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Clinical Trial Results:
A Randomized Phase 2 Study of PF-05212384 Plus Irinotecan Versus Cetuximab Plus Irinotecan in Patients With KRAS and NRAS Wild Type Metastatic Colorectal Cancer

Summary
EudraCT number	2013-002095-40
Trial protocol	BE IT ES
Global end of trial date	06 Apr 2016

Results information
Results version number	v1(current)
This version publication date	10 Feb 2017
First version publication date	10 Feb 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

B2151005

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Sep 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

06 Apr 2016

Global end of trial reached?

Yes

Global end of trial date

06 Apr 2016

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of this study was to investigate whether PF-05212384 in combination with irinotecan was superior to cetuximab in combination with irinotecan in prolonging progression-free survival (PFS) in subjects with Kirsten ras oncogene (KRAS) and neuroblastoma ras viral oncogene homolog (NRAS) wild type mCRC who had progressed following prior treatment with irinotecan, oxaliplatin, and fluoropyrimidine.

Protection of trial subjects

This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Nov 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

18 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 8

Country: Number of subjects enrolled

Japan: 6

Country: Number of subjects enrolled

Korea, Republic of: 5

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Prior to study termination, a total of 20 potential subjects were screened, and 19 of them were enrolled and treated, which included 8 subjects from the United States, 6 subjects from Japan, and 5 subjects from Korea.

Screening details

A total of 20 potential subjects were screened.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

PF-05212384 + Irinotecan: Arm A

Arm description

PF-05212384 was administered intravenously (IV) every week (Days 2, 9, 16 and 23 of each 28-day cycle) at a starting dose level of 110 mg. During Cycle 1, PF 05212384 was only dosed on Days 9, 16 and 23. After one cycle of dosing with PF-05212384, in subsequent cycles, the dose level remained at 110 mg or was escalated based on the occurrences of dose limiting toxicities (DLTs) in previous cycle and at the discretion of the investigator. Subjects enrolled in Korea remained at the 110 mg starting dose level of PF-05212384. Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m^2. Both the dose levels of PF 05212384 and irinotecan were adjusted according to severity of toxicities. Infusion of PF-05212384 followed irinotecan infusion by at least 24 hours (+/- 10%).

Arm type

Experimental

Investigational medicinal product name

PF-05212384

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Irinotecan hydrochloride trihydrate

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m^2.

Cetuximab + Irinotecan: Arm B

Arm description

Cetuximab was administered IV every week (Days 1, 8, 15 and 22 of each 28-day cycle) at a starting dose level of 400 mg/m^2 on Cycle 1 Day 1 followed by 250 mg/m^2 in subsequent infusions. Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m^2. Both the dose levels of cetuximab and irinotecan were adjusted according to severity of toxicities.

Arm type

Active comparator

Investigational medicinal product name

Irinotecan hydrochloride trihydrate

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m^2.

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cetuximab was administered IV every week (Days 1, 8, 15 and 22 of each 28-day cycle) at a starting dose level of 400 mg/m^2 on Cycle 1 Day 1 followed by 250 mg/m^2 in subsequent infusions.

PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)

Arm description

PF-05212384 was administered intravenously (IV) every week (Days 2, 9, 16 and 23 of each 28-day cycle) at a starting dose level of 110 mg. During Cycle 1, PF-05212384 was only dosed on Days 9, 16 and 23. Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m^2. Both the dose levels of PF-05212384 and irinotecan were adjusted according to severity of toxicities. Infusion of PF-05212384 followed irinotecan infusion by at least 24 hours (+/- 10%).

Arm type

Experimental

Investigational medicinal product name

Irinotecan hydrochloride trihydrate

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m^2.

Investigational medicinal product name

PF-05212384

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 1	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
Adverse event, serious fatal	1	-	-
Consent withdrawn by subject	1	2	-
Protocol amendment	1	3	6
Study terminated by sponsor	4	-	-
Lost to follow-up	-	1	-

Baseline characteristics

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Reporting group title

PF-05212384 + Irinotecan: Arm A

Reporting group description

Reporting group title

Cetuximab + Irinotecan: Arm B

Reporting group description

Reporting group title

PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)

Reporting group description

PF-05212384 was administered intravenously (IV) every week (Days 2, 9, 16 and 23 of each 28-day cycle) at a starting dose level of 110 mg. During Cycle 1, PF-05212384 was only dosed on Days 9, 16 and 23. Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m^2. Both the dose levels of PF-05212384 and irinotecan were adjusted according to severity of toxicities. Infusion of PF-05212384 followed irinotecan infusion by at least 24 hours (+/- 10%).

