A Study of Trastuzumab-Mcc-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT00679211
• Recruitment Status: Completed
• First Posted: May 16, 2008
• Results First Posted: April 23, 2013
• Last Update Posted: March 31, 2017
• Sponsor: Genentech, Inc.
• Information provided by (Responsible Party): Genentech, Inc.

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Breast Cancer
• Intervention: Drug: Trastuzumab emtansine [Kadcyla]
• Enrollment: 110

Participant Flow

Recruitment Details
Pre-assignment Details	Between 13 August 2008 and 2 April 2009, 110 patients from 44 study sites in the United States were enrolled and treated in the study.

Arm/Group Title	Trastuzumab Emtansine
Arm/Group Description	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
Period Title: Overall Study
Started	110
Completed	0
Not Completed	110
Reason Not Completed
Progressive disease	82
Adverse Event	7
Withdrawal by Subject	2
Physician Decision	5
Refused to undergo protocol procedures	1
Transferred to extension study TDM4529g	12
Other	1

Baseline Characteristics

Arm/Group Title		Trastuzumab Emtansine
Arm/Group Description		Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
Overall Number of Baseline Participants		110
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	110 participants
		53.0 (9.1)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	110 participants
	Female	108 98.2%
	Male	2 1.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With an Objective Response as Assessed Through Independent Radiologic Review
Description	Objective response was defined as a complete response (CR) or partial response (PR) determined on two consecutive occasions ≥ 4 weeks apart, assessed using Response Evaluation Criteria in Solid Tumors (RECIST). CR: the disappearance of all target lesions and all nontarget lesions and normalization of tumor marker level and no new lesions. PR: disappearance of all target lesions and persistence of ≥ 1 nontarget lesion(s) and/or the maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diameter of target lesions, and no new lesions or unequivocal progression of existing nontarget lesions. The primary data cut-off date was 17 September 2009 (approximately 6 months after the last patient was enrolled). The final efficacy analysis was performed using a data cut-off date of 1 January 2010 (approximately 9 months after the last patient was enrolled).
Time Frame	From randomization until the primary analysis data cut-off date of September 2009 (6 months after last patient enrolled) and until the final efficacy analysis cut-off date of 1 January 2010 (approximately 9 months after the last patient enrolled).

Outcome Measure Data

Analysis Population Description

Treated population (patients who received at least one dose of T-DM1). Participants without a post-baseline tumor assessment were considered to be non-responders.

Arm/Group Title	6 Months of Follow-up	9 Months of Follow-up
Arm/Group Description:	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
Overall Number of Participants Analyzed	110	110
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	32.7; (24.1 to 42.1)	32.7; (24.1 to 42.1)

2. Secondary Outcome

Title	Duration of Objective Response as Assessed Through Independent Radiologic Review
Description	For participants who achieved an objective response, duration of objective response was defined as the time from the first tumor assessment that supported a participant's objective response to the time of disease progression or death on study (i.e., death from any cause within 30 days of the last dose of study drug), whichever occurred first. Response was assessed by the independent review facility. Disease progression was at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. For participants who experienced no disease progression and did not die while on study, data were censored at the date of the last tumor assessment. Kaplan-Meier methodology was used to estimate the duration of objective response.
Time Frame	From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled.

Outcome Measure Data

Analysis Population Description

Participants with an objective response.

Arm/Group Title	Trastuzumab Emtansine
Arm/Group Description:	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
Overall Number of Participants Analyzed	36
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (4.6 to NA)

[1]

The median duration of objective response was not reached due to a low number of events (defined as disease progression or death from any cause on study, whichever occurred first).

3. Secondary Outcome

Title	Progression-free Survival as Assessed Through Independent Radiologic Review
Description	Progression-Free Survival (PFS) was defined as the time from the first day of study treatment to documented disease progression or death on study (i.e., death from any cause within 30 days of the last dose of study drug), whichever occurred first. Disease progression was at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. Disease progression was assessed by the independent review facility. For patients who experienced no disease progression and did not die while on study, data were censored at the date of the last tumor assessment. Kaplan-Meier methodology was used to estimate PFS.
Time Frame	From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled.

