A Study of Herceptin (Trastuzumab) in Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Advanced and/or Metastatic Breast Cancer

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02748213
• Collaborator: (none)
• Enrollment: 225
• Locations: 51
• Arms: 2
• Duration (Months): 71
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will assess the efficacy and safety of intravenous (IV) trastuzumab (Herceptin) and IV docetaxel (Taxotere), with or without oral capecitabine (Xeloda), in women with previously untreated HER2-positive advanced and/or metastatic breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Xeloda; Drug: Taxotere; Drug: Herceptin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 225 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Randomized Phase II Study of Herceptin (Trastuzumab), Taxotere (Docetaxel), and Xeloda (Capecitabine) in Combination, Versus Herceptin (Trastuzumab) Plus Taxotere (Docetaxel), in Patients With Advanced and/or Metastatic Breast Cancers That Overexpress HER2
• Study Start Date: Feb 1, 2002
• Actual Primary Completion Date: Mar 1, 2006
• Actual Study Completion Date: Jan 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Herceptin + Taxotere Participants will receive dual therapy with Herceptin and Taxotere until disease progression, unmanageable toxicity, or withdrawal.	Drug: Taxotere; Participants will receive Taxotere, 75 milligrams per meter-squared (mg/m^2) in the Herceptin + Taxotere + Xeloda arm or 100 mg/m^2 in the Herceptin + Taxotere arm, via IV infusion on Day 1 of each 21-day cycle. The lower starting dose will be used in the triple-therapy arm.; Other Names: docetaxel ; Drug: Herceptin; Participants will receive Herceptin, 6 milligrams per kilogram (mg/kg) via IV infusion, on Day 1 of each 21-day cycle. The first dose will be a loading dose of 8 mg/kg in Cycle 1; the dose of 6 mg/kg will be given from Cycle 2 onward.; Other Names: trastuzumab
Experimental: Herceptin + Taxotere + Xeloda Participants will receive triple therapy with Herceptin, Taxotere, and Xeloda until disease progression, unmanageable toxicity, or withdrawal.	Drug: Xeloda; Participants will receive oral Xeloda, 950 mg/m^2 twice a day on Days 1 to 14 of each 21-day cycle.; Other Names: capecitabine ; Drug: Taxotere; Participants will receive Taxotere, 75 milligrams per meter-squared (mg/m^2) in the Herceptin + Taxotere + Xeloda arm or 100 mg/m^2 in the Herceptin + Taxotere arm, via IV infusion on Day 1 of each 21-day cycle. The lower starting dose will be used in the triple-therapy arm.; Other Names: docetaxel ; Drug: Herceptin; Participants will receive Herceptin, 6 milligrams per kilogram (mg/kg) via IV infusion, on Day 1 of each 21-day cycle. The first dose will be a loading dose of 8 mg/kg in Cycle 1; the dose of 6 mg/kg will be given from Cycle 2 onward.; Other Names: trastuzumab

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) [Tumor assessments at Baseline, then every 6 weeks until Cycle 8 (cycle length of 21 days), then every 12 weeks until progressive disease and/or one year after enrollment; thereafter according to routine clinical practice (up to 66 months overall)]

   Tumor response was assessed by RECIST during the study. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels. PR was defined as greater than or equal to (≥) 30 percent (%) decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR. The percentage of participants with a best overall response for CR or PR was reported. The exact 95% confidence interval (CI) for one-sample binomial was determined using the Pearson-Clopper method.

Secondary Outcome Measures

1. Percentage of Participants With Death or Disease Progression According to RECIST [Tumor assessments at Baseline, then every 6 weeks until Cycle 8 (cycle length of 21 days), then every 12 weeks until progressive disease and/or one year after enrollment; thereafter according to routine clinical practice (up to 66 months overall)]

   Tumor response was assessed by RECIST during the study. Disease progression or progressive disease (PD) was defined as ≥20% increase in sum LD in reference to the smallest on-treatment sum LD, or the appearance of new lesions. The percentage of participants who died or experienced PD was reported.