Reporting group values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)	Total
Number of subjects	7	6	6	19
Age Categorical
Units: Subjects
<18 years	0	0	0	0
18-64 years	5	4	4	13
>=65 years	2	2	2	6
Age continuous
Units: years
arithmetic mean (standard deviation)	59.4 ( 7.8 )	61.5 ( 6.1 )	60.3 ( 6.7 )	-
Gender, Male/Female
Units: Subjects
FEMALE	4	3	4	11
MALE	3	3	2	8

End points

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Reporting group title

PF-05212384 + Irinotecan: Arm A

Reporting group description

Reporting group title

Cetuximab + Irinotecan: Arm B

Reporting group description

Reporting group title

PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)

Reporting group description

PF-05212384 was administered intravenously (IV) every week (Days 2, 9, 16 and 23 of each 28-day cycle) at a starting dose level of 110 mg. During Cycle 1, PF-05212384 was only dosed on Days 9, 16 and 23. Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m^2. Both the dose levels of PF-05212384 and irinotecan were adjusted according to severity of toxicities. Infusion of PF-05212384 followed irinotecan infusion by at least 24 hours (+/- 10%).

Primary: Progression Free Survival (PFS) as Assessed by Investigators

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End point title

Progression Free Survival (PFS) as Assessed by Investigators ^[1] ^[2]

End point description

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. Per protocol analysis set was used for analysis of this end point, and it included all subjects who were randomized, with KRAS and NRAS wild type status confirmed by our central lab, and with treatment arm assignment designated according to randomization.

End point type

Primary

End point timeframe

36 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to early termination of this study and therefore limited data, no statistical analysis was conducted on this primary end point.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B
Number of subjects analysed	4	3 ^[3]
Units: months
median (confidence interval 95%)	3.7 (1.5 to 7.4)	16.6 (0.9999 to 99999)

Notes
[3] - Only one non-censored data point, the CI range is set from 0.9999 to 99999 as it was not computed.

No statistical analyses for this end point

Secondary: Number of Subjects With Unacceptable Toxicity in Cycle 1 (Japanese LIC only)

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End point title

Number of Subjects With Unacceptable Toxicity in Cycle 1 (Japanese LIC only) ^[4]

End point description

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. All subjects enrolled into Japanese LIC were included.

End point type

Secondary

End point timeframe

28 days

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As indicated in this end point title, data were collected only in the Japanese Lead-In Cohort.

End point values	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	6
Units: subjects	0

No statistical analyses for this end point

Secondary: Number of Subjects With Objective Response

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End point title

Number of Subjects With Objective Response

End point description

Number of subjects 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. Response evaluable analysis set was used for analysis of this end point, and it included all subjects in the full analysis set (all subjects who were randomized, with treatment arm assignments designated according to randomization) who had an adequate baseline assessment of disease and measurable disease.

End point type

Secondary

End point timeframe

2 years

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6	6
Units: subjects	1	3	0

Objective response in Arm A versus Arm B

Comparison groups

Cetuximab + Irinotecan: Arm B v PF-05212384 + Irinotecan: Arm A

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.164

Method

Chi-squared

Parameter type

Mean difference (net)

Point estimate

-35.71

Confidence interval

level

95%

sides

2-sided

lower limit

-83.4

upper limit

Secondary: Duration of Response

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End point title

Duration of Response ^[5]

End point description

For subjects 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 assessment of response. All subjects who achieved CR or PR in Arm A and Arm B were included for analysis of this end point

End point type

Secondary

End point timeframe

2 years

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B
Number of subjects analysed	1 ^[6]	3 ^[7]
Units: months
median (confidence interval 95%)	5.6 (0.9999 to 99999)	14.8 (0.9999 to 99999)

Notes
[6] - Only one non-censored data point, the CI range is set from 0.9999 to 99999 as it was not computed.
[7] - Only one non-censored data point, the CI range is set from 0.9999 to 99999 as it was not computed.

