A Phase 2 interventional study of PF-05212384 and irinotecan in Metastatic Colorectal Cancer, sponsored by Pfizer. Terminated at 32 sites in 4 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-01-08.
Sponsored by Pfizer · Phase 2, Interventional, and Treatment
This study will investigate whether the combination of PF-05212384 plus Irinotecan improves progression free survival in patients with KRAS and NRAS wild type metastatic colorectal cancer when compared with the combination of cetuximab plus Irinotecan. A Japanese Lead in Cohort will assess the safety of the combination of PF-05212384 + irinotecan in patients enrolled at Japanese sites.
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Exclusion Criteria:
PF-05212384 plus Irinotecan
Drug: PF-05212384 · Drug: irinotecan
Cetuximab plus Irinotecan
Drug: Cetuximab · Drug: Irinotecan
30 minute IV infusion of PF-05212384 on days 2, 9, 16 and 23 of each cycle. Intra-patient dose escalation will commence with 110mg and will increase depending on tolerability.
Also known as: PKI-587
90 minutes IV infusion of irinotecan 180mg/m\^2 on days 1 and 15 of each cycle
Also known as: Camptosar, Campto, CPT-11
120 minute IV infusion of cetuximab 400mg/m\^2 on cycle 1 day 1; 60 minute IV infusion of cetuximab on days 8, 15, and 22 of each cycle, and on day 1 of each cycle after cycle 1
Also known as: Erbitux
90 minutes IV infusion of Irinotecan 180mg/m\^2 on days 1 and 15 of each cycle
Also known as: Camptosar, Campto, CPT-11
Progression Free Survival (PFS) as Assessed by Investigators
Progression-free survival (PFS) was the time from the first dose of study treatment to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. Objective progression was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. Median PFS was estimated based on the Kaplan-Meier method.
Time frame: From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
Number of Participants With Unacceptable Toxicity in Cycle 1 (Japanese LIC Only)
Unacceptable toxicity (according to Common Terminology Criteria for Adverse Events \[CTCAE\], Version 4.0) was any of the following occurrences: (1) Grade 4 neutropenia \>7 days, or febrile neutropenia, or Grade 4 thrombocytopenia; (2) Grade \>=3 nausea/vomiting despite optimal antiemetic treatment, or Grade \>=3 diarrhea despite optimal anti diarrheal treatment; (3) unmanageable Grade \>=3 hyperglycemia; (4) mean QTc interval (time from electrocardiogram \[ECG\] Q wave to the end of the T wave corresponding to electrical systole, corrected for heart rate) \>501 msec in triplicate 12-lead ECG, or myocardial infarction, or ventricular arrhythmia; (5) Grade \>=3 non-hematologic toxicity; (6) treatment delay of \>=2 weeks due to study drug related toxicity; (7) persistent, intolerable toxicities which resulted in failure to deliver at least 75% of doses of both PF-05212384 and irinotecan during Cycle 1; (8) Grade \>=2 respiratory toxicities.
Time frame: 28 days
Percentage of Participants With Objective Response
Percentage of participants with objective response was based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1. Confirmed PR was defined as disappearance of all target lesions. Confirmed PR was defined as \>=30% decrease in sum of the longest dimensions of the target lesions taking the baseline sum as a reference. Confirmed responses were those that persisted on repeat imaging study \>=4 weeks after initial documentation of response.
Time frame: 2 years
Duration of Response
For participants with an objective response (CR or PR), duration of response was defined as the time from first documentation of CR or PR to date of first documentation of objective progression or death. Date of first documentation of progression and date of first documentation of CR or PR were based on Investigator's assessment of response.
Time frame: 2 years
Overall Survival (OS)
Overall survival (OS) was defined as the duration from enrollment to death. Participants last known to be alive were censored at date of last contact.
Time frame: 2 years
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE was defined as any untoward occurrence at any dose that resulted in death; was life threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect. AEs included both serious and non-serious AEs. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study drug.
