A Phase Ib, Open-label, Multicenter Study of the Safety and PK of the Combination of rhuMAb2c4 (Omnitarg), a Recombinant Humanized Antibody to HER2, and Capecitabine (Xeloda) in Patients With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT02494596
• Recruitment Status: Completed
• First Posted: July 10, 2015
• Results First Posted: September 30, 2015
• Last Update Posted: November 10, 2015
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumor
• Interventions: Drug: Capecitabine; Drug: RhuMab 2C4
• Enrollment: 19

Participant Flow

Recruitment Details
Pre-assignment Details	Participants were grouped into three cohorts and received either 825 mg, 1000 mg or 1250 mg capecitabine to determine the maximum tolerated dose.

Arm/Group Title	Capecitabine 825 Plus (+) Pertuzumab 1050	Capecitabine 1000 + Pertuzumab 1050	Capecitabine 1250 + Pertuzumab 1050
Arm/Group Description	Participants received a single dose of capecitabine 825 milligrams per square meter (mg/m^2) orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg intravenous (IV) infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1000 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Period Title: Overall Study
Started	5	7	7
Completed	2	2	6
Not Completed	3	5	1
Reason Not Completed
Insufficient Therapeutic Response	3	3	1
Adverse Event	0	1	0
Refused Treatment	0	1	0

Baseline Characteristics

Arm/Group Title		Capecitabine + Pertuzumab
Arm/Group Description		Participants received a single dose of capecitabine either 825, 1000 or 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Baseline Participants		18
Baseline Analysis Population Description		The Intent-To-Treat (ITT) Population included all participants who received any amount of the study medication. The baseline analysis population represents participants from all three cohorts.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	18 participants
		60.9 (9.10)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	18 participants
	Female	11 61.1%
	Male	7 38.9%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of the Combination of Pertuzumab and Capecitabine
Description	MTD was defined as the highest tolerated dose combination of capecitabine (825 mg, 1000 mg or 1250 mg) and pertuzumab, without causing Dose Limiting Toxicities (DLTs). DLTs were defined as follows: 1) Any non-hematological toxicity greater than or equal to (≥) Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 except for fever, chills and flu-like symptoms, in spite of adequate toxicity management; 2) Grade 4 neutropenia lasting > 7 days; 3) Febrile neutropenia; 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion; 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds. Participants who withdrew from the study without completing the first treatment cycle for reasons other than DLT were not considered evaluable for DLT. MTD was measured in mg/m^2.
Time Frame	Cycle 1 (3 Weeks)

Outcome Measure Data

Analysis Population Description

The Safety Population included all participants who received any amount of study medication and who had at least one post-baseline safety follow-up.

Arm/Group Title	Capecitabine + Pertuzumab
Arm/Group Description:	Participants received a single dose of capecitabine either 825,1000 or 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	18
Measure Type: Number; Unit of Measure: mg/m^2
	1250

2. Secondary Outcome

Title	Percentage of Participants With DLTs
Description	DLTs were defined as follows: 1)Any non-hematological toxicity greater than or equal to (≥) Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 except for fever, chills and flu-like symptoms, in spite of adequate toxicity management; 2) Grade 4 neutropenia lasting > 7 days; 3) Febrile neutropenia; 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion; 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds. Participants who withdrew from the study without completing the first treatment cycle for reasons other than DLT were not considered evaluable for DLT.
Time Frame	Cycle 1 (3 Weeks)

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Capecitabine 825 Plus (+) Pertuzumab 1050	Capecitabine 1000 + Pertuzumab 1050	Capecitabine 1250 + Pertuzumab 1050
Arm/Group Description:	Participants received a single dose of capecitabine 825 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg intravenous (IV) infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1000 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	5	6	7
Measure Type: Number; Unit of Measure: percentage of participants
	0.0	0.0	0.0

3. Secondary Outcome

Title	Plasma Half-Life (t1/2) of Pertuzumab
Description	The biological half-life or terminal half-life of pertuzumab is the time in days it takes for it to lose half of its pharmacologic activity. t1/2 was measured in days.
Time Frame	Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and Predose on Days 8, 15 and 22

