THELMA: T-DM1 and Non-pegylated Liposomal Doxorubicin in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer

• Sponsor: MedSIR (Other)
• Overall Status: Completed
• CT.gov ID: NCT02562378
• Collaborator: Roche Pharma AG (Industry), Experior (Industry)
• Enrollment: 15
• Locations: 4
• Arm: 1
• Duration (Months): 38
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary goal is to determine the maximum tolerated dose (MTD) of the combination of T-DM1 and non-pegylated liposomal doxorubicin in metastatic breast cancer (mBC) patients previously treated with taxanes and trastuzumab-based therapy.

In addition, pharmacokinetic data on the combination of T-DM1 and liposomal doxorubicin will be obtained.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Trastuzumab and non-pegylated liposomal doxorubicin	Phase 1

Detailed Description

Subjects: Age ≥ 18 years with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer that have relapsed or progressed on or after taxanes and trastuzumab-based therapy. Subjects must have histologic or cytologic confirmation of the HER2-positive metastatic breast cancer. Evidence of measurable or evaluable metastatic disease is required.

Primary objective:

• To determine the maximum tolerated dose (MTD) of the combination of T-DM1 and non-pegylated liposomal doxorubicin in metastatic breast cancer (mBC) patients previously treated with taxanes and trastuzumab-based therapy.

Secondary objectives:

• To determine the efficacy of the combination of T-DM1 and non-pegylated liposomal doxorubicin, defined by the overall response rate (ORR), clinical benefit rate (CBR), number of progressions and number and reasons for deaths.

• To assess the safety profile of the combination of T-DM1 and non-pegylated liposomal doxorubicin, defined by all toxicities reported during the study.

• To evaluate the cardiac safety of the combination of T-DM1 and non-pegylated liposomal doxorubicin measured by left ventricular ejection fraction (LVEF) as assessed by echocardiography, cardiac troponin I and B-type natriuretic peptide (BNP) levels.

• To evaluate the potential role of single nucleotide polymorphisms (SNP) in the predisposition for developing cardiotoxicity.

• To analyze the pharmacokinetics (PK) profile of T-DM1 and its metabolites and non-pegylated liposomal doxorubicin.

Type of study: This is a prospective dose-finding, multicenter and open-label phase I clinical trial.

Treatment: Trastuzumab emtansine (T-DM1) will be administered at a fixed dose of 3.6 mg/kg IV on Day 1 every 3 weeks and three cohorts of patients with three different dose levels of conventional non-pegylated liposomal doxorubicin (45 mg/m2, 50 mg/m2 and 60 mg/m2) IV on Day 1 in cycles of 21 days each are planned.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Multicenter Clinical Trial Evaluating the Combination of Trastuzumab Emtansine (T-DM1) and Non-pegylated Liposomal Doxorubicin in HER2-positive Metastatic Breast Cancer
• Study Start Date: Oct 1, 2015
• Actual Primary Completion Date: Dec 1, 2018
• Actual Study Completion Date: Dec 1, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Experimental arm Trastuzumab emtansine (T-DM1) will be administered at a fixed dose of 3.6 mg/kg IV on Day 1 every 3 weeks and three cohorts of patients with three different dose levels of conventional non-pegylated liposomal doxorubicin (45 mg/m2, 50 mg/m2 and 60 mg/m2) IV

Drug: Trastuzumab and non-pegylated liposomal doxorubicin; 3 Cohorts (3+3 design): Cohort 1- Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV Cohort 2- Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV Cohort 3- Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV; Other Names: T-DM1 and non-pegylated liposomal doxorubicin

Outcome Measures

Primary Outcome Measures

1. Hematological - Dose Limiting Toxicities [Baseline up to 6 weeks after patient entry (Cycle2Day21)]

   Treatment-related adverse events (AEs) of any grade reported in ≥10% of patients.

2. Non-Hematological - Dose Limiting Toxicities [Baseline up to 6 weeks after patient entry (Cycle2Day21)]

   Treatment-related AEs of any grade reported in ≥10% of patients.

Secondary Outcome Measures

1. Overall Response Rate [Baseline up to 24 months after patient entry]

   Patients with best overall response of confirmed complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST criteria guidelines (version 1.1) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

2. Best Overall Response [Baseline up to 24 months after patient entry]

   Patients with best overall response of confirmed complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST criteria guidelines (version 1.1)

3. Clinical Benefit Rate [Baseline up to 24 months after patient entry]

   Clinical benefit rate (CBR) is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) lasting more than 24 weeks based on local investigator's assessment

4. Progression-free Survival [Baseline up to 24 months after patient entry]

   Patients with progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or measurable increase in a non-target lesion, or the appearance of new lesions

5. Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations [Baseline up to 24 months after patient entry]

   Patients with grade 3/4 adverse events, Serious Adverse Events (SAEs), deaths and discontinuations

6. Discontinuation of the Study Drugs Due to Any Cardiotoxicity [Baseline up to 24 months after patient entry]

   Rate of patients who discontinued treatment due to Cardiac Function or Due to Cardiac Cause

7. Left Ventricular Dysfunction Class IV [Baseline up to 24 months after patient entry]

   New York Heart Association grading of Level II cardiotoxicities characterized by dose-independent reversible myocardial damage. The classes used in this system, I to IV with I indicating less severity and higher numbers indicating greater severity.

8. Serum HER-2 Levels [Baseline and after 4 cycles of treatment (Cycle4Day21)]

   Serum human epidermal growth factor receptor 2 (HER-2) Levels (ng/mL) - Cycle 1 Day 1 and Cycle 4 Day 1.

9. Doxorubicinol - Concentration (Cmax) [Baseline (Cycle1Day1) and end of Cycle 2 (C2D21)]

   Plasma concentration of Doxorubicinol using a validated liquid chromatography electrospray tandem mass spectrometry (LC-MS/MS) method

10. Doxorubicinol - Area Under Curve (AUC) [Baseline (Cycle1Day1) and end of Cycle 2 (C2D21)]

    Area under the plasma concentration versus time curve for the pharmacokinetic parameters for doxorubicinol by treatment dose level

11. Doxorubicinol - Apparent Half-life (t1/2) [Baseline (Cycle1Day1) and end of Cycle 2 (C2D21)]

    Apparent half-life for doxorubicinol by treatment dose level.

12. Doxorubicinol - Tmax [Baseline (Cycle1Day1) and end of Cycle 2 (C2D21)]

    Maximum concentration of drug in plasma (Tmax)

13. Trastuzumab - Cmax [Baseline (Cycle1 Day1)]

    Pharmacokinetic parameters for trastuzumab

14. Trastuzumab - AUC [Baseline (Cycle1Day1)]

    Pharmacokinetic parameters for trastuzumab

15. Trastuzumab - Tmax [Baseline (Cycle1Day1)]

    Pharmacokinetic parameters for trastuzumab

16. DM-1 - Cmax [Baseline (Cycle1Day1)]

    Pharmacokinetic parameters for emtansine (DM1) by treatment dose level

17. DM-1 - AUC [Baseline (Cycle1Day1)]

    Pharmacokinetic parameters for DM1 by treatment dose level

18. DM-1 - Tmax [Baseline (Cycle1Day1)]

    Pharmacokinetic parameters for DM1 by treatment dose level

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Signed informed consent

• Patient able and willing to comply with protocol

• Cytologically or histologically confirmed carcinoma of the breast.

• Incurable locally advanced or metastatic disease who have previously received up to two previous chemotherapy regimens in this setting. Patient must have progressed or relapsed on or after taxane and trastuzumab-based therapy.

• HER2-positive disease

• At least one measurable lesion according to RECIST version 1.1; or patients with non measurable lesions could be included with these exceptions:

o patients with only blastic bone lesions / with only pleural, peritoneal or cardiac effusion, or meningeal carcinomatosis

• ≥ 18 years of age

• Eastern Cooperative Oncology Group (ECOG) 0 or 1

• Life expectancy ≥ 3 months

• Adequate bone marrow function:

• Hemoglobin ≥ 10 g/dl.

• Absolute neutrophil count ≥ 1.5 x 109/L.

• Platelets ≥ 100 x 109/L without transfusions within 21 days

• International normalized ratio (INR) < 1.5 × the upper limit of normal (ULN).

• Adequate hepatic and renal function

• Adequate cardiovascular function with LVEF ≥ 55%

• Recovery from all reported toxicities of previous anti-cancer therapies to baseline or grade ≤ 1 (CTCAE version 4.0), except for alopecia

• For women of childbearing potential and not postmenopausal, and who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy, and men with partners of childbearing potential, use of forms of contraception

Exclusion Criteria:

• Previous treatment with T-DM1 or anthracyclines

• More than two chemotherapeutic regimens for locally advanced incurable disease or metastatic disease

• Prior anti-cancer treatment with chemotherapy, immunotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin-C), hormonal therapy or lapatinib within 7 days, prior trastuzumab within 21 days (7 days if weekly trastuzumab) or any other targeted therapy within the last 21 days prior to starting study treatment

• Previous radiotherapy for the treatment of unresectable, locally advanced/recurrent or mBC is not allowed if:

• The last fraction of radiotherapy has been administered within 21 days prior to first study drug administration (except for brain irradiation; at least 28 days will be required)

• More than 25% of marrow-bearing bone has been irradiated

• History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to the active substance or to any of the excipients of T-DM1 or non-pegylated liposomal doxorubicin

• Patients with central nervous system (CNS) involvement. However, patients with metastatic CNS tumors may participate in this trial if the patient is > 4 weeks from radiotherapy completion, is clinically stable with respect to CNS tumor at the time of study entry and is not receiving steroid therapy for brain metastases

• Severe/uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.

• Cardiopulmonary dysfunction

• Current peripheral neuropathy of Grade ≥ 3 per the NCI CTCAE, v4.0

• History of a decrease in LVEF to < 40% or symptomatic congestive heart failure (CHF) with previous trastuzumab treatment

• Prior malignancy, other than carcinoma in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was cured ≥ 5 years before first dose of study drug with no subsequent evidence of recurrence

• Current known active infection with HIV, hepatitis B, and/or hepatitis C virus

• Women who are pregnant or breast-feeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	MedSIR investigative site	Paris		France	75020
2	MedSIR investigative site	Paris		France	92210
3	MedSIR investigative site	Barcelone		Spain	00835
4	MedSIR investigative site	Madrid		Spain	08035

Sponsors and Collaborators

• MedSIR
• Roche Pharma AG
• Experior

Investigators

• Study Director: Javier Cortés, MD, Hospital Ramon y Cajal, Madrid, Spain

Study Documents (Full-Text)

• Study Protocol - Jun 27, 2017
• Statistical Analysis Plan - Feb 13, 2019

More Information

Publications

None provided.

• Responsible Party: MedSIR
• ClinicalTrials.gov Identifier: NCT02562378
• Other Study ID Numbers: MedOPP038; 2014-001056-28
• First Posted: Sep 29, 2015
• Last Update Posted: Feb 23, 2022
• Last Verified: Oct 1, 2021

• Additional relevant MeSH terms: Breast Neoplasms; Doxorubicin; Liposomal doxorubicin; Trastuzumab

Study Results

Participant Flow

Arm/Group Title	Period 1: Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Period 2: Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Period 3: Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab emtansine (T-DM1) will be administered at a fixed dose of 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin at a dose level of 45 mg/m2.	Trastuzumab emtansine (T-DM1) will be administered at a fixed dose of 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin at a dose level of 50 mg/m2.	Trastuzumab emtansine (T-DM1) will be administered at a fixed dose of 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin at a dose level of 60 mg/m2.
Period Title: Overall Study
STARTED	3	3	9
COMPLETED	3	3	9
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)	Total
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV	Total of all reporting groups
Overall Participants	3	3	9	15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.3 (11.5)	58.7 (2.1)	45.9 (12.5)	49.3 (11.6)
Sex: Female, Male (Count of Participants)
Female	3 100%	3 100%	9 100%	15 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 100%	3 100%	9 100%	15 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
France	0 0%	1 33.3%	2 22.2%	3 20%
Spain	3 100%	2 66.7%	5 55.6%	10 66.7%
Slovenia	0 0%	0 0%	2 22.2%	2 13.3%
ECOG Performance Status (ITT) (participants) [Number]
ECOG score 0 (Fully active)	3 100%	3 100%	7 77.8%	13 86.7%
ECOG score 1 (Restricted physical activity)	0 0%	0 0%	2 22.2%	2 13.3%
Prior Medication (Count of Participants)
No	0 0%	0 0%	5 55.6%	5 33.3%
Yes	3 100%	3 100%	4 44.4%	10 66.7%
Estrogen Receptor (ER) (ITT) (Count of Participants)
Positive	2 66.7%	3 100%	6 66.7%	11 73.3%
Negative	1 33.3%	0 0%	3 33.3%	4 26.7%
Progesterone Receptor (PgR) (ITT) (Count of Participants)
Positive	1 33.3%	2 66.7%	4 44.4%	7 46.7%
Negative	2 66.7%	1 33.3%	5 55.6%	8 53.3%
Human Epidermal Growth Factor Receptor 2 (HER2) (ITT) (Count of Participants)
Count of Participants [Participants]	3 100%	3 100%	9 100%	15 100%
HER2 detection method (Count of Participants)
Immunohistochemistry (IHC)	2 66.7%	2 66.7%	7 77.8%	11 73.3%
Fluorescence in situ hybridization (FISH)	1 33.3%	1 33.3%	1 11.1%	3 20%
Chromogenic in situ hybridization (CISH)	0 0%	0 0%	1 11.1%	1 6.7%
TNM Staging (ITT) (Count of Participants)
Core biopsy	3 100%	3 100%	7 77.8%	13 86.7%
Fine needle aspiration	0 0%	0 0%	1 11.1%	1 6.7%
Missing	0 0%	0 0%	1 11.1%	1 6.7%
TNM Staging T Category (Count of Participants)
Tx	0 0%	0 0%	2 22.2%	2 13.3%
T1	1 33.3%	0 0%	3 33.3%	4 26.7%
T2	0 0%	1 33.3%	1 11.1%	2 13.3%
T3	2 66.7%	1 33.3%	2 22.2%	5 33.3%
T4	0 0%	1 33.3%	1 11.1%	2 13.3%
TNM Staging N Category (Count of Participants)
Nx	0 0%	0 0%	2 22.2%	2 13.3%
N0	0 0%	1 33.3%	1 11.1%	2 13.3%
N1	0 0%	0 0%	6 66.7%	6 40%
N2	3 100%	2 66.7%	0 0%	5 33.3%
TNM Staging M Category (Count of Participants)
Mx	0 0%	0 0%	2 22.2%	2 13.3%
M0	0 0%	0 0%	4 44.4%	4 26.7%
M1	3 100%	3 100%	3 33.3%	9 60%
Disease Stage at Initial Diagnostic (Count of Participants)
I	0 0%	0 0%	1 11.1%	1 6.7%
II	0 0%	0 0%	2 22.2%	2 13.3%
III	0 0%	0 0%	3 33.3%	3 20%
IV	3 100%	3 100%	3 33.3%	9 60%
Metastasis sites (ITT) (participants) [Number]
Metastasis	3 100%	3 100%	9 100%	15 100%
Lymph node	2 66.7%	1 33.3%	7 77.8%	10 66.7%
Bone	3 100%	3 100%	4 44.4%	10 66.7%
Liver	0 0%	2 66.7%	4 44.4%	6 40%
Lung	0 0%	1 33.3%	4 44.4%	5 33.3%
Brain	1 33.3%	0 0%	1 11.1%	2 13.3%
Skin	0 0%	0 0%	2 22.2%	2 13.3%
Other sites	0 0%	1 33.3%	1 11.1%	2 13.3%
Previous Treatment for Metastatic Breast Cancer (Count of Participants)
1	0 0%	3 100%	8 88.9%	11 73.3%
2	3 100%	0 0%	0 0%	3 20%
3	0 0%	0 0%	1 11.1%	1 6.7%

Outcome Measures

1. Primary Outcome

Title	Hematological - Dose Limiting Toxicities
Description	Treatment-related adverse events (AEs) of any grade reported in ≥10% of patients.
Time Frame	Baseline up to 6 weeks after patient entry (Cycle2Day21)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Neutropenia	1 33.3%	3 100%	7 77.8%
Thrombopenia	1 33.3%	2 66.7%	6 66.7%
Anemia	1 33.3%	1 33.3%	4 44.4%
Leukopenia	0 0%	1 33.3%	2 22.2%
Lymphopenia	0 0%	1 33.3%	2 22.2%
Decreased hemoglobin	1 33.3%	1 33.3%	0 0%
Decreased lymphocyte count	0 0%	1 33.3%	1 11.1%

2. Primary Outcome

Title	Non-Hematological - Dose Limiting Toxicities
Description	Treatment-related AEs of any grade reported in ≥10% of patients.
Time Frame	Baseline up to 6 weeks after patient entry (Cycle2Day21)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Asthenia	3 100%	2 66.7%	4 44.4%
Nausea	2 66.7%	3 100%	4 44.4%
Inc. aspartate aminotransferase	1 33.3%	1 33.3%	6 66.7%
Inc. alanine aminotransferase	1 33.3%	1 33.3%	4 44.4%
Inc. brain natriuretic peptide	0 0%	2 66.7%	4 44.4%
Inc. gamma-glutamyl transferasehemoglobin	2 66.7%	2 66.7%	2 22.2%
Increased troponin Ilymphocyte count	0 0%	1 33.3%	4 44.4%
Decreased appetite	1 33.3%	1 33.3%	3 33.3%
Alopecia	0 0%	1 33.3%	3 33.3%
Epistaxis	0 0%	1 33.3%	2 22.2%
Rhinorrhea	0 0%	1 33.3%	2 22.2%
Headache	0 0%	2 66.7%	0 0%
Fatigue	0 0%	0 0%	2 22.2%
Mucosal inflammation	0 0%	0 0%	2 22.2%
Inc. blood alkaline phosphatase	0 0%	1 33.3%	1 11.1%
Aphthous ulcer	0 0%	1 33.3%	1 11.1%
Constipation	1 33.3%	0 0%	1 11.1%
Diarrhea	1 33.3%	0 0%	1 11.1%
Dry mouth	0 0%	1 33.3%	1 11.1%
Gingival bleeding	0 0%	0 0%	2 22.2%
Vomiting	0 0%	1 33.3%	1 11.1%
Hypoalbuminemia	0 0%	1 33.3%	1 11.1%
Rash	0 0%	1 33.3%	1 11.1%

3. Secondary Outcome

Title	Overall Response Rate
Description	Patients with best overall response of confirmed complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST criteria guidelines (version 1.1) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	Baseline up to 24 months after patient entry

Outcome Measure Data

Analysis Population Description

Best Overall Response (percentage of participants) with confirmed complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST v1.1 criteria guidelines

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Number (95% Confidence Interval) [percentage of participants]	33.3 1110%	66.7 2223.3%	33.3 370%

4. Secondary Outcome

Title	Best Overall Response
Description	Patients with best overall response of confirmed complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST criteria guidelines (version 1.1)
Time Frame	Baseline up to 24 months after patient entry

Outcome Measure Data

Analysis Population Description

Best Overall Response, n (%)

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Partial response	1 33.3%	2 66.7%	3 33.3%
Stable disease ≥24 weeks	1 33.3%	0 0%	3 33.3%
Stable disease <24 weeks	0 0%	1 33.3%	2 22.2%
Progressive disease	1 33.3%	0 0%	0 0%
Not evaluable	0 0%	0 0%	1 11.1%

5. Secondary Outcome

Title	Clinical Benefit Rate
Description	Clinical benefit rate (CBR) is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) lasting more than 24 weeks based on local investigator's assessment
Time Frame	Baseline up to 24 months after patient entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Number (95% Confidence Interval) [percentage of participants]	66.7 2223.3%	66.7 2223.3%	66.7 741.1%

6. Secondary Outcome

Title	Progression-free Survival
Description	Patients with progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	Baseline up to 24 months after patient entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Median (95% Confidence Interval) [months]	8.2	7.0	7.2

7. Secondary Outcome

Title	Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations
Description	Patients with grade 3/4 adverse events, Serious Adverse Events (SAEs), deaths and discontinuations
Time Frame	Baseline up to 24 months after patient entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Neutropenia	0 0%	2 66.7%	6 66.7%
Thrombopenia	0 0%	0 0%	2 22.2%
Leukopenia	0 0%	1 33.3%	1 11.1%
Lymphopenia	0 0%	1 33.3%	1 11.1%
Increase in aspartate aminotransferase (AST)	0 0%	0 0%	2 22.2%
Fatigue	0 0%	0 0%	1 11.1%

8. Secondary Outcome

Title	Discontinuation of the Study Drugs Due to Any Cardiotoxicity
Description	Rate of patients who discontinued treatment due to Cardiac Function or Due to Cardiac Cause
Time Frame	Baseline up to 24 months after patient entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Count of Participants [Participants]	0 0%	0 0%	0 0%

9. Secondary Outcome

Title	Left Ventricular Dysfunction Class IV
Description	New York Heart Association grading of Level II cardiotoxicities characterized by dose-independent reversible myocardial damage. The classes used in this system, I to IV with I indicating less severity and higher numbers indicating greater severity.
Time Frame	Baseline up to 24 months after patient entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Count of Participants [Participants]	0 0%	1 33.3%	2 22.2%

10. Secondary Outcome

Title	Serum HER-2 Levels
Description	Serum human epidermal growth factor receptor 2 (HER-2) Levels (ng/mL) - Cycle 1 Day 1 and Cycle 4 Day 1.
Time Frame	Baseline and after 4 cycles of treatment (Cycle4Day21)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Baseline, Serum HER-2 (ng/mL)	12.7 (5.8)	38.1 (35.7)	17.5 (6.0)
Cycle 4 Day 21, Serum HER-2 (ng/mL)	7.4 (0)	15.2 (0.6)	18.8 (5.4)

11. Secondary Outcome

Title	Doxorubicinol - Concentration (Cmax)
Description	Plasma concentration of Doxorubicinol using a validated liquid chromatography electrospray tandem mass spectrometry (LC-MS/MS) method
Time Frame	Baseline (Cycle1Day1) and end of Cycle 2 (C2D21)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Cycle 1 Day 1	14.8 (8.4)	9.19 (42.1)	15.2 (70.6)
Cycle 2 Day 21	16.0 (25.2)	10.1 (38.9)	15.6 (54.5)

12. Secondary Outcome

Title	Doxorubicinol - Area Under Curve (AUC)
Description	Area under the plasma concentration versus time curve for the pharmacokinetic parameters for doxorubicinol by treatment dose level
Time Frame	Baseline (Cycle1Day1) and end of Cycle 2 (C2D21)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Cycle 1 Day 1- AUC	982 (28.4)	888 (27.8)	1340 (65.0)
Cycle 2 Day 21- AUC	899 (40.7)	763 (25.4)	1100 (50.3)

13. Secondary Outcome

Title	Doxorubicinol - Apparent Half-life (t1/2)
Description	Apparent half-life for doxorubicinol by treatment dose level.
Time Frame	Baseline (Cycle1Day1) and end of Cycle 2 (C2D21)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Cycle 1 Day 1	93.4 (37.9)	78.5 (6.0)	69.3 (11.7)
Cycle 2 Day 21	51.91 (0.5)	64.01 (23.6)	49.41 (1.9)

14. Secondary Outcome

Title	Doxorubicinol - Tmax
Description	Maximum concentration of drug in plasma (Tmax)
Time Frame	Baseline (Cycle1Day1) and end of Cycle 2 (C2D21)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Cycle 1 Day 1- Tmax	3.75	3.58	3.63
Cycle 2 Day 21- Tmax	4.02	3.58	3.78

15. Secondary Outcome

Title	Trastuzumab - Cmax
Description	Pharmacokinetic parameters for trastuzumab
Time Frame	Baseline (Cycle1 Day1)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Mean (Standard Deviation) [μg/mL]	94.6 (16.8)	114 (2.8)	78.3 (7.6)

16. Secondary Outcome

Title	Trastuzumab - AUC
Description	Pharmacokinetic parameters for trastuzumab
Time Frame	Baseline (Cycle1Day1)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Mean (Standard Deviation) [μg x h/mL]	348 (14.4)	372 (30.3)	317 (18.9)

17. Secondary Outcome

Title	Trastuzumab - Tmax
Description	Pharmacokinetic parameters for trastuzumab
Time Frame	Baseline (Cycle1Day1)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Mean (Full Range) [hours]	1.95	1.83	1.95

18. Secondary Outcome

Title	DM-1 - Cmax
Description	Pharmacokinetic parameters for emtansine (DM1) by treatment dose level
Time Frame	Baseline (Cycle1Day1)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Mean (Standard Deviation) [μg/mL]	3.76 (18.2)	8.03 (67.3)	5.13 (59.1)

19. Secondary Outcome

Title	DM-1 - AUC
Description	Pharmacokinetic parameters for DM1 by treatment dose level
Time Frame	Baseline (Cycle1Day1)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Mean (Standard Deviation) [μg x h/mL]	23.1 (143.1)	10.1 (25.0)	5.63 (24.9)

20. Secondary Outcome

Title	DM-1 - Tmax
Description	Pharmacokinetic parameters for DM1 by treatment dose level
Time Frame	Baseline (Cycle1Day1)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)	