2. Progression-Free Survival (PFS) According to RECIST [Tumor assessments at Baseline, then every 6 weeks until Cycle 8 (cycle length of 21 days), then every 12 weeks until progressive disease and/or one year after enrollment; thereafter according to routine clinical practice (up to 66 months overall)]

   Tumor response was assessed by RECIST during the study. Disease progression or PD was defined as ≥20% increase in sum LD in reference to the smallest on-treatment sum LD, or the appearance of new lesions. PFS was defined as the time from start of treatment to the first event of death or PD. Participants without event at the time of analysis were censored at the latest date of last tumor assessment or last date in drug log. The median duration of PFS and corresponding 95% CI were estimated by Kaplan-Meier analysis and expressed in months.

3. Percentage of Participants Who Died [Continuously during treatment (up to 66 months) and at any time after treatment discontinuation until 18 months after last participant enrolled (up to 66 months overall)]

   The percentage of participants who died from any cause was reported.

4. Overall Survival (OS) [Continuously during treatment (up to 66 months) and at any time after treatment discontinuation until 18 months after last participant enrolled (up to 66 months overall)]

   OS was defined as the time from start of treatment to date of death for any reason. Participants who were alive at the time of analysis were censored at the latest date of last tumor assessment, last drug intake, or last follow-up information. The median duration of OS and corresponding 95% CI were estimated by Kaplan-Meier analysis and expressed in months.

5. Duration of Response (DOR) According to RECIST [Tumor assessments at Baseline, then every 6 weeks until Cycle 8 (cycle length of 21 days), then every 12 weeks until progressive disease and/or one year after enrollment; thereafter according to routine clinical practice (up to 66 months overall)]

   Tumor response was assessed by RECIST during the study. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels. PR was defined as ≥30% decrease in sum LD of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR. DOR was defined as the time from first assessment of CR or PR until the first occurrence of documented PD, death, or withdrawal. The median DOR was reported and expressed in months.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed, HER2-positive advanced and/or metastatic breast cancer not amenable to curative therapy

• At least one measurable lesion according to RECIST

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Baseline left ventricular ejection fraction (LVEF) at least 50%

Exclusion Criteria:

• Pregnant, lactating, or women of childbearing potential who are not surgically sterile or not willing to use adequate contraceptive methods

• Previous treatment with Herceptin or other anti-HER therapies, or any previous chemotherapy for advanced or metastatic disease

• Past medical history significant for any cardiac or central nervous system (CNS) disorders

• Poor hematologic, renal, or hepatic function

• Chronic corticosteroid therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Adelaide		Australia	5011
2		Brisbane		Australia	4066
3		Camperdown		Australia	2050
4		Geelong		Australia	3220
5		Melbourne		Australia	3002
6		Melbourne		Australia	3181
7		Perth		Australia	6000
8		Southport		Australia	4215
9		Porto Alegre		Brazil	91350-200
10		Rio de Janeiro		Brazil	20560-120
11		Sao Paulo		Brazil	01401-901
12		Calgary	Alberta	Canada	T2N 4N2
13		Ottawa	Ontario	Canada	K1H 8L6
14		Quebec		Canada	G1S 4L8
15		San Jose		Costa Rica	10103
16		Turku		Finland	20520
17		Besancon		France	25030
18		Grenoble		France	38000
19		Marseille		France	13273
20		Paris		France	75231
21		Pierre Benite		France	69310
22		Rennes		France	35042
23		Athens		Greece	11526
24		Heraklion		Greece	71110
25		Patras		Greece	26500
26		Guatemala City		Guatemala	01010
27		Legnago		Italy	37045
28		Noale		Italy	30033
29		Rozzano		Italy	20089
30		Trento		Italy	38100
31		Treviglio		Italy	24047
32		Distrito Federal		Mexico	14080
33		Merida		Mexico	97500
34		Monterrey		Mexico	64020
35		Monterrey		Mexico	64060
36		Panama City		Panama	0
37		Gdansk		Poland	80-214
38		Szczecin		Poland	71-730
39		Barcelona		Spain	08035
40		Lerida		Spain	25198
41		Sabadell, Barcelona		Spain	08208
42		Zaragoza		Spain	50009
43		Karlstad		Sweden	65185
44		Västerås		Sweden	72189
45		Ipswich		United Kingdom	IP4 5PD
46		Leeds		United Kingdom	LS9 7TF
47		Manchester		United Kingdom	M20 4BX
48		Northwood		United Kingdom	HA6 2RN
49		Oxford		United Kingdom	OX3 7LJ
50		Southampton		United Kingdom	SO16 6YD
51		Weston Super Mare		United Kingdom	BS23 4TQ