Time frame: Administration of the first dose of study drug through 28 calendar days after the last administration of study drug
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Common Terminology Criteria for Adverse Events (CTCAE) Grade
TEAEs were those AEs with initial onset or increasing in severity after the first dose of study drug. CTCAE version 4.0 was used to grade the severity of TEAEs. Grade 1 referred to mild AEs; Grade 2 referred to moderate AEs; Grade 3 referred to severe AEs; Grade 4 referred to AEs with life-threatening consequences, and urgent intervention was needed to manage them; Grade 5 referred to death related to AE.
Time frame: Administration of the first dose of study drug through 28 calendar days after the last administration of study drug
Number of Participants With Laboratory Test (Hematology) Abnormalities
The following hematology parameters were evaluated in this study: hemoglobin, white blood cells (WBC) with differential, and platelets.
Time frame: 2 years
Number of Participants With Laboratory Test (Chemistry) Abnormalities
The following chemistry parameters were evaluated in this study: sodium, potassium, magnesium, chloride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, albumin, blood urea nitrogen (BUN) or urea, creatinine, total calcium, glycosylated hemoglobin (HbA1c), glucose, uric acid, phosphorus or phosphate, insulin, and C-peptide.
Time frame: 2 years
Number of Participants With Laboratory Test (Urinalysis) Abnormalities
Urinalysis included urine dipstick for protein and blood: if positive, perform a microscopic analysis. Number of participants with urine protein tested positive is presented.
Time frame: 2 years
Number of Participants With Laboratory Test (Coagulation) Abnormalities
Coagulation analysis included partial thromboplastin time (PTT) and international normalized ratio (INR) or prothrombin time (PT).
Time frame: 2 years
Number of Participants With ECG Post-Baseline Maximum Absolute Values Meeting Pre-defined Criteria
The number of participants with ECG post-baseline maximum absolute values meeting the following criteria was reported: (1) maximum QTc interval ranged from 450 to 480 msec; \>480-500 msec; \>500 msec; (2) maximum QTcB (QT corrected for heart rate using Bazett's formula) interval ranged from 450 to 480 msec; \>480-500 msec; \>500 msec; (3) maximum QTcF (QT corrected for heart rate using Fridericia's formula) interval ranged from 450 to 480 msec; \>480-500 msec; \>500 msec.
Time frame: 2 years
Number of Participants With ECG Maximum Increase From Baseline Meeting Pre-defined Criteria
The number of participants with ECG maximum increase from baseline meeting the following criteria was reported: Criterion A: maximum QTc interval increase from baseline \>30 msec and ≤60 msec; criterion B: maximum QTc interval increase from baseline \>60 msec; criterion C: maximum QTcB interval increase from baseline \>30 msec and ≤60 msec; criterion D: maximum QTcB interval increase from baseline \>60 msec; criterion E: maximum QTcF interval increase from baseline \>30 msec and ≤60 msec; criterion F: maximum QTcF interval increase from baseline \>60 msec.
Time frame: 2 years
Maximum Plasma Concentration (Cmax) of PF-05212384
Cmax of PF-05212384 was observed directly from data.
Time frame: Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9 and Cycle 1 Day 16.
Maximum Plasma Concentration (Cmax) of Irinotecan
Cmax of irinotecan was observed directly from data.
Time frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1.
Maximum Plasma Concentration (Cmax) of SN-38
SN-38 is an irinotecan metabolite. Cmax of SN-38 was observed directly from data.
Time frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1.
Time for Maximum Plasma Concentration (Tmax) of PF-05212384
Tmax of PF-05212384 was observed directly from data as time of first occurrence.
Time frame: Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9 and Cycle 1 Day 16.
Time for Maximum Plasma Concentration (Tmax) of Irinotecan
Tmax of irinotecan was observed directly from data as time of first occurrence.
Time frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1.