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Capecitabine + Pertuzumab
Arm/Group Description:	Participants received a single dose of capecitabine either 825, 1000 or 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	18
Mean (Standard Deviation); Unit of Measure: days
	14.6 (41.0)

4. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Pertuzumab
Description	Cmax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose and was measured as nanograms per milliliter (ng/mL).
Time Frame	Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Capecitabine + Pertuzumab
Arm/Group Description:	Participants received a single dose of capecitabine either 825,1000 or 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	18
Mean (Standard Deviation); Unit of Measure: ng/mL
	355111 (59051)

5. Secondary Outcome

Title	Time to Maximum Plasma Concentration (Tmax) of Pertuzumab
Description	Tmax is defined as the time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination. Tmax was measured in days.
Time Frame	Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Capecitabine + Pertuzumab
Arm/Group Description:	Participants received a single dose of capecitabine either 825, 1000 or 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	18
Mean (Standard Deviation); Unit of Measure: days
	0.137 (0.076)

6. Secondary Outcome

Title	Area Under the Concentration Curve From Time Zero to Last Measurement (AUC 0-last) of Pertuzumab
Description	The area under the plot of plasma concentration of drug against time after drug administration is defined as the area under the curve (AUC). The AUC0-last is calculated from time 0 (prior to administration of medication) to last measured data point. The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUC was measured as ng*day/mL.
Time Frame	Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Capecitabine + Pertuzumab
Arm/Group Description:	Participants received a single dose of capecitabine either 825,1000 or 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	18
Mean (Standard Deviation); Unit of Measure: ng*day/mL
	2742561 (743598)

7. Secondary Outcome

Title	AUC From Time Zero to Infinity (AUC 0-infinity) of Pertuzumab
Description	The AUC0-infinity is calculated from time 0 (prior to administration of medication) to infinity (the time of complete elimination of the drug). The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUC is measured as nanograms times days per milliliter (ng*day/mL).
Time Frame	Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Capecitabine + Pertuzumab
Arm/Group Description:	Participants received a single dose of capecitabine either 825,1000 or 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	18
Mean (Standard Deviation); Unit of Measure: ng*day/mL
	4096501 (1282130)

8. Secondary Outcome

Title	Apparent Volume of Distribution of Pertuzumab
Description	The volume of distribution at steady state (Vss), also known as apparent volume of distribution, is a pharmacological, theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. Vss was measured in mL
Time Frame	Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Capecitabine + Pertuzumab
Arm/Group Description:	Participants received a single dose of capecitabine either 825,1000 or 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	18
Mean (Standard Deviation); Unit of Measure: mL
	5202 (1007)

9. Secondary Outcome

Title	Apparent Total Clearance of Pertuzumab
Description	Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). It is measured as milliliters per day (mL/day).
Time Frame	Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Capecitabine + Pertuzumab
Arm/Group Description:	Participants received a single dose of capecitabine either 825,1000 or 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	18
Mean (Standard Deviation); Unit of Measure: mL/day
	283.0 (98.0)