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS) ^[8]

End point description

Overall survival (OS) was defined as the duration from enrollment to death. Subjects last known to be alive were censored at date of last contact. Per protocol analysis set was used for analysis of this end point, and it included all subjects who were randomized, with KRAS and NRAS wild type status confirmed by central lab and with treatment arm assignment designated according to randomization.

End point type

Secondary

End point timeframe

2 years

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B
Number of subjects analysed	4 ^[9]	3 ^[10]
Units: months
median (confidence interval 95%)	99999 (3.3 to 99999)	99999 (99999 to 99999)

Notes
[9] - Only 1 subject had evaluable value, and 99999 was used as the high range value.
[10] - No subject had evaluable value, and 99999 was entered instead.

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

End point description

An AE was defined as any untoward medical occurrence in a clinical investigation subject 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. Safety analysis set was used for analysis of this end point, and it included all subjects who received at least one dose of study drug, with treatment arm assignment designated according to actual study treatment received.

End point type

Secondary

End point timeframe

Administration of the first dose of study drug through 28 calendar days after the last administration of study drug

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6	6
Units: subjects
AEs	7	6	6
SAEs	3	1	1

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) by Common Terminology Criteria for Adverse Events (CTCAE) Grade

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) by Common Terminology Criteria for Adverse Events (CTCAE) Grade

End point description

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. Safety analysis set was used for the analysis of this end point, and it included all subjects who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received.

End point type

Secondary

End point timeframe

Administration of the first dose of study drug through 28 calendar days after the last administration of study drug

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6	6
Units: subjects
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

No statistical analyses for this end point

Secondary: Number of Subjects With Laboratory Test (Hematology) Abnormalities

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End point title

Number of Subjects With Laboratory Test (Hematology) Abnormalities

End point description

The following hematology parameters were evaluated in this study: hemoglobin, white blood cells (WBC) with differential, and platelets. Safety analysis set was used for the analysis of this end point, and it included all subjects who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received.

End point type

Secondary

End point timeframe

2 years

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6	6
Units: subjects
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

No statistical analyses for this end point

Secondary: Number of Subjects with Laboratory Test (Chemistry) Abnormalities

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End point title

Number of Subjects with Laboratory Test (Chemistry) Abnormalities

End point description

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. Safety analysis set was used for the analysis of this end point, and it included all subjects who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received.

End point type

Secondary

End point timeframe

2 years

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6	6
Units: subjects
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

No statistical analyses for this end point

Secondary: Number of Subjects With Laboratory Test (Urinalysis) Abnormalities

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End point title

Number of Subjects With Laboratory Test (Urinalysis) Abnormalities

End point description

Urinalysis included urine dipstick for protein and blood: if positive, perform a microscopic analysis. Safety analysis set was used for the analysis of this end point, and it included all subjects who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received. Number of subjects with urine protein tested positive is presented.

End point type

Secondary

End point timeframe

2 years

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6	6
Units: subjects	3	1	4

No statistical analyses for this end point

Secondary: Number of Subjects With Laboratory Test (Coagulation) Abnormalities

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End point title

Number of Subjects With Laboratory Test (Coagulation) Abnormalities

End point description

Coagulation analysis included partial thromboplastin time (PTT) and international normalized ratio (INR) or prothrombin time (PT). Safety analysis set was used for the analysis of this end point, and it included all subjects who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm.

End point type

Secondary

End point timeframe

2 years

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6	6
Units: subjects
PTT (n=7, 6, 5)	2	4	0
PT (n=7, 5, 6)	3	3	1
PT INR (n=7, 6, 6)	1	2	2

No statistical analyses for this end point

Secondary: Number of Subjects With ECG Post-Baseline Maximum Absolute Values Meeting Pre-defined Criteria

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End point title

Number of Subjects With ECG Post-Baseline Maximum Absolute Values Meeting Pre-defined Criteria

End point description

The number of subjects 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. QTc analysis set was used for analysis of this end point, and it included all subjects in the safety analysis set who had at least one ECG assessment after receiving study treatment.

End point type

Secondary

End point timeframe

2 years

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	6	3	6
Units: subjects
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

No statistical analyses for this end point

Secondary: Number of Subjects With ECG Maximum Increase From Baseline Meeting Pre-defined Criteria

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End point title

Number of Subjects With ECG Maximum Increase From Baseline Meeting Pre-defined Criteria

End point description

The number of subjects 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. QTc analysis set was used for analysis of this end point, and it included all subjects in the safety analysis set who had at least one ECG assessment after receiving study treatment.

