A Study Of PF-05212384 Plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS And NRAS Wild Type Metastatic Colorectal Cancer

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

Population: All participants who were randomized, with KRAS (Kirsten ras oncogene) and NRAS (neuroblastoma ras viral oncogene homolog) wild type status confirmed by central lab, and with treatment arm assignment designated according to randomization. As pre-specified in the protocol, this outcome measure was not analyzed for Japanese Lead-In Cohort.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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

Population: Data for this outcome measure were no longer collected after approval of protocol amendment 4, and data previously collected were insufficient to perform any analysis.

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

Population: The analysis population included all participants who achieved CR or PR in Arm A and Arm B. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm PF 05212384 + Irinotecan: Japanese Lead-In Cohort (LIC).

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

Population: Data for this outcome measure were not collected due to early termination of this study.

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.

Population: The pharmacokinetic concentration analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one time point with a concentration measurement recorded. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic concentration analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one time point with a concentration measurement recorded. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic concentration analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one time point with a concentration measurement recorded. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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

Population: QTc analysis set included all participants in the safety analysis set who had at least one ECG assessment after receiving study treatment.

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

Population: QTc analysis set included all participants in the safety analysis set who had at least one ECG assessment after receiving study treatment.

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

Population: All participants for whom at least one of these pre-defined gene sequences was analyzed were included.

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

Population: Safety analysis set included all participants who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received.

Coagulation analysis included partial thromboplastin time (PTT) and international normalized ratio (INR) or prothrombin time (PT).

Time frame: 2 years

Population: Safety analysis set included all participants who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received.

The following hematology parameters were evaluated in this study: hemoglobin, white blood cells (WBC) with differential, and platelets.

Time frame: 2 years

Population: Safety analysis set included all participants who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received.

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

Population: Safety analysis set included all participants who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received.

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

Population: Safety analysis set included all participants who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received.

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

Population: Safety analysis set included all participants who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received.

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

Population: The analysis population included all participants enrolled into Japanese LIC. As pre-specified in protocol, this outcome measure was not analyzed for reporting arms: PF-05212384 + Irinotecan: Arm A and Cetuximab + Irinotecan: Arm B.

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

Population: Per protocol analysis set, i.e. all participants who were randomized, with KRAS and NRAS wild type status confirmed by central lab and with treatment arm assignment designated according to randomization. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm PF 05212384 + Irinotecan: Japanese Lead-In Cohort (LIC).

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

Population: Response evaluable analysis set was used for the analysis of objective response, and it included all participants in the full analysis set (all participants who were randomized, with treatment arm assignment designated according to randomization) who had an adequate baseline assessment of disease and measurable disease.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.

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.

Population: The pharmacokinetic parameter analysis set included all randomized participants (or enrolled participants to the Japanese LIC) who started treatment and had at least one of the pharmacokinetic parameters of interest estimated. As pre specified in protocol, this outcome measure was not analyzed for reporting arm: Cetuximab + Irinotecan: Arm B.