10. Secondary Outcome

Title	Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab
Description	Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and α-fluoro-β-alanine (FBAL). The biological half-life or terminal half-life is the time in days it takes for it to lose half of its pharmacologic activity.
Time Frame	Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Capecitabine 825 + Pertuzumab 1050	Capecitabine 1000 + Pertuzumab 1050	Capecitabine 1250 + Pertuzumab 1050
Arm/Group Description:	Participants received a single dose of capecitabine 825 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg intravenous (IV) infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1000 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	5	6	7
Mean (Standard Deviation); Unit of Measure: hours
Capecitabine Alone 5'-DFCR	0.89 (0.27)	0.82 (0.28)	0.82 (0.23)
Capecitabine Alone 5'-DFUR	0.75 (0.26)	0.76 (0.23)	0.66 (0.09)
Capecitabine Alone 5-FU	0.67 (0.22)	0.64 (0.13)	0.70 (0.16)
Capecitabine Alone Capecitabine	0.54 (0.19)	0.40 (0.10)	0.36 (0.11)
Capecitabine Alone FBAL	2.54 (0.30)	2.69 (0.39)	3.08 (0.78)
Capecitabine + Pertuzumab 5'-DFCR	0.78 (0.38)	0.76 (0.18)	0.75 (0.14)
Capecitabine + Pertuzumab 5'-DFUR	0.62 (0.13)	0.73 (0.21)	0.79 (0.28)
Capecitabine + Pertuzumab 5-FU	0.73 (0.40)	0.67 (0.14)	0.80 (0.35)
Capecitabine + Pertuzumab Capecitabine	0.42 (0.14)	0.62 (0.28)	0.54 (0.28)
Capecitabine + Pertuzumab FBAL	2.59 (0.64)	2.58 (0.57)	2.81 (0.44)

11. Secondary Outcome

Title	Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab
Description	Capecitabine is an oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety 5-FU in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-DFCR, 5'-DFUR, and FBAL. Cmax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose and is measures as nanograms per milliliter (ng/mL).
Time Frame	Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Capecitabine 825 + Pertuzumab 1050	Capecitabine 1000 + Pertuzumab 1050	Capecitabine 1250 + Pertuzumab 1050
Arm/Group Description:	Participants received a single dose of capecitabine 825 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg intravenous (IV) infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1000 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	5	6	7
Mean (Standard Deviation); Unit of Measure: ng/mL
Capecitabine Alone 5'-DFCR	4508 (2317)	7687 (1443)	8647 (3254)
Capecitabine Alone 5'-DFUR	5274 (1832)	7657 (2708)	10311 (3323)
Capecitabine Alone 5-FU	201 (94)	355 (119)	369 (107)
Capecitabine Alone Capecitabine	4802 (3159)	9112 (6189)	7543 (2944)
Capecitabine Alone FBAL	3214 (396)	3963 (947)	5290 (576)
Capecitabine + Pertuzumab 5'-DFCR	4909 (2518)	3917 (1411)	6569 (2827)
Capecitabine + Pertuzumab 5'-DFUR	5736 (1831)	4103 (1595)	8683 (4142)
Capecitabine + Pertuzumab 5-FU	219 (106)	187 (92)	345 (214)
Capecitabine + Pertuzumab Capecitabine	8060 (4800)	3367 (1741)	4731 (3198)
Capecitabine + Pertuzumab FBAL	3674 (1121)	3498 (809)	5136 (843)

12. Secondary Outcome

Title	Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab
Description	Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and α-fluoro-β-alanine (FBAL). Tmax is defined as the time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination.
Time Frame	Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Capecitabine 825 + Pertuzumab 1050	Capecitabine 1000 + Pertuzumab 1050	Capecitabine 1250 + Pertuzumab 1050
Arm/Group Description:	Participants received a single dose of capecitabine 825 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg intravenous (IV) infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1000 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	5	6	7
Mean (Standard Deviation); Unit of Measure: hours
Capecitabine Alone 5'-DFCR	1.3 (0.66)	0.82 (0.26)	1.05 (0.51)
Capecitabine Alone 5'-DFUR	1.3 (0.66)	0.76 (0.49)	1.05 (0.51)
Capecitabine Alone 5-FU	1.3 (0.66)	0.64 (0.49)	1.05 (0.51)
Capecitabine Alone Capecitabine	1.2 (0.75)	0.4 (0.28)	0.77 (0.35)
Capecitabine Alone FBAL	2.4 (0.55)	2.69 (0.41)	2.21 (0.40)
Capecitabine + Pertuzumab 5'-DFCR	0.9 (0.65)	1.42 (0.66)	1.86 (1.32)
Capecitabine + Pertuzumab 5'-DFUR	1.0 (0.61)	2.0 (1.10)	1.86 (1.32)
Capecitabine + Pertuzumab 5-FU	0.9 (0.65)	1.84 (1.17)	1.93 (1.24)
Capecitabine + Pertuzumab Capecitabine	0.7 (0.28)	1.17 (0.40)	1.15 (0.62)
Capecitabine + Pertuzumab FBAL	2.6 (0.90)	3.16 (1.17)	2.50 (1.39)