End point type

Secondary

End point timeframe

2 years

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	6	3	6
Units: subjects
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

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration (Cmax) of PF-05212384

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End point title

Maximum Plasma Concentration (Cmax) of PF-05212384 ^[11]

End point description

Cmax of PF-05212384 was observed directly from data. The pharmacokinetic (PK) concentration analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects in Japanese LIC) who started treatment and had at least one time point with a concentration measurement recorded. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", because PF-05212384 was not administered to subjects in this arm as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	6	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 9 (n=6, 6)	8345 ( 19 )	8534 ( 10 )
Cycle 1 Day 16 (n=5, 6)	10120 ( 27 )	9670 ( 26 )

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration (Cmax) of Irinotecan

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End point title

Maximum Plasma Concentration (Cmax) of Irinotecan ^[12]

End point description

Cmax of irinotecan was observed directly from data. The PK concentration analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects in Japanese LIC) who started treatment and had at least one time point with a concentration measurement recorded. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle Day 1 (n=7, 6)	2283 ( 30 )	2123 ( 18 )
Cycle 2 Day 1 (n=4, 5)	1620 ( 41 )	1999 ( 13 )

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration (Cmax) of SN-38

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End point title

Maximum Plasma Concentration (Cmax) of SN-38 ^[13]

End point description

SN-38 is an irinotecan metabolite. Cmax of SN-38 was observed directly from data. The PK concentration analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects in Japanese LIC) who started treatment and had at least one time point with a concentration measurement recorded. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=7, 6)	23.51 ( 32 )	24.25 ( 50 )
Cycle 2 Day 1 (n=4, 5)	22.81 ( 67 )	28.04 ( 33 )

No statistical analyses for this end point

Secondary: Time for maximum plasma concentration (Tmax) of PF-05212384

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End point title

Time for maximum plasma concentration (Tmax) of PF-05212384 ^[14]

End point description

Tmax of PF-05212384 was observed directly from data as time of first occurrence. The PK parameter analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects to the Japanese LIC) who started treatment and had at least one of the PK parameters of interest estimated. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", because PF-05212384 was not administered to subjects in this arm as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	6	6
Units: hours
median (full range (min-max))
Cycle 1 Day 9 (n=6, 6)	0.483 (0.467 to 0.517)	0.483 (0.467 to 0.5)
Cycle 1 Day 16 (n=5, 6)	0.5 (0.467 to 0.517)	0.5 (0.483 to 0.517)

No statistical analyses for this end point

Secondary: Time for maximum plasma concentration (Tmax) of Irinotecan

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End point title

Time for maximum plasma concentration (Tmax) of Irinotecan ^[15]

End point description

Tmax of irinotecan was observed directly from data as time of first occurrence. The PK parameter analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects to the Japanese LIC) who started treatment and had at least one of the PK parameters of interest estimated. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6
Units: hours
median (full range (min-max))
Cycle 1 Day 1 (n=7, 6)	1.5 (1.47 to 1.62)	1.53 (1.48 to 1.58)
Cycle 2 Day 1 (n=4, 5)	1.55 (1.5 to 2.05)	1.53 (1.5 to 1.57)

No statistical analyses for this end point

Secondary: Time for maximum plasma concentration (Tmax) of SN-38

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End point title

Time for maximum plasma concentration (Tmax) of SN-38 ^[16]

End point description

SN-38 is an irinotecan metabolite. Tmax of SN-38 was observed directly from data as time of first occurrence. The PK parameter analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects to the Japanese LIC) who started treatment and had at least one of the PK parameters of interest estimated. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6
Units: hours
median (full range (min-max))
Cycle 1 Day 1 (n=7, 6)	2 (1.5 to 2.18)	1.98 (1.48 to 2.08)
Cycle 2 Day 1 (n=4, 5)	2.03 (1.53 to 3.98)	1.93 (1.9 to 2)

No statistical analyses for this end point

Secondary: Terminal Elimination Half Life (t½) of PF-05212384

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End point title

Terminal Elimination Half Life (t½) of PF-05212384 ^[17]