Time for Maximum Plasma Concentration (Tmax) of SN-38
SN-38 is an irinotecan metabolite. Tmax of SN-38 was observed directly from data as time of first occurrence.
Time frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1.
Terminal Elimination Half Life (t½) of PF-05212384
T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.
Time frame: Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9 and Cycle 1 Day 16.
Terminal Elimination Half Life (t½) of Irinotecan
T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.
Time frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1.
Terminal Elimination Half Life (t½) of SN-38
T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.
Time frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1.
Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of PF-05212384
AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of PF-05212384 was determined using linear/log trapezoidal method.
Time frame: Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9.
Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of Irinotecan
AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of irinotecan was determined using linear/log trapezoidal method.
Time frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1.
Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of SN-38
AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of SN-38 (an irinotecan metabolite) was determined using linear/log trapezoidal method.
Time frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1.
Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05212384
AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of PF-05212384 was calculated using the formula: AUCinf = AUClast + (Clast\*/kel), where Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.
Time frame: Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9.
Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Irinotecan
AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of irinotecan was calculated using the formula: AUCinf = AUClast + (Clast\*/kel), where Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.
Time frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1.
Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of SN-38
AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of SN-38 (an irinotecan metabolite) was calculated using the formula: AUCinf = AUClast + (Clast\*/kel), where Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.
Time frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1.
Levels of Signaling Proteins in Paired and Single Tumor Biopsies
Pre defined signaling proteins included Akt (protein kinase B), p-Akt (phosphorylated Akt), p-S6 (phosphorylated ribosomal protein S6), p-Met (phosphorylated Met, a receptor tyrosine kinase), p-mTOR (phosphorylated mammalian target of rapamycin), EGFR (epithelial growth factor receptor), and p-EGFR (phosphorylated EGFR).
Time frame: 2 years
Number of Participants With Expression of Pre-defined Gene Sequences in Biopsied Tumor Tissues
Pre-defined gene sequences were those related to EGFR, PI3K (phosphoinositide-3 kinase) and other oncogenic pathways; examples included but were not limited to PIK3CA (this gene encodes the catalytic subunit of PI3K), PIK3R1 (this gene encodes the regulatory subunit of PI3K), KRAS, NRAS and BRAF (this gene encodes serine/threonine-protein kinase B-Raf) sequences and PIK3CA gene amplification. Due to early termination of this study, these pre-defined gene sequences were not analyzed, except for KRAS and NRAS. Number of participants who had KRAS and NRAS wild type status confirmed by the central laboratory is presented.
Time frame: 2 years
Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C)
Functional Assessment of Cancer Therapy-Colorectal (FACT-C) was used in this study to assess Health-Related Quality of Life (HRQoL) and CRC-related symptoms in participants enrolled to the randomized portion of the study. The FACT-C is part of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system, a comprehensive and extensive set of self-reported instruments for the assessment of health-related quality of life in participants with cancer or other chronic illnesses.
Time frame: 2 years
| Milestone | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| Started | 7 | 6 | 6 |
| Completed | 0 | 0 | 0 |
| Not completed | 7 | 6 | 6 |
| Withdrew: Death | 1 | 0 | 0 |
| Withdrew: Lost to follow-up | 0 | 1 | 0 |
| Withdrew: Withdrawal by subject | 1 | 2 | 0 |
| Withdrew: Study terminated by sponsor | 4 | 0 | 0 |
| Withdrew: Protocol amendment | 1 | 3 | 6 |
Progression-free survival (PFS) was the time from the first dose of study treatment to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. Objective progression was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. Median PFS was estimated based on the Kaplan-Meier method.