Adverse Events

Time Frame	Adverse events were recorded continuously from Day -7 until 4 weeks after the final visit.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Capecitabine 825 + Pertuzumab 1050	Capecitabine 1000 + Pertuzumab 1050	Capecitabine 1250 + Pertuzumab 1050
Arm/Group Description	Participants received a single dose of capecitabine 825 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1000 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.	Participants received a single dose of capecitabine 1250 mg/m^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent.
All-Cause Mortality
	Capecitabine 825 + Pertuzumab 1050	Capecitabine 1000 + Pertuzumab 1050	Capecitabine 1250 + Pertuzumab 1050
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Capecitabine 825 + Pertuzumab 1050	Capecitabine 1000 + Pertuzumab 1050	Capecitabine 1250 + Pertuzumab 1050
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/5 (0.00%)	1/6 (16.67%)	1/7 (14.29%)
Gastrointestinal disorders
Intestinal Obstruction * 1	0/5 (0.00%)	1/6 (16.67%)	0/7 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (7.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Capecitabine 825 + Pertuzumab 1050	Capecitabine 1000 + Pertuzumab 1050	Capecitabine 1250 + Pertuzumab 1050
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	5/5 (100.00%)	6/6 (100.00%)	7/7 (100.00%)
Eye disorders
Keratoconjunctivitis sicca * 1	0/5 (0.00%)	0/6 (0.00%)	4/7 (57.14%)
Gastrointestinal disorders
Diarrhoea * 1	3/5 (60.00%)	3/6 (50.00%)	7/7 (100.00%)
Nausea * 1	4/5 (80.00%)	4/6 (66.67%)	4/7 (57.14%)
Vomiting * 1	2/5 (40.00%)	3/6 (50.00%)	2/7 (28.57%)
Abdominal pain upper * 1	0/5 (0.00%)	2/6 (33.33%)	2/7 (28.57%)
Constipation * 1	0/5 (0.00%)	0/6 (0.00%)	3/7 (42.86%)
Haemorrhoids * 1	1/5 (20.00%)	0/6 (0.00%)	1/7 (14.29%)
Abdominal distension * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Cheilitis * 1	0/5 (0.00%)	1/6 (16.67%)	0/7 (0.00%)
Dyspepsia * 1	0/5 (0.00%)	1/6 (16.67%)	0/7 (0.00%)
Flatulence * 1	0/5 (0.00%)	1/6 (16.67%)	0/7 (0.00%)
Glossitis * 1	0/5 (0.00%)	1/6 (16.67%)	0/7 (0.00%)
Lip dry * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Odynophagia * 1	0/5 (0.00%)	1/6 (16.67%)	0/7 (0.00%)
Oral pain * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Stomatitis * 1	0/5 (0.00%)	1/6 (16.67%)	0/7 (0.00%)
Toothache * 1	1/5 (20.00%)	0/6 (0.00%)	0/7 (0.00%)
General disorders
Asthenia * 1	1/5 (20.00%)	3/6 (50.00%)	4/7 (57.14%)
Mucosal inflammation * 1	0/5 (0.00%)	2/6 (33.33%)	4/7 (57.14%)
Pyrexia * 1	0/5 (0.00%)	2/6 (33.33%)	2/7 (28.57%)
Oedema Peripheral * 1	2/5 (40.00%)	0/6 (0.00%)	0/7 (0.00%)
Catheter site pain * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Chest pain * 1	1/5 (20.00%)	0/6 (0.00%)	0/7 (0.00%)
Chills * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Feeling hot * 1	1/5 (20.00%)	0/6 (0.00%)	0/7 (0.00%)
Infections and infestations
Influenza * 1	2/5 (40.00%)	0/6 (0.00%)	1/7 (14.29%)
Herpes simplex * 1	0/5 (0.00%)	0/6 (0.00%)	2/7 (28.57%)