End point description

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. The PK parameter analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects to the Japanese LIC) who started treatment and had at least one of the PK parameters of interest estimated. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", because PF-05212384 was not administered to subjects in this arm as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	6	6
Units: hours
arithmetic mean (standard deviation)
Cycle 1 Day 9 (n=6, 6)	37.65 ( 4.55 )	37.78 ( 3.61 )
Cycle 1 Day 16 (n=4, 6)	35.1 ( 6.9 )	36.07 ( 4.56 )

No statistical analyses for this end point

Secondary: Terminal Elimination Half Life (t½) of Irinotecan

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End point title

Terminal Elimination Half Life (t½) of Irinotecan ^[18]

End point description

End point type

Secondary

End point timeframe

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.

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6
Units: hours
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=7, 6)	5.547 ( 0.562 )	5.255 ( 0.42 )
Cycle 2 Day 1 (n=4, 5)	5.293 ( 0.488 )	5.344 ( 0.719 )

No statistical analyses for this end point

Secondary: Terminal Elimination Half Life (t½) of SN-38

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End point title

Terminal Elimination Half Life (t½) of SN-38 ^[19]

End point description

End point type

Secondary

End point timeframe

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.

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	2 ^[20]	3
Units: hours
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=2, 3)	99999 ( 99999 )	9.89 ( 0.811 )
Cycle 2 Day 1 (n=2, 4)	99999 ( 99999 )	8.84 ( 1.091 )

Notes
[20] - No evaluable value, and 99999 was entered instead.

No statistical analyses for this end point

Secondary: Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of PF-05212384

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End point title

Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of PF-05212384 ^[21]

End point description

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

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9.

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", because PF-05212384 was not administered to subjects in this arm as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	6	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	11530 ( 15 )	13390 ( 17 )

No statistical analyses for this end point

Secondary: Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of Irinotecan

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End point title

Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of Irinotecan ^[22]

End point description

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. The PK parameter analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects to the Japanese LIC) who started treatment and had at least one of the PK parameters of interest estimated. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=7, 6)	11860 ( 23 )	11030 ( 29 )
Cycle 2 Day 1 (n=4, 5)	8776 ( 62 )	10380 ( 29 )

No statistical analyses for this end point

Secondary: Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of SN-38

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End point title

Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of SN-38 ^[23]

End point description

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. The PK parameter analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects to the Japanese LIC) who started treatment and had at least one of the PK parameters of interest estimated. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=7, 6)	217 ( 29 )	217.9 ( 38 )
Cycle 2 Day 1 (n=4, 5)	182.4 ( 43 )	228.5 ( 38 )

No statistical analyses for this end point

Secondary: Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05212384

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End point title

Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05212384 ^[24]

End point description

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

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9.

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", because PF-05212384 was not administered to subjects in this arm as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	6	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	11700 ( 15 )	13580 ( 17 )

No statistical analyses for this end point

Secondary: Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Irinotecan

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End point title

Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Irinotecan ^[25]

End point description

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. The PK parameter analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects to the Japanese LIC) who started treatment and had at least one of the PK parameters of interest estimated. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=7, 6)	12480 ( 23 )	11570 ( 30 )
Cycle 2 Day 1 (n=4, 5)	9216 ( 63 )	10950 ( 31 )

No statistical analyses for this end point

Secondary: Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of SN-38

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End point title

Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of SN-38 ^[26]

End point description

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. The PK parameter analysis set was used for analysis of this end point, and it included all randomized subjects (or enrolled subjects to the Japanese LIC) who started treatment and had at least one of the PK parameters of interest estimated. Here, n in parentheses represents the number of subjects who were evaluable for each category in each arm. As pre-specified in protocol, this end point was not analyzed for reporting arm: "Cetuximab + Irinotecan: Arm B".

End point type

Secondary

End point timeframe

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.

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "Cetuximab + Irinotecan: Arm B", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	2 ^[27]	3
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=2, 3)	99999 ( 99999 )	230.4 ( 13 )
Cycle 2 Day 1 (n=2, 4)	99999 ( 99999 )	279.7 ( 45 )

Notes
[27] - No evaluable value, and 99999 was entered instead.

No statistical analyses for this end point

Secondary: Levels of signaling proteins in paired and single tumor biopsies

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End point title

Levels of signaling proteins in paired and single tumor biopsies

End point description

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).

