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

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.

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.

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.

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.

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.

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.

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

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.

Urinalysis included urine dipstick for protein and blood: if positive, perform a microscopic analysis. Number of participants with urine protein tested positive is presented.

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

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.

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.

Cmax of PF-05212384 was observed directly from data.

Cmax of irinotecan was observed directly from data.

SN-38 is an irinotecan metabolite. Cmax of SN-38 was observed directly from data.

Tmax of PF-05212384 was observed directly from data as time of first occurrence.

Tmax of irinotecan was observed directly from data as time of first occurrence.

SN-38 is an irinotecan metabolite. Tmax of SN-38 was observed directly from data as time of first occurrence.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.