| months | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B |
|---|---|---|
| Progression Free Survival (PFS) as Assessed by Investigators | 3.7 (1.5 to 7.4) | NA (NA to NA) |
Unacceptable toxicity (according to Common Terminology Criteria for Adverse Events \[CTCAE\], Version 4.0) was any of the following occurrences: (1) Grade 4 neutropenia \>7 days, or febrile neutropenia, or Grade 4 thrombocytopenia; (2) Grade \>=3 nausea/vomiting despite optimal antiemetic treatment, or Grade \>=3 diarrhea despite optimal anti diarrheal treatment; (3) unmanageable Grade \>=3 hyperglycemia; (4) mean QTc interval (time from electrocardiogram \[ECG\] Q wave to the end of the T wave corresponding to electrical systole, corrected for heart rate) \>501 msec in triplicate 12-lead ECG, or myocardial infarction, or ventricular arrhythmia; (5) Grade \>=3 non-hematologic toxicity; (6) treatment delay of \>=2 weeks due to study drug related toxicity; (7) persistent, intolerable toxicities which resulted in failure to deliver at least 75% of doses of both PF-05212384 and irinotecan during Cycle 1; (8) Grade \>=2 respiratory toxicities.
| participants | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|
| Number of Participants With Unacceptable Toxicity in Cycle 1 (Japanese LIC Only) | 0 |
Percentage of participants with objective response was based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1. Confirmed PR was defined as disappearance of all target lesions. Confirmed PR was defined as \>=30% decrease in sum of the longest dimensions of the target lesions taking the baseline sum as a reference. Confirmed responses were those that persisted on repeat imaging study \>=4 weeks after initial documentation of response.
| percentage of participants | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| Percentage of Participants With Objective Response | 14.3 (0.4 to 57.9) | 50.0 (11.8 to 88.2) | 0 (0.0 to 45.9) |
For participants with an objective response (CR or PR), duration of response was defined as the time from first documentation of CR or PR to date of first documentation of objective progression or death. Date of first documentation of progression and date of first documentation of CR or PR were based on Investigator's assessment of response.
| months | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B |
|---|---|---|
| Duration of Response | NA (NA to NA) | NA (NA to NA) |
Overall survival (OS) was defined as the duration from enrollment to death. Participants last known to be alive were censored at date of last contact.
| months | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B |
|---|---|---|
| Overall Survival (OS) | NA (3.3 to NA) | NA (NA to NA) |
An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE was defined as any untoward occurrence at any dose that resulted in death; was life threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect. AEs included both serious and non-serious AEs. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study drug.
| participants | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| AEs | 7 | 6 | 6 |
| SAEs | 3 | 1 | 1 |
TEAEs were those AEs with initial onset or increasing in severity after the first dose of study drug. CTCAE version 4.0 was used to grade the severity of TEAEs. Grade 1 referred to mild AEs; Grade 2 referred to moderate AEs; Grade 3 referred to severe AEs; Grade 4 referred to AEs with life-threatening consequences, and urgent intervention was needed to manage them; Grade 5 referred to death related to AE.
| participants | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| Grade 1 | 1 | 2 | 2 |
| Grade 2 | 1 | 1 | 0 |
| Grade 3 | 3 | 2 | 4 |
| Grade 4 | 2 | 0 | 0 |
| Grade 5 | 0 | 1 | 0 |
The following hematology parameters were evaluated in this study: hemoglobin, white blood cells (WBC) with differential, and platelets.
| participants | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| Anemia | 6 | 6 | 6 |
| Hemoglobin increased | 0 | 0 | 0 |
| Lymphocyte count increased | 0 | 2 | 0 |
| Lymphopenia | 5 | 4 | 5 |
| Neutrophils (absolute) | 4 | 3 | 5 |
| Platelets | 0 | 3 | 1 |
| White blood cells | 4 | 4 | 5 |
The following chemistry parameters were evaluated in this study: sodium, potassium, magnesium, chloride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, albumin, blood urea nitrogen (BUN) or urea, creatinine, total calcium, glycosylated hemoglobin (HbA1c), glucose, uric acid, phosphorus or phosphate, insulin, and C-peptide.