Rhinitis * 1	0/5 (0.00%)	0/6 (0.00%)	2/7 (28.57%)
Upper respiratory tract infection * 1	0/5 (0.00%)	1/6 (16.67%)	0/7 (0.00%)
Investigations
Blood bilirubin increased * 1	1/5 (20.00%)	1/6 (16.67%)	0/7 (0.00%)
Haematocrit decreased * 1	1/5 (20.00%)	1/6 (16.67%)	0/7 (0.00%)
Metabolism and nutrition disorders
Anorexia * 1	2/5 (40.00%)	3/6 (50.00%)	4/7 (57.14%)
Decreased appetite * 1	1/5 (20.00%)	1/6 (16.67%)	1/7 (14.29%)
Musculoskeletal and connective tissue disorders
Ligament disorder * 1	1/5 (20.00%)	0/6 (0.00%)	1/7 (14.29%)
Arthralgia * 1	1/5 (20.00%)	0/6 (0.00%)	0/7 (0.00%)
Joint swelling * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Pain in extremity * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Nervous system disorders
Lethargy * 1	2/5 (40.00%)	2/6 (33.33%)	2/7 (28.57%)
Dizziness * 1	0/5 (0.00%)	0/6 (0.00%)	2/7 (28.57%)
Dysgeusia * 1	1/5 (20.00%)	0/6 (0.00%)	0/7 (0.00%)
Paraesthesia * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Psychiatric disorders
Insomnia * 1	0/5 (0.00%)	0/6 (0.00%)	3/7 (42.86%)
Depressed mood * 1	1/5 (20.00%)	1/6 (16.67%)	0/7 (0.00%)
Anxiety * 1	1/5 (20.00%)	0/6 (0.00%)	0/7 (0.00%)
Confusional state * 1	1/5 (20.00%)	0/6 (0.00%)	0/7 (0.00%)
Renal and urinary disorders
Dysuria * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Micturition disorder * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Pollakiuria * 1	1/5 (20.00%)	0/6 (0.00%)	0/7 (0.00%)
Reproductive system and breast disorders
Metrorrhagia * 1	1/5 (20.00%)	0/6 (0.00%)	1/7 (14.29%)
Pelvic pain * 1	1/5 (20.00%)	0/6 (0.00%)	0/7 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	1/5 (20.00%)	1/6 (16.67%)	0/7 (0.00%)
Pleuritic pain * 1	0/5 (0.00%)	2/6 (33.33%)	0/7 (0.00%)
Productive cough * 1	0/5 (0.00%)	1/6 (16.67%)	1/7 (14.29%)
Dyspnoea * 1	1/5 (20.00%)	0/6 (0.00%)	0/7 (0.00%)
Epistaxis * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Rhinorrhoea * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Skin and subcutaneous tissue disorders
Skin reaction * 1	2/5 (40.00%)	0/6 (0.00%)	2/7 (28.57%)
Erythema * 1	1/5 (20.00%)	1/6 (16.67%)	1/7 (14.29%)
Palmar-plantar erythrodysaesthesia syndrome * 1	0/5 (0.00%)	0/6 (0.00%)	3/7 (42.86%)
Rash * 1	0/5 (0.00%)	1/6 (16.67%)	1/7 (14.29%)
Blister * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Pruritus * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
Vascular disorders
Hypotension * 1	0/5 (0.00%)	1/6 (16.67%)	1/7 (14.29%)
Haemorrhage * 1	0/5 (0.00%)	0/6 (0.00%)	1/7 (14.29%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (7.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffmann-La Roche
• Phone: 800-821-8590
• EMail: genentech@druginfo.com

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02494596
• Other Study ID Numbers: BO17003
• First Submitted: July 8, 2015
• First Posted: July 10, 2015
• Results First Submitted: July 30, 2015
• Results First Posted: September 30, 2015
• Last Update Posted: November 10, 2015