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Chair: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02748213
• Other Study ID Numbers: MO16419
• First Posted: Apr 22, 2016
• Last Update Posted: Nov 22, 2016
• Last Verified: Sep 1, 2016

• Additional relevant MeSH terms: Breast Neoplasms; Docetaxel; Capecitabine; Trastuzumab

Study Results

Participant Flow

Arm/Group Title	Herceptin + Taxotere + Xeloda	Herceptin + Taxotere
Arm/Group Description	Participants received triple therapy with Herceptin, Taxotere, and Xeloda until disease progression, unmanageable toxicity, or withdrawal. Herceptin and Taxotere were given via intravenous (IV) infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 milligrams per kilogram (mg/kg) in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 75 milligrams per meter-squared (mg/m^2), with adjustments allowed only for toxicity. Xeloda was given orally as 950 mg/m^2 twice a day on Days 1 to 14 of each 21-day cycle, with adjustments allowed only for toxicity.	Participants received dual therapy with Herceptin and Taxotere until disease progression, unmanageable toxicity, or withdrawal. Treatments were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 100 mg/m^2, with adjustments allowed only for toxicity.
Period Title: Overall Study
STARTED	113	112
Treated	112	110
COMPLETED	0	0
NOT COMPLETED	113	112

Baseline Characteristics

Arm/Group Title	Herceptin + Taxotere + Xeloda	Herceptin + Taxotere	Total
Arm/Group Description	Participants received triple therapy with Herceptin, Taxotere, and Xeloda until disease progression, unmanageable toxicity, or withdrawal. Herceptin and Taxotere were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 75 mg/m^2, with adjustments allowed only for toxicity. Xeloda was given orally as 950 mg/m^2 twice a day on Days 1 to 14 of each 21-day cycle, with adjustments allowed only for toxicity.	Participants received dual therapy with Herceptin and Taxotere until disease progression, unmanageable toxicity, or withdrawal. Treatments were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 100 mg/m^2, with adjustments allowed only for toxicity.	Total of all reporting groups
Overall Participants	112	110	222
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.7 (11.18)	51.6 (10.74)	52.1 (10.95)
Sex: Female, Male (Count of Participants)
Female	112 100%	110 100%	222 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST)
Description	Tumor response was assessed by RECIST during the study. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels. PR was defined as greater than or equal to (≥) 30 percent (%) decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR. The percentage of participants with a best overall response for CR or PR was reported. The exact 95% confidence interval (CI) for one-sample binomial was determined using the Pearson-Clopper method.
Time Frame	Tumor assessments at Baseline, then every 6 weeks until Cycle 8 (cycle length of 21 days), then every 12 weeks until progressive disease and/or one year after enrollment; thereafter according to routine clinical practice (up to 66 months overall)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) Population.