| participants | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| ALT | 2 | 1 | 1 |
| Alkaline phosphatase | 3 | 4 | 4 |
| AST | 2 | 1 | 1 |
| Total bilirubin | 0 | 1 | 0 |
| Creatitine | 4 | 3 | 6 |
| Hypercalcemia | 1 | 0 | 0 |
| Hyperglycemia | 6 | 4 | 4 |
| Hyperkalemia | 1 | 0 | 0 |
| Hypermagnesemia | 0 | 0 | 0 |
| Hypernatremia | 1 | 0 | 1 |
| Hypoalbuminemia | 2 | 4 | 4 |
| Hypocalcemia | 2 | 3 | 3 |
| Hypoglycemia | 0 | 1 | 0 |
| Hypokalemia | 2 | 2 | 3 |
| Hypomagnesemia | 3 | 4 | 1 |
| Hyponatremia | 2 | 1 | 0 |
| Hypophosphatemia | 2 | 1 | 0 |
Urinalysis included urine dipstick for protein and blood: if positive, perform a microscopic analysis. Number of participants with urine protein tested positive is presented.
| participants | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| Number of Participants With Laboratory Test (Urinalysis) Abnormalities | 3 | 1 | 4 |
Coagulation analysis included partial thromboplastin time (PTT) and international normalized ratio (INR) or prothrombin time (PT).
| participants | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| PTT (number of participants =7, 6, 5) | 2 | 4 | 0 |
| PT (number of participants =7, 5, 6) | 3 | 3 | 1 |
| PT INR | 1 | 2 | 2 |
The number of participants with ECG post-baseline maximum absolute values meeting the following criteria was reported: (1) maximum QTc interval ranged from 450 to 480 msec; \>480-500 msec; \>500 msec; (2) maximum QTcB (QT corrected for heart rate using Bazett's formula) interval ranged from 450 to 480 msec; \>480-500 msec; \>500 msec; (3) maximum QTcF (QT corrected for heart rate using Fridericia's formula) interval ranged from 450 to 480 msec; \>480-500 msec; \>500 msec.
| participants | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| Maximum QTc interval: 450-480 msec | 2 | 1 | 1 |
| Maximum QTc interval: >480-500 msec | 0 | 0 | 0 |
| Maximum QTc interval: >500 msec | 0 | 0 | 0 |
| Maximum QTcB interval: 450-480 msec | 3 | 1 | 0 |
| Maximum QTcB interval: >480-500 msec | 0 | 0 | 0 |
| Maximum QTcB interval: >500 msec | 0 | 0 | 0 |
| Maximum QTcF interval: >450-480 msec | 1 | 0 | 0 |
| Maximum QTcF interval: >480-500 msec | 0 | 0 | 0 |
| Maximum QTcF interval: >500 msec | 0 | 0 | 0 |
The number of participants with ECG maximum increase from baseline meeting the following criteria was reported: Criterion A: maximum QTc interval increase from baseline \>30 msec and ≤60 msec; criterion B: maximum QTc interval increase from baseline \>60 msec; criterion C: maximum QTcB interval increase from baseline \>30 msec and ≤60 msec; criterion D: maximum QTcB interval increase from baseline \>60 msec; criterion E: maximum QTcF interval increase from baseline \>30 msec and ≤60 msec; criterion F: maximum QTcF interval increase from baseline \>60 msec.
| participants | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| Criterion A | 1 | 1 | 0 |
| Criterion B | 0 | 0 | 0 |
| Criterion C | 0 | 1 | 0 |
| Criterion D | 0 | 0 | 0 |
| Criterion E | 0 | 0 | 0 |
| Criterion F | 0 | 0 | 0 |
Cmax of PF-05212384 was observed directly from data.
| ng/mL | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 9 | 8345 ± 19 | 8534 ± 10 |
| Cycle 1 Day 16 (number of participants =5, 6) | 10120 ± 27 | 9670 ± 26 |
Cmax of irinotecan was observed directly from data.