Outcome Measure Data

Analysis Population Description

Treated population.

Arm/Group Title	Trastuzumab Emtansine
Arm/Group Description:	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
Overall Number of Participants Analyzed	110
Median (95% Confidence Interval); Unit of Measure: months
	6.9; (4.2 to 9.5)

4. Secondary Outcome

Title	Percentage of Participants With Clinical Benefit Based on Independent Radiologic Review
Description	Clinical benefit was defined as participants who achieved an objective response (confirmed complete or partial response) between randomization and 1 January 2010, or with stable disease at 6 months. Stable disease at 6 months was defined as participants who achieved at least stable disease based on tumor assessments by the independent review facility, and remained alive and progression-free at 6 months. Stable disease was defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started, and no new lesions and/or unequivocal progression of existing nontarget lesions. Response was assessed by the independent review facility.
Time Frame	From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled.

Outcome Measure Data

Analysis Population Description

Treated population. Participants without a post-baseline tumor assessment were considered to have experienced no clinical benefit.

Arm/Group Title	Trastuzumab Emtansine
Arm/Group Description:	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
Overall Number of Participants Analyzed	110
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	48.2; (38.8 to 57.9)

5. Secondary Outcome

Title	Objective Response Based on Investigator Assessment
Description	Objective response was defined as a complete response (CR) or partial response (PR) determined on two consecutive occasions ≥ 4 weeks apart, assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Response was assessed by the study Investigator. CR: the disappearance of all target lesions and all nontarget lesions and normalization of tumor marker level and no new lesions. PR: disappearance of all target lesions and persistence of ≥ 1 nontarget lesion(s) and/or the maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diameter of target lesions, and no new lesions or unequivocal progression of existing nontarget lesions.
Time Frame	From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled.

Outcome Measure Data

Analysis Population Description

Treated population. Participants without a post-baseline tumor assessment were considered to be non-responders.

Arm/Group Title	Trastuzumab Emtansine
Arm/Group Description:	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
Overall Number of Participants Analyzed	110
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	32.7; (24.1 to 42.1)

6. Secondary Outcome

Title	Progression-free Survival Based on Investigator Assessment
Description	Progression-Free Survival (PFS) was defined as the time from the first day of study treatment to documented disease progression or death on study (i.e., death from any cause within 30 days of the last dose of study drug), whichever occurred first. Disease progression was at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. For patients who experienced no disease progression and did not die while on study, data were censored at the date of the last tumor assessment. Kaplan-Meier methodology was used to estimate PFS.
Time Frame	From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled.

Outcome Measure Data

Analysis Population Description

Treated population

Arm/Group Title	Trastuzumab Emtansine
Arm/Group Description:	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
Overall Number of Participants Analyzed	110
Median (95% Confidence Interval); Unit of Measure: months
	5.5; (4.1 to 7.5)

7. Secondary Outcome

Title	Duration of Objective Response Based on Investigator Assessment
Description	For participants who achieved an objective response, duration of objective response was defined as the time from the first tumor assessment that supported a participant's objective response to the time of disease progression or death on study (i.e., death from any cause within 30 days of the last dose of study drug), whichever occurred first. Response was determined by the Investigator's assessment. Disease progression was at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. For participants who experienced no disease progression and did not die while on study, data were censored at the date of the last tumor assessment. Kaplan-Meier methodology was used to estimate the duration of objective response.
Time Frame	From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled.

Outcome Measure Data

Analysis Population Description

Participants with an objective response.

Arm/Group Title	Trastuzumab Emtansine
Arm/Group Description:	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
Overall Number of Participants Analyzed	36
Median (95% Confidence Interval); Unit of Measure: months
	9.7 [1]; (6.6 to NA)

[1]

Upper limit of the confidence interval not reached due to low number of events (defined as disease progression or death from any cause on study, whichever occurred first).