End point type

Secondary

End point timeframe

2 years

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	0 ^[28]	0 ^[29]	0 ^[30]
Units: ng/g
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[28] - This endpoint was not analyzed due to early termination of this study.
[29] - This endpoint was not analyzed due to early termination of this study.
[30] - This endpoint was not analyzed due to early termination of this study.

No statistical analyses for this end point

Secondary: Number of Subjects With Expression of Pre-defined Gene Sequences in Biopsied Tumor Tissues

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End point title

Number of Subjects With Expression of Pre-defined Gene Sequences in Biopsied Tumor Tissues

End point description

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 subjects who had KRAS and NRAS wild type status confirmed by the central laboratory is presented. All subjects for whom at least one of these pre-defined gene sequences was analyzed were included. Here, number of subjects analyzed represents the total number of subjects enrolled into each arm, and n refers to the number of subjects who had measurements for each category.

End point type

Secondary

End point timeframe

2 years

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Number of subjects analysed	7	6	6
Units: subjects
Confirmed wild type KRAS (n=4, 3, 6)	4	3	6
Confirmed wild type NRAS (n=4, 3, 3)	4	3	3

No statistical analyses for this end point

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C)

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End point title

Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C) ^[31]

End point description

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 subjects 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 subjects with cancer or other chronic illnesses. All subjects enrolled into the randomized portion of this study (ie, reporting arm A and B) were included. however, this outcome measure was not summarized due to early termination of this study. Here, number of subjects analyzed represents the total number of subjects enrolled into each arm.

End point type

Secondary

End point timeframe

2 years

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This end point was not analyzed for reporting arm "PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)", as pre-specified in the protocol.

End point values	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B
Number of subjects analysed	7 ^[32]	6 ^[33]
Units: score on a scale	99999	99999

Notes
[32] - No evaluable value, and 99999 was entered instead.
[33] - No evaluable value, and 99999 was entered instead.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Administration of the first dose of study drug through 28 calendar days after the last administration of study drug

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

PF-05212384 + Irinotecan: Arm A

Reporting group description

PF-05212384 was administered intravenously (IV) every week (Days 2, 9, 16 and 23 of each 28-day cycle) at a starting dose level of 110 mg. During Cycle 1, PF-05212384 was only dosed on Days 9, 16 and 23. After one cycle of dosing with PF-05212384, in subsequent cycles, the dose level remained at 110 mg or was escalated based on the occurrences of dose limiting toxicities (DLTs) in previous cycle and at the discretion of the investigator. Subjects enrolled in Korea remained at the 110 mg starting dose level of PF-05212384. Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m^2. Both the dose levels of PF-05212384 and irinotecan were adjusted according to severity of toxicities. Infusion of PF-05212384 followed irinotecan infusion by at least 24 hours (+/- 10%).

Reporting group title

Cetuximab + Irinotecan: Arm B

Reporting group description

Reporting group title

PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)

Reporting group description

PF-05212384 was administered intravenously (IV) every week (Days 2, 9, 16 and 23 of each 28-day cycle) at a starting dose level of 110 mg. During Cycle 1, PF-05212384 was only dosed on Days 9, 16 and 23. Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m^2. Both the dose levels of PF-05212384 and irinotecan were adjusted according to severity of toxicities. Infusion of PF-05212384 followed irinotecan infusion by at least 24 hours (+/- 10%).