| ng/mL | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 1 | 2283 ± 30 | 2123 ± 18 |
| Cycle 2 Day 1 (number of participants =4, 5) | 1620 ± 41 | 1999 ± 13 |
SN-38 is an irinotecan metabolite. Cmax of SN-38 was observed directly from data.
| ng/mL | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 1 | 23.51 ± 32 | 24.25 ± 50 |
| Cycle 2 Day 1 (number of participants =4, 5) | 22.81 ± 67 | 28.04 ± 33 |
Tmax of PF-05212384 was observed directly from data as time of first occurrence.
| hours | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 9 | 0.483 (0.467 to 0.517) | 0.483 (0.467 to 0.500) |
| Cycle 1 Day 16 (number of participants =5, 6) | 0.500 (0.467 to 0.517) | 0.500 (0.483 to 0.517) |
Tmax of irinotecan was observed directly from data as time of first occurrence.
| hours | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 1 | 1.50 (1.47 to 1.62) | 1.53 (1.48 to 1.58) |
| Cycle 2 Day 1 (number of participants =4, 5) | 1.55 (1.50 to 2.05) | 1.53 (1.50 to 1.57) |
SN-38 is an irinotecan metabolite. Tmax of SN-38 was observed directly from data as time of first occurrence.
| hours | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 1 | 2.00 (1.50 to 2.18) | 1.98 (1.48 to 2.08) |
| Cycle 2 Day 1 (number of participants =4, 5) | 2.03 (1.53 to 3.98) | 1.93 (1.90 to 2.00) |
T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.
| hours | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 9 | 37.65 ± 4.55 | 37.78 ± 3.61 |
| Cycle 1 Day 16 (number of participants =4, 6) | 35.10 ± 6.90 | 36.07 ± 4.56 |
T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.
| hours | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 1 | 5.547 ± 0.562 | 5.255 ± 0.420 |
| Cycle 2 Day 1 (number of participants =4, 5) | 5.293 ± 0.488 | 5.344 ± 0.719 |
T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.
| hours | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 1 (number of participants =2, 3) | NA ± NA | 9.890 ± 0.811 |
| Cycle 2 Day 1 | NA ± NA | 8.840 ± 1.091 |
AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of PF-05212384 was determined using linear/log trapezoidal method.
| ng*hr/mL | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of PF-05212384 | 11530 ± 15 | 13390 ± 17 |
AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of irinotecan was determined using linear/log trapezoidal method.
| ng*hr/mL | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 1 | 11860 ± 23 | 11030 ± 29 |
| Cycle 2 Day 1 (number of participants =4, 5) | 8776 ± 62 | 10380 ± 29 |
AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of SN-38 (an irinotecan metabolite) was determined using linear/log trapezoidal method.
| ng*hr/mL | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 1 | 217.0 ± 29 | 217.9 ± 38 |
| Cycle 2 Day 1 (number of participants =4, 5) | 182.4 ± 43 | 228.5 ± 38 |
AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of PF-05212384 was calculated using the formula: AUCinf = AUClast + (Clast\*/kel), where Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.
| ng*hr/mL | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05212384 | 11700 ± 15 | 13580 ± 17 |
AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of irinotecan was calculated using the formula: AUCinf = AUClast + (Clast\*/kel), where Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.
| ng*hr/mL | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 1 | 12480 ± 23 | 11570 ± 30 |
| Cycle 2 Day 1 (number of participants =4, 5) | 9216 ± 63 | 10950 ± 31 |
AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of SN-38 (an irinotecan metabolite) was calculated using the formula: AUCinf = AUClast + (Clast\*/kel), where Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.
| ng*hr/mL | PF-05212384 + Irinotecan: Arm A | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|
| Cycle 1 Day 1 (number of participants =2, 3) | NA ± NA | 230.4 ± 13 |
| Cycle 2 Day 1 | NA ± NA | 279.7 ± 45 |
Pre defined signaling proteins included Akt (protein kinase B), p-Akt (phosphorylated Akt), p-S6 (phosphorylated ribosomal protein S6), p-Met (phosphorylated Met, a receptor tyrosine kinase), p-mTOR (phosphorylated mammalian target of rapamycin), EGFR (epithelial growth factor receptor), and p-EGFR (phosphorylated EGFR).