Arm/Group Title	Herceptin + Taxotere + Xeloda	Herceptin + Taxotere
Arm/Group Description	Participants received triple therapy with Herceptin, Taxotere, and Xeloda until disease progression, unmanageable toxicity, or withdrawal. Herceptin and Taxotere were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 75 mg/m^2, with adjustments allowed only for toxicity. Xeloda was given orally as 950 mg/m^2 twice a day on Days 1 to 14 of each 21-day cycle, with adjustments allowed only for toxicity.	Participants received dual therapy with Herceptin and Taxotere until disease progression, unmanageable toxicity, or withdrawal. Treatments were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 100 mg/m^2, with adjustments allowed only for toxicity.
Measure Participants	112	110
Number (95% Confidence Interval) [percentage of participants]	70.5 62.9%	72.7 66.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin + Taxotere + Xeloda, Herceptin + Taxotere
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.717
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in Response Rates
	Estimated Value	2.2
	Confidence Interval	(2-Sided) 95%; -10.17 to 14.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	The approximate 95% CI for the difference in response (CR or PR) rates was determined using the Hauck-Anderson correction.

2. Secondary Outcome

Title	Percentage of Participants With Death or Disease Progression According to RECIST
Description	Tumor response was assessed by RECIST during the study. Disease progression or progressive disease (PD) was defined as ≥20% increase in sum LD in reference to the smallest on-treatment sum LD, or the appearance of new lesions. The percentage of participants who died or experienced PD was reported.
Time Frame	Tumor assessments at Baseline, then every 6 weeks until Cycle 8 (cycle length of 21 days), then every 12 weeks until progressive disease and/or one year after enrollment; thereafter according to routine clinical practice (up to 66 months overall)

Outcome Measure Data

Analysis Population Description

FAS Population.

Arm/Group Title	Herceptin + Taxotere + Xeloda	Herceptin + Taxotere
Arm/Group Description	Participants received triple therapy with Herceptin, Taxotere, and Xeloda until disease progression, unmanageable toxicity, or withdrawal. Herceptin and Taxotere were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 75 mg/m^2, with adjustments allowed only for toxicity. Xeloda was given orally as 950 mg/m^2 twice a day on Days 1 to 14 of each 21-day cycle, with adjustments allowed only for toxicity.	Participants received dual therapy with Herceptin and Taxotere until disease progression, unmanageable toxicity, or withdrawal. Treatments were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 100 mg/m^2, with adjustments allowed only for toxicity.
Measure Participants	112	110
Number [percentage of participants]	67.9 60.6%	77.3 70.3%

3. Secondary Outcome

Title	Progression-Free Survival (PFS) According to RECIST
Description	Tumor response was assessed by RECIST during the study. Disease progression or PD was defined as ≥20% increase in sum LD in reference to the smallest on-treatment sum LD, or the appearance of new lesions. PFS was defined as the time from start of treatment to the first event of death or PD. Participants without event at the time of analysis were censored at the latest date of last tumor assessment or last date in drug log. The median duration of PFS and corresponding 95% CI were estimated by Kaplan-Meier analysis and expressed in months.
Time Frame	Tumor assessments at Baseline, then every 6 weeks until Cycle 8 (cycle length of 21 days), then every 12 weeks until progressive disease and/or one year after enrollment; thereafter according to routine clinical practice (up to 66 months overall)

Outcome Measure Data

Analysis Population Description

FAS Population.

Arm/Group Title	Herceptin + Taxotere + Xeloda	Herceptin + Taxotere
Arm/Group Description	Participants received triple therapy with Herceptin, Taxotere, and Xeloda until disease progression, unmanageable toxicity, or withdrawal. Herceptin and Taxotere were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 75 mg/m^2, with adjustments allowed only for toxicity. Xeloda was given orally as 950 mg/m^2 twice a day on Days 1 to 14 of each 21-day cycle, with adjustments allowed only for toxicity.	Participants received dual therapy with Herceptin and Taxotere until disease progression, unmanageable toxicity, or withdrawal. Treatments were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 100 mg/m^2, with adjustments allowed only for toxicity.
Measure Participants	112	110
Median (95% Confidence Interval) [months]	17.9	12.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin + Taxotere + Xeloda, Herceptin + Taxotere
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0449
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio (HR) calculated using Herceptin + Taxotere arm as reference.

4. Secondary Outcome

Title	Percentage of Participants Who Died
Description	The percentage of participants who died from any cause was reported.
Time Frame	Continuously during treatment (up to 66 months) and at any time after treatment discontinuation until 18 months after last participant enrolled (up to 66 months overall)

Outcome Measure Data

Analysis Population Description

FAS Population.