Serious adverse events	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 7 (42.86%)	1 / 6 (16.67%)	1 / 6 (16.67%)
number of deaths (all causes)	0	1	0
number of deaths resulting from adverse events	0	1	0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumothorax
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	PF-05212384 + Irinotecan: Arm A	Cetuximab + Irinotecan: Arm B	PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	7	0	0
Hypotension
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Chest pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Fatigue
subjects affected / exposed	4 / 7 (57.14%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	10	2	1
Influenza like illness
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Malaise
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	0	5
Mucosal inflammation
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Oedema peripheral
subjects affected / exposed	2 / 7 (28.57%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	6	1	1
Pyrexia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	1	0
Dry throat
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Dyspnoea
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0
Epistaxis
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	1	1	1
Hiccups
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Hypoxia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	1
Pulmonary embolism
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Rhinitis allergic
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1
Sinus congestion
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Insomnia
subjects affected / exposed	0 / 7 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	0	2	1
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Haemoglobin decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1
Neutrophil count decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Weight decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Platelet count decreased
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0
Laceration
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Skin abrasion
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Thermal burn
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	2	0
Cardiac disorders
Sinus bradycardia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Tachycardia
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	1	0
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 7 (42.86%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	5	0	0
Dysgeusia
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	1	0
Headache
subjects affected / exposed	3 / 7 (42.86%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	3	1	0
Lethargy
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Neuropathy peripheral
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 7 (28.57%)	3 / 6 (50.00%)	0 / 6 (0.00%)
occurrences all number	8	5	0
Leukopenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	0	2
Neutropenia
subjects affected / exposed	2 / 7 (28.57%)	1 / 6 (16.67%)	3 / 6 (50.00%)
occurrences all number	2	4	6
Eye disorders
Conjunctivitis allergic
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Abdominal distension
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	1	0
Abdominal pain
subjects affected / exposed	3 / 7 (42.86%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0
Abdominal pain lower
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Abdominal pain upper
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Ascites
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	2	0
Colitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Colonic fistula
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Constipation
subjects affected / exposed	3 / 7 (42.86%)	3 / 6 (50.00%)	0 / 6 (0.00%)
occurrences all number	4	4	0
Diarrhoea
subjects affected / exposed	5 / 7 (71.43%)	3 / 6 (50.00%)	3 / 6 (50.00%)
occurrences all number	17	16	3
Dry mouth
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Dyspepsia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Anal incontinence
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Gingival bleeding
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Haemorrhoidal haemorrhage
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	1	0
Haemorrhoids
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Nausea
subjects affected / exposed	6 / 7 (85.71%)	3 / 6 (50.00%)	3 / 6 (50.00%)
occurrences all number	14	4	5
Stomatitis
subjects affected / exposed	5 / 7 (71.43%)	1 / 6 (16.67%)	4 / 6 (66.67%)
occurrences all number	9	1	4
Vomiting
subjects affected / exposed	4 / 7 (57.14%)	1 / 6 (16.67%)	2 / 6 (33.33%)
occurrences all number	6	1	2
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	3 / 7 (42.86%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	3	2	1
Dermatitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1
Dermatitis acneiform
subjects affected / exposed	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	3	0
Dry skin
subjects affected / exposed	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	2	0
Nail disorder
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	3	0
Pruritus
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	0	0
Rash
subjects affected / exposed	2 / 7 (28.57%)	1 / 6 (16.67%)	2 / 6 (33.33%)
occurrences all number	2	1	2
Rash pruritic
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Skin fissures
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1
Pollakiuria
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Renal failure
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Back pain
subjects affected / exposed	3 / 7 (42.86%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	3	1	0
Muscle spasms
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Musculoskeletal chest pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Pain in extremity
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	1
Infections and infestations
Anorectal infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Eye infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1
Paronychia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Rash pustular
subjects affected / exposed	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	3	0
Upper respiratory tract infection
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	1	0
Urinary tract infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	0	1
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	2	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 7 (42.86%)	2 / 6 (33.33%)	3 / 6 (50.00%)
occurrences all number	6	2	5
Dehydration
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	3	1	0
Diabetes mellitus
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Hyperglycaemia
subjects affected / exposed	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0
Hyperuricaemia
subjects affected / exposed	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0
Hypoalbuminaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Hypocalcaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0
Hypomagnesaemia
subjects affected / exposed	1 / 7 (14.29%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	1	6	0
Hypophosphataemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0
Hypokalaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

16 Dec 2013

Objective to observe anti-tumor activity in the Japanese lead in cohort subjects was added; clarification was added to sections regarding acceptable KRAS test methods, in order to more closely match cetuximab drug labeling.

28 Jan 2014

Additional language was added to section 5.2.2 to specify timing between reconstitution of PF-05212384 and infusion.

29 May 2014

Intra-subject PF-05212384 dose escalation was added for subjects who are tolerating treatment at the lower dose levels; revision was made to timing of second biopsy for those subjects enrolled to Arm A.

10 Dec 2014

Rationale for enrollment termination was added, and information regarding handling of ongoing subjects was added; changes to procedures after enrollment termination were added; language was added regarding data handling and analysis after termination of enrollment.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

This study was terminated by sponsor due to strategic reasons and not due to any safety or efficacy concerns with treatment of PF-05212384.