8. Secondary Outcome

Title	Percentage of Participants With Clinical Benefit Based on Investigator Assessment
Description	Clinical benefit was defined as participants with an objective response (confirmed complete or partial response) or stable disease at 6 months. Patients with stable disease at 6 months were defined as patients who achieved at least stable disease based on tumor assessments and remained alive and progression free at 6 months. Response was based on the Investigator's assessment.
Time Frame	From randomization until 1 January 2010, approximately 9 months after the last participant was enrolled.

Outcome Measure Data

Analysis Population Description

Treated population. Patients without a post-baseline tumor assessment were considered to have experienced no clinical benefit.

Arm/Group Title	Trastuzumab Emtansine
Arm/Group Description:	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
Overall Number of Participants Analyzed	110
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	46.4; (37.1 to 56.1)

Adverse Events

Time Frame	From the date of first dose until 26 April 2011, approximately 25 months of follow-up.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Trastuzumab Emtansine
Arm/Group Description	Trastuzumab emtansine (T-DM1) was administered to participants at a dose of 3.6 mg/kg by intravenous (IV) infusion every 3 weeks until documented disease progression, unmanageable toxicity, or study termination.
All-Cause Mortality
	Trastuzumab Emtansine
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Trastuzumab Emtansine
	Affected / at Risk (%)
Total	29/110 (26.36%)
Cardiac disorders
Atrial fibrillation † 1	1/110 (0.91%)
Gastrointestinal disorders
Nausea † 1	2/110 (1.82%)
Abdominal pain † 1	1/110 (0.91%)
Abdominal pain upper † 1	1/110 (0.91%)
Constipation † 1	1/110 (0.91%)
Pancreatitis † 1	1/110 (0.91%)
Vomiting † 1	1/110 (0.91%)
General disorders
Pyrexia † 1	3/110 (2.73%)
Axillary pain † 1	2/110 (1.82%)
Chest pain † 1	1/110 (0.91%)
Influenza like illness † 1	1/110 (0.91%)
Hepatobiliary disorders
Bile duct obstruction † 1	1/110 (0.91%)
Cholecystitis acute † 1	1/110 (0.91%)
Hepatic function abnormal † 1	1/110 (0.91%)
Infections and infestations
Cellulitis † 1	4/110 (3.64%)
Pneumonia † 1	3/110 (2.73%)
Bacteraemia † 1	1/110 (0.91%)
Herpes zoster † 1	1/110 (0.91%)
Pharyngitis streptococcal † 1	1/110 (0.91%)
Sepsis † 1	2/110 (1.82%)
Staphylococcal infection † 1	1/110 (0.91%)
Wound infection † 1	1/110 (0.91%)
Gastroenteritis viral † 1	1/110 (0.91%)
Injury, poisoning and procedural complications
Fall † 1	1/110 (0.91%)
Femur fracture † 1	1/110 (0.91%)
Foreign body † 1	1/110 (0.91%)
Road traffic accident † 1	1/110 (0.91%)
Investigations
Blood creatinine increased † 1	1/110 (0.91%)
Blood culture positive † 1	1/110 (0.91%)
Metabolism and nutrition disorders
Fluid overload † 1	1/110 (0.91%)
Nervous system disorders
Convulsion † 1	1/110 (0.91%)
Spinal cord compression † 1	2/110 (1.82%)
Central nervous system necrosis † 1	1/110 (0.91%)
Psychiatric disorders
Confusional state † 1	1/110 (0.91%)
Reproductive system and breast disorders
Vaginal haemorrhage † 1	1/110 (0.91%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	2/110 (1.82%)
Pleural effusion † 1	1/110 (0.91%)
Pneumothorax † 1	1/110 (0.91%)
Interstitial lung disease † 1	1/110 (0.91%)