Arm/Group Title	Herceptin + Taxotere + Xeloda	Herceptin + Taxotere
Arm/Group Description	Participants received triple therapy with Herceptin, Taxotere, and Xeloda until disease progression, unmanageable toxicity, or withdrawal. Herceptin and Taxotere were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 75 mg/m^2, with adjustments allowed only for toxicity. Xeloda was given orally as 950 mg/m^2 twice a day on Days 1 to 14 of each 21-day cycle, with adjustments allowed only for toxicity.	Participants received dual therapy with Herceptin and Taxotere until disease progression, unmanageable toxicity, or withdrawal. Treatments were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 100 mg/m^2, with adjustments allowed only for toxicity.
Measure Participants	112	110
Number [percentage of participants]	35.7 31.9%	41.8 38%

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from start of treatment to date of death for any reason. Participants who were alive at the time of analysis were censored at the latest date of last tumor assessment, last drug intake, or last follow-up information. The median duration of OS and corresponding 95% CI were estimated by Kaplan-Meier analysis and expressed in months.
Time Frame	Continuously during treatment (up to 66 months) and at any time after treatment discontinuation until 18 months after last participant enrolled (up to 66 months overall)

Outcome Measure Data

Analysis Population Description

FAS Population.

Arm/Group Title	Herceptin + Taxotere + Xeloda	Herceptin + Taxotere
Arm/Group Description	Participants received triple therapy with Herceptin, Taxotere, and Xeloda until disease progression, unmanageable toxicity, or withdrawal. Herceptin and Taxotere were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 75 mg/m^2, with adjustments allowed only for toxicity. Xeloda was given orally as 950 mg/m^2 twice a day on Days 1 to 14 of each 21-day cycle, with adjustments allowed only for toxicity.	Participants received dual therapy with Herceptin and Taxotere until disease progression, unmanageable toxicity, or withdrawal. Treatments were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 100 mg/m^2, with adjustments allowed only for toxicity.
Measure Participants	112	110
Median (95% Confidence Interval) [months]	43.5	47.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin + Taxotere + Xeloda, Herceptin + Taxotere
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4758
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR calculated using Herceptin + Taxotere arm as reference.

6. Secondary Outcome

Title	Duration of Response (DOR) According to RECIST
Description	Tumor response was assessed by RECIST during the study. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels. PR was defined as ≥30% decrease in sum LD of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR. DOR was defined as the time from first assessment of CR or PR until the first occurrence of documented PD, death, or withdrawal. The median DOR was reported and expressed in months.
Time Frame	Tumor assessments at Baseline, then every 6 weeks until Cycle 8 (cycle length of 21 days), then every 12 weeks until progressive disease and/or one year after enrollment; thereafter according to routine clinical practice (up to 66 months overall)

Outcome Measure Data

Analysis Population Description

FAS Population. The "Number of Participants Analyzed" reflects the number of participants with a best overall response of CR or PR who provided evaluable data for the analysis.

Arm/Group Title	Herceptin + Taxotere + Xeloda	Herceptin + Taxotere
Arm/Group Description	Participants received triple therapy with Herceptin, Taxotere, and Xeloda until disease progression, unmanageable toxicity, or withdrawal. Herceptin and Taxotere were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 75 mg/m^2, with adjustments allowed only for toxicity. Xeloda was given orally as 950 mg/m^2 twice a day on Days 1 to 14 of each 21-day cycle, with adjustments allowed only for toxicity.	Participants received dual therapy with Herceptin and Taxotere until disease progression, unmanageable toxicity, or withdrawal. Treatments were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 100 mg/m^2, with adjustments allowed only for toxicity.
Measure Participants	78	80
Median (Full Range) [months]	15.9	13.4

