkers | Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, circulating biomarkers were not evaluated. | Posted | Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years |
|
|
| 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. | Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, Best overall response was not evaluated. | Posted | Up to 2 years |
|
|
| 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. | Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, safety outcome measure could not be performed. | Posted | From the first dose of study drug administration up to 28 days after the last dose of study drug administration |
|
|
| 4 |
| 10 |
| 10 |
| 10 |
| EG001 | 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. | 4 | 6 | 6 | 6 |
| Enteritis | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Intestinal obstruction | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Mucosal inflammation | General disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Asthenia | General disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| General physical health deterioration | General disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Cardiomyopathy | Cardiac disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Perirectal abscess | Infections and infestations | MedDRA (14.1) | Non-systematic Assessment |
|
| Electrocardiogram QT prolonged | Investigations | MedDRA (14.1) | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Memory impairment | Nervous system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Nephrolithiasis | Renal and urinary disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Deep vein thrombosis | Vascular disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Aphthous stomatitis | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Cheilitis | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Proctalgia | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Mucosal inflammation | General disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| fatigue | General disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Fluid retention | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Hyperuricaemia | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Iron deficiency | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Palmar-plantar erythrodysaesthesia syndrome | Skin and subcutaneous tissue disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Anaemia macrocytic | Blood and lymphatic system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Iron deficiency anaemia | Blood and lymphatic system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Neurotoxicity | Nervous system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Presyncope | Nervous system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Visual field defect | Nervous system disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Detachment of retinal pigment epithelium | Eye disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Macular degeneration | Eye disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Maculopathy | Eye disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Visual impairment | Eye disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA (14.1) | Non-systematic Assessment |
|
| Rash pustular | Infections and infestations | MedDRA (14.1) | Non-systematic Assessment |
|
| Respiratory tract infection viral | Infections and infestations | MedDRA (14.1) | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (14.1) | Non-systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (14.1) | Non-systematic Assessment |
|
| Vulvovaginal candidiasis | Infections and infestations | MedDRA (14.1) | Non-systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| cough | Respiratory, thoracic and mediastinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Dry throat | Respiratory, thoracic and mediastinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Hiccups | Respiratory, thoracic and mediastinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Nasal dryness | Respiratory, thoracic and mediastinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Upper airway obstruction | Respiratory, thoracic and mediastinal disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA (14.1) | Non-systematic Assessment |
|
| Electrocardiogram T wave inversion | Investigations | MedDRA (14.1) | Non-systematic Assessment |
|
| Dysuria | Renal and urinary disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Faecaluria | Renal and urinary disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Renal failure | Renal and urinary disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Renal pain | Renal and urinary disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Palpitations | Cardiac disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Tinnitus | Ear and labyrinth disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Hypertransaminasaemia | Hepatobiliary disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA (14.1) | Non-systematic Assessment |
|
| Procedural site reaction | Injury, poisoning and procedural complications | MedDRA (14.1) | Non-systematic Assessment |
|
| Depressed mood | Psychiatric disorders | MedDRA (14.1) | Non-systematic Assessment |
|
| Embolism | Vascular disorders | MedDRA (14.1) | Non-systematic Assessment |
|
Not provided
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| TEAEs leading to discontinuation |
|
| TEAEs leading to death |
|
| Irinotecan: Day 1 (n=10, 6) |
|
| Irinotecan: Day 15 (n=8, 6) |
|
| SN-38: Day 1 (n=10, 6) |
|
| SN-38: Day 15 (n=8, 6) |
|
| Irinotecan: Day 1 (n=10, 6) |
|
| Irinotecan: Day 15 (n=8, 6) |
|
| SN-38: Day 1 (n=10, 6) |
|
| SN-38: Day 15 (n=8, 6) |
|
| Irinotecan: Day 1 (n=10, 6) |
|
| Irinotecan: Day 15 (n=8, 6) |
|
| SN-38: Day 1 (n=10, 6) |
|
| SN-38: Day 15 (n=8, 6) |
|
| Irinotecan: Day 1 (n=9, 6) |
|
| Irinotecan: Day 15 (n=8, 6) |
|
| SN-38: Day 1 (n=9, 6) |
|
| SN-38: Day 15 (n=8, 6) |
|
| Irinotecan: Day 1 (n=9, 6) |
|
| Irinotecan: Day 15 (n=8, 6) |
|
| SN-38: Day 1 (n=9, 6) |
|
| SN-38: Day 15 (n=8, 6) |
|
| Irinotecan: Day 1 (n=9, 6) |
|
| Irinotecan: Day 15 (n=8, 6) |
|
| SN-38: Day 1 (n=9, 6) |
|
| SN-38: Day 15 (n=8, 6) |
|
| Irinotecan: Day 1 (n=9, 6) |
|
| Irinotecan: Day 15 (n=8, 6) |
|
| SN-38: Day 1 (n=9, 6) |
|
| SN-38: Day 15 (n=8, 6) |
|
| SN-38 (n=8, 6) |
|
| SN-38 (n=8, 6) |
|
| SD |
|
| PD |
|
| Not evaluable |
|