No measurements were reported for this outcome.
Pre-defined gene sequences were those related to EGFR, PI3K (phosphoinositide-3 kinase) and other oncogenic pathways; examples included but were not limited to PIK3CA (this gene encodes the catalytic subunit of PI3K), PIK3R1 (this gene encodes the regulatory subunit of PI3K), KRAS, NRAS and BRAF (this gene encodes serine/threonine-protein kinase B-Raf) sequences and PIK3CA gene amplification. Due to early termination of this study, these pre-defined gene sequences were not analyzed, except for KRAS and NRAS. Number of participants who had KRAS and NRAS wild type status confirmed by the central laboratory is presented.
| participants | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| Confirmed wild type KRAS | 4 | 3 | 6 |
| Confirmed wild type NRAS | 4 | 3 | 3 |
Functional Assessment of Cancer Therapy-Colorectal (FACT-C) was used in this study to assess Health-Related Quality of Life (HRQoL) and CRC-related symptoms in participants enrolled to the randomized portion of the study. The FACT-C is part of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system, a comprehensive and extensive set of self-reported instruments for the assessment of health-related quality of life in participants with cancer or other chronic illnesses.
No measurements were reported for this outcome.
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| PF-05212384 + Irinotecan: Arm A | — | 3/7 (42.9%) | 7/7 (100%) |
| Cetuximab + Irinotecan: Arm B | — | 1/6 (16.7%) | 6/6 (100%) |
| PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) | — | 1/6 (16.7%) | 6/6 (100%) |
| Event | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| Disease progressionGeneral disorders | 0/7 | 1/6 | 0/6 |
| Urinary tract infectionInfections and infestations | 0/7 | 0/6 | 1/6 |
| ColitisGastrointestinal disorders | 1/7 | 0/6 | 0/6 |
| Transient ischaemic attackNervous system disorders | 1/7 | 0/6 | 0/6 |
| PneumothoraxRespiratory, thoracic and mediastinal disorders | 1/7 | 0/6 | 0/6 |
| Event | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) |
|---|---|---|---|
| NauseaGastrointestinal disorders | 6/7 | 3/6 | 3/6 |
| DiarrhoeaGastrointestinal disorders | 5/7 | 3/6 | 3/6 |
| StomatitisGastrointestinal disorders | 5/7 | 1/6 | 4/6 |
| VomitingGastrointestinal disorders | 4/7 | 1/6 | 2/6 |
| FatigueGeneral disorders | 4/7 | 2/6 | 1/6 |
| AnaemiaBlood and lymphatic system disorders | 2/7 | 3/6 | 0/6 |
| NeutropeniaBlood and lymphatic system disorders | 2/7 | 1/6 | 3/6 |
| ConstipationGastrointestinal disorders | 3/7 | 3/6 | 0/6 |
| Decreased appetiteMetabolism and nutrition disorders | 3/7 | 2/6 | 3/6 |
| Abdominal painGastrointestinal disorders | 3/7 | 0/6 | 0/6 |
The baseline analysis population included all enrolled participants who received the study drug.
| Age, Customized(participants) | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) | Total |
|---|---|---|---|---|
| <18 years | 0 ± 7.8 | 0 ± 6.1 | 0 ± 6.7 | 0 |
| 18-64 years | 5 | 4 | 4 | 13 |
| >=65 years | 2 | 2 | 2 | 6 |
| Sex: Female, Male(Participants) | PF-05212384 + Irinotecan: Arm A | Cetuximab + Irinotecan: Arm B | PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC) | Total |
|---|---|---|---|---|
| Female | 4 | 3 | 4 | 11 |
| Male | 3 | 3 | 2 | 8 |
Plan to share: Yes — Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
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