Adverse Events

Time Frame	Continuously during treatment (up to 66 months) and up to 28 days after last dose (up to 66 months overall)
Adverse Event Reporting Description	Safety Population: All randomized participants, according to treatment actually received, who received at least one dose of study medication.
Arm/Group Title	Herceptin + Taxotere + Xeloda		Herceptin + Taxotere
Arm/Group Description	Participants received triple therapy with Herceptin, Taxotere, and Xeloda until disease progression, unmanageable toxicity, or withdrawal. Herceptin and Taxotere were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 75 mg/m^2, with adjustments allowed only for toxicity. Xeloda was given orally as 950 mg/m^2 twice a day on Days 1 to 14 of each 21-day cycle, with adjustments allowed only for toxicity.		Participants received dual therapy with Herceptin and Taxotere until disease progression, unmanageable toxicity, or withdrawal. Treatments were given via IV infusion on Day 1 of each 21-day cycle. The first dose of Herceptin was a loading dose of 8 mg/kg in Cycle 1, and a maintenance dose of 6 mg/kg was given from Cycle 2 through the end of treatment. The dose of Taxotere was 100 mg/m^2, with adjustments allowed only for toxicity.
All Cause Mortality
	Herceptin + Taxotere + Xeloda		Herceptin + Taxotere
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Herceptin + Taxotere + Xeloda		Herceptin + Taxotere
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/112 (46.4%)		51/110 (46.4%)
Blood and lymphatic system disorders
Febrile neutropenia	16/112 (14.3%)		26/110 (23.6%)
Neutropenia	7/112 (6.3%)		7/110 (6.4%)
Anaemia	1/112 (0.9%)		1/110 (0.9%)
Cardiac disorders
Cardiac failure	1/112 (0.9%)		0/110 (0%)
Coronary artery disease	1/112 (0.9%)		0/110 (0%)
Left ventricular dysfunction	1/112 (0.9%)		0/110 (0%)
Pericardial effusion	0/112 (0%)		1/110 (0.9%)
Endocrine disorders
Hyperthyroidism	1/112 (0.9%)		0/110 (0%)
Gastrointestinal disorders
Diarrhoea	5/112 (4.5%)		0/110 (0%)
Vomiting	3/112 (2.7%)		1/110 (0.9%)
Rectal haemorrhage	0/112 (0%)		1/110 (0.9%)
Stomatitis	1/112 (0.9%)		0/110 (0%)
General disorders
Pyrexia	3/112 (2.7%)		4/110 (3.6%)
Oedema peripheral	1/112 (0.9%)		1/110 (0.9%)
Chest pain	0/112 (0%)		1/110 (0.9%)
Hyperthermia	1/112 (0.9%)		0/110 (0%)
Inflammation of wound	0/112 (0%)		1/110 (0.9%)
Mucosal inflammation	0/112 (0%)		1/110 (0.9%)
Pitting oedema	0/112 (0%)		1/110 (0.9%)
Hepatobiliary disorders
Acute hepatic failure	0/112 (0%)		1/110 (0.9%)
Cholelithiasis	1/112 (0.9%)		0/110 (0%)
Jaundice	1/112 (0.9%)		0/110 (0%)
Immune system disorders
Hypersensitivity	0/112 (0%)		1/110 (0.9%)
Infections and infestations
Neutropenic sepsis	5/112 (4.5%)		1/110 (0.9%)
Bronchopneumonia	3/112 (2.7%)		0/110 (0%)
Central line infection	2/112 (1.8%)		1/110 (0.9%)