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Clinical trials

Clinical Trial Results: A Randomized Phase 2 Study of PF-05212384 Plus Irinotecan Versus Cetuximab Plus Irinotecan in Patients With KRAS and NRAS Wild Type Metastatic Colorectal Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression Free Survival (PFS) as Assessed by Investigators

Primary: Progression Free Survival (PFS) as Assessed by Investigators

Secondary: Number of Subjects With Unacceptable Toxicity in Cycle 1 (Japanese LIC only)

Secondary: Number of Subjects With Unacceptable Toxicity in Cycle 1 (Japanese LIC only)

Secondary: Number of Subjects With Objective Response

Secondary: Number of Subjects With Objective Response

Secondary: Duration of Response

Secondary: Duration of Response

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) by Common Terminology Criteria for Adverse Events (CTCAE) Grade

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) by Common Terminology Criteria for Adverse Events (CTCAE) Grade

Secondary: Number of Subjects With Laboratory Test (Hematology) Abnormalities

Secondary: Number of Subjects With Laboratory Test (Hematology) Abnormalities

Secondary: Number of Subjects with Laboratory Test (Chemistry) Abnormalities

Secondary: Number of Subjects with Laboratory Test (Chemistry) Abnormalities

Secondary: Number of Subjects With Laboratory Test (Urinalysis) Abnormalities

Secondary: Number of Subjects With Laboratory Test (Urinalysis) Abnormalities

Secondary: Number of Subjects With Laboratory Test (Coagulation) Abnormalities

Secondary: Number of Subjects With Laboratory Test (Coagulation) Abnormalities

Secondary: Number of Subjects With ECG Post-Baseline Maximum Absolute Values Meeting Pre-defined Criteria

Secondary: Number of Subjects With ECG Post-Baseline Maximum Absolute Values Meeting Pre-defined Criteria

Secondary: Number of Subjects With ECG Maximum Increase From Baseline Meeting Pre-defined Criteria

Secondary: Number of Subjects With ECG Maximum Increase From Baseline Meeting Pre-defined Criteria

Secondary: Maximum Plasma Concentration (Cmax) of PF-05212384

Secondary: Maximum Plasma Concentration (Cmax) of PF-05212384

Secondary: Maximum Plasma Concentration (Cmax) of Irinotecan

Secondary: Maximum Plasma Concentration (Cmax) of Irinotecan

Secondary: Maximum Plasma Concentration (Cmax) of SN-38

Secondary: Maximum Plasma Concentration (Cmax) of SN-38

Secondary: Time for maximum plasma concentration (Tmax) of PF-05212384

Secondary: Time for maximum plasma concentration (Tmax) of PF-05212384

Secondary: Time for maximum plasma concentration (Tmax) of Irinotecan

Secondary: Time for maximum plasma concentration (Tmax) of Irinotecan

Secondary: Time for maximum plasma concentration (Tmax) of SN-38

Secondary: Time for maximum plasma concentration (Tmax) of SN-38

Secondary: Terminal Elimination Half Life (t½) of PF-05212384

Secondary: Terminal Elimination Half Life (t½) of PF-05212384

Secondary: Terminal Elimination Half Life (t½) of Irinotecan

Secondary: Terminal Elimination Half Life (t½) of Irinotecan

Secondary: Terminal Elimination Half Life (t½) of SN-38

Secondary: Terminal Elimination Half Life (t½) of SN-38

Secondary: Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of PF-05212384

Secondary: Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of PF-05212384

Secondary: Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of Irinotecan

Secondary: Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of Irinotecan

Secondary: Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of SN-38

Secondary: Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of SN-38

Secondary: Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05212384

Secondary: Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05212384

Secondary: Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Irinotecan

Secondary: Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Irinotecan

Secondary: Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of SN-38

Secondary: Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of SN-38

Secondary: Levels of signaling proteins in paired and single tumor biopsies

Secondary: Levels of signaling proteins in paired and single tumor biopsies

Secondary: Number of Subjects With Expression of Pre-defined Gene Sequences in Biopsied Tumor Tissues

Secondary: Number of Subjects With Expression of Pre-defined Gene Sequences in Biopsied Tumor Tissues

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C)

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Randomized Phase 2 Study of PF-05212384 Plus Irinotecan Versus Cetuximab Plus Irinotecan in Patients With KRAS and NRAS Wild Type Metastatic Colorectal Cancer