Vascular disorders
Deep vein thrombosis † 1	1/110 (0.91%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (12.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Trastuzumab Emtansine
	Affected / at Risk (%)
Total	105/110 (95.45%)
Blood and lymphatic system disorders
Thrombocytopenia † 1	37/110 (33.64%)
Anaemia † 1	23/110 (20.91%)
Leukopenia † 1	6/110 (5.45%)
Eye disorders
Lacrimation increased † 1	9/110 (8.18%)
Vision blurred † 1	7/110 (6.36%)
Gastrointestinal disorders
Nausea † 1	41/110 (37.27%)
Constipation † 1	27/110 (24.55%)
Dry mouth † 1	22/110 (20.00%)
Vomiting † 1	18/110 (16.36%)
Diarrhoea † 1	14/110 (12.73%)
Abdominal pain † 1	11/110 (10.00%)
Dyspepsia † 1	8/110 (7.27%)
Stomatitis † 1	7/110 (6.36%)
Gastrooesophageal reflux disease † 1	6/110 (5.45%)
General disorders
Fatigue † 1	69/110 (62.73%)
Pyrexia † 1	24/110 (21.82%)
Chills † 1	11/110 (10.00%)
Oedema peripheral † 1	11/110 (10.00%)
Pain † 1	10/110 (9.09%)
Chest pain † 1	7/110 (6.36%)
Influenza like illness † 1	6/110 (5.45%)
Infections and infestations
Urinary tract infection † 1	11/110 (10.00%)
Upper respiratory tract infection † 1	10/110 (9.09%)
Sinusitis † 1	8/110 (7.27%)
Injury, poisoning and procedural complications
Infusion related reaction † 1	15/110 (13.64%)
Investigations
Aspartate aminotransferase increased † 1	30/110 (27.27%)
Alanine aminotransferase increased † 1	16/110 (14.55%)
Blood alkaline phosphatase increased † 1	12/110 (10.91%)
Weight decreased † 1	12/110 (10.91%)
Blood lactate dehydrogenase increase † 1	10/110 (9.09%)
Platelet count decreased † 1	8/110 (7.27%)
Haemoglobin decreased † 1	7/110 (6.36%)
White blood cell count decreased † 1	7/110 (6.36%)
Metabolism and nutrition disorders
Hypokalaemia † 1	25/110 (22.73%)
Decreased appetite † 1	23/110 (20.91%)
Hyperglycaemia † 1	9/110 (8.18%)
Hypoalbuminaemia † 1	6/110 (5.45%)
Musculoskeletal and connective tissue disorders
Back pain † 1	20/110 (18.18%)
Arthralgia † 1	16/110 (14.55%)
Pain in extremity † 1	16/110 (14.55%)
Myalgia † 1	15/110 (13.64%)
Muscle spasms † 1	13/110 (11.82%)
Bone pain † 1	9/110 (8.18%)
Musculoskeletal pain † 1	8/110 (7.27%)
Musculoskeletal chest pain † 1	7/110 (6.36%)
Nervous system disorders
Headache † 1	26/110 (23.64%)
Neuropathy peripheral † 1	20/110 (18.18%)
Dysgeusia † 1	9/110 (8.18%)
Peripheral sensory neuropathy † 1	9/110 (8.18%)
Dizziness † 1	7/110 (6.36%)
Psychiatric disorders
Depression † 1	11/110 (10.00%)
Anxiety † 1	9/110 (8.18%)
Insomnia † 1	7/110 (6.36%)
Reproductive system and breast disorders
Breast pain † 1	6/110 (5.45%)
Respiratory, thoracic and mediastinal disorders
Epistaxis † 1	25/110 (22.73%)
Cough † 1	21/110 (19.09%)
Dyspnoea † 1	17/110 (15.45%)
Oropharyngeal pain † 1	9/110 (8.18%)
Skin and subcutaneous tissue disorders
Pruritus † 1	9/110 (8.18%)
Rash † 1	9/110 (8.18%)
Vascular disorders
Hot flush † 1	7/110 (6.36%)
Lymphoedema † 1	7/110 (6.36%)
Hypertension † 1	6/110 (5.45%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (12.1)

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: Genentech, Inc.
• Phone: 800-821-8590

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT00679211
• Other Study ID Numbers: TDM4374g
• First Submitted: May 14, 2008
• First Posted: May 16, 2008
• Results First Submitted: March 12, 2013
• Results First Posted: April 23, 2013
• Last Update Posted: March 31, 2017