Cellulitis	2/112 (1.8%)		0/110 (0%)
Lower respiratory tract infection	1/112 (0.9%)		0/110 (0%)
Lymphangitis	0/112 (0%)		1/110 (0.9%)
Neutropenic infection	0/112 (0%)		1/110 (0.9%)
Oral candidiasis	1/112 (0.9%)		0/110 (0%)
Pneumonia	1/112 (0.9%)		0/110 (0%)
Postoperative wound infection	1/112 (0.9%)		0/110 (0%)
Pyelonephritis	0/112 (0%)		1/110 (0.9%)
Pyelonephritis acute	0/112 (0%)		1/110 (0.9%)
Respiratory tract infection	1/112 (0.9%)		0/110 (0%)
Skin infection	0/112 (0%)		1/110 (0.9%)
Tuberculosis	1/112 (0.9%)		0/110 (0%)
Urinary tract infection	1/112 (0.9%)		0/110 (0%)
Wound sepsis	0/112 (0%)		1/110 (0.9%)
Injury, poisoning and procedural complications
Femur fracture	1/112 (0.9%)		0/110 (0%)
Investigations
Ejection fraction decreased	0/112 (0%)		3/110 (2.7%)
Metabolism and nutrition disorders
Dehydration	1/112 (0.9%)		0/110 (0%)
Hypoalbuminaemia	0/112 (0%)		1/110 (0.9%)
Hypocalcaemia	0/112 (0%)		1/110 (0.9%)
Metabolic acidosis	1/112 (0.9%)		0/110 (0%)
Musculoskeletal and connective tissue disorders
Joint swelling	1/112 (0.9%)		0/110 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukemia	0/112 (0%)		1/110 (0.9%)
Nervous system disorders
Diplegia	1/112 (0.9%)		0/110 (0%)
Dizziness	1/112 (0.9%)		0/110 (0%)
Neuropathy	0/112 (0%)		1/110 (0.9%)
Psychiatric disorders
Neurosis	1/112 (0.9%)		0/110 (0%)
Reproductive system and breast disorders
Menorrhagia	1/112 (0.9%)		0/110 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	6/112 (5.4%)		0/110 (0%)
Dyspnoea	2/112 (1.8%)		3/110 (2.7%)
Asthma	0/112 (0%)		1/110 (0.9%)
Bronchospasm	1/112 (0.9%)		0/110 (0%)
Pulmonary oedema	1/112 (0.9%)		0/110 (0%)
Vascular disorders
Haemorrhage	1/112 (0.9%)		0/110 (0%)
Hypovolaemic shock	0/112 (0%)		1/110 (0.9%)
Thrombophlebitis	1/112 (0.9%)		0/110 (0%)
Other (Not Including Serious) Adverse Events
	Herceptin + Taxotere + Xeloda		Herceptin + Taxotere
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/112 (100%)		107/110 (97.3%)
Blood and lymphatic system disorders
Neutropenia	35/112 (31.3%)		23/110 (20.9%)
Anaemia	15/112 (13.4%)		19/110 (17.3%)
Leukopenia	10/112 (8.9%)		10/110 (9.1%)
Febrile neutropenia	3/112 (2.7%)		6/110 (5.5%)
Eye disorders
Lacrimation increased	25/112 (22.3%)		22/110 (20%)
Conjunctivitis	15/112 (13.4%)		14/110 (12.7%)
Dry eye	7/112 (6.3%)		7/110 (6.4%)
Vision blurred	3/112 (2.7%)		6/110 (5.5%)
Gastrointestinal disorders
Diarrhoea	75/112 (67%)		55/110 (50%)
Nausea	61/112 (54.5%)		39/110 (35.5%)
Vomiting	37/112 (33%)		30/110 (27.3%)
Constipation	29/112 (25.9%)		23/110 (20.9%)
Stomatitis	29/112 (25.9%)		19/110 (17.3%)
Abdominal pain	25/112 (22.3%)		16/110 (14.5%)
Dyspepsia	22/112 (19.6%)		12/110 (10.9%)
Abdominal pain upper	13/112 (11.6%)		5/110 (4.5%)
Gastritis	6/112 (5.4%)		4/110 (3.6%)
Haemorrhoids	8/112 (7.1%)		1/110 (0.9%)
Odynophagia	6/112 (5.4%)		1/110 (0.9%)
General disorders
Asthenia	35/112 (31.3%)		35/110 (31.8%)
Oedema peripheral	28/112 (25%)		42/110 (38.2%)
Fatigue	35/112 (31.3%)		29/110 (26.4%)
Mucosal inflammation	34/112 (30.4%)		30/110 (27.3%)
Pyrexia	25/112 (22.3%)		19/110 (17.3%)
Chest pain	9/112 (8%)		10/110 (9.1%)
Chills	10/112 (8.9%)		9/110 (8.2%)
Oedema	3/112 (2.7%)		15/110 (13.6%)
Pain	6/112 (5.4%)		8/110 (7.3%)
Infections and infestations
Nasopharyngitis	15/112 (13.4%)		12/110 (10.9%)
Rhinitis	13/112 (11.6%)		11/110 (10%)
Influenza	13/112 (11.6%)		10/110 (9.1%)
Urinary tract infection	8/112 (7.1%)		11/110 (10%)
Investigations
Weight decreased	7/112 (6.3%)		1/110 (0.9%)
Metabolism and nutrition disorders
Anorexia	23/112 (20.5%)		19/110 (17.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	28/112 (25%)		28/110 (25.5%)
Myalgia	15/112 (13.4%)		38/110 (34.5%)
Back pain	14/112 (12.5%)		15/110 (13.6%)
Bone pain	15/112 (13.4%)		10/110 (9.1%)
Musculoskeletal pain	10/112 (8.9%)		10/110 (9.1%)
Pain in extremity	9/112 (8%)		11/110 (10%)
Musculoskeletal chest pain	6/112 (5.4%)		2/110 (1.8%)
Nervous system disorders
Headache	20/112 (17.9%)		28/110 (25.5%)
Paraesthesia	11/112 (9.8%)		20/110 (18.2%)
Dizziness	12/112 (10.7%)		16/110 (14.5%)
Dysgeusia	17/112 (15.2%)		11/110 (10%)
Neuropathy peripheral	13/112 (11.6%)		14/110 (12.7%)
Peripheral sensory neuropathy	10/112 (8.9%)		13/110 (11.8%)
Neuropathy	11/112 (9.8%)		11/110 (10%)
Lethargy	8/112 (7.1%)		13/110 (11.8%)
Neurotoxicity	6/112 (5.4%)		5/110 (4.5%)
Psychiatric disorders
Insomnia	10/112 (8.9%)		12/110 (10.9%)
Depression	4/112 (3.6%)		10/110 (9.1%)
Anxiety	4/112 (3.6%)		8/110 (7.3%)
Renal and urinary disorders
Dysuria	8/112 (7.1%)		6/110 (5.5%)
Respiratory, thoracic and mediastinal disorders
Cough	20/112 (17.9%)		18/110 (16.4%)
Dyspnoea	13/112 (11.6%)		19/110 (17.3%)
Pharyngolaryngeal pain	11/112 (9.8%)		13/110 (11.8%)
Epistaxis	10/112 (8.9%)		7/110 (6.4%)
Rhinorrhoea	5/112 (4.5%)		9/110 (8.2%)
Dyspnoea exertional	6/112 (5.4%)		5/110 (4.5%)
Skin and subcutaneous tissue disorders
Alopecia	76/112 (67.9%)		68/110 (61.8%)
Palmar-plantar erythrodysaesthesia syndrome	57/112 (50.9%)		7/110 (6.4%)
Nail disorder	28/112 (25%)		20/110 (18.2%)
Rash	22/112 (19.6%)		18/110 (16.4%)
Onycholysis	20/112 (17.9%)		14/110 (12.7%)
Erythema	13/112 (11.6%)		10/110 (9.1%)
Skin reaction	15/112 (13.4%)		4/110 (3.6%)
Pruritus	8/112 (7.1%)		8/110 (7.3%)
Dry skin	9/112 (8%)		6/110 (5.5%)
Skin hyperpigmentation	10/112 (8.9%)		3/110 (2.7%)
Nail toxicity	4/112 (3.6%)		6/110 (5.5%)
Onychomadesis	6/112 (5.4%)		2/110 (1.8%)
Vascular disorders
Hot flush	9/112 (8%)		14/110 (12.7%)
Lymphoedema	8/112 (7.1%)		13/110 (11.8%)
Phlebitis	6/112 (5.4%)		4/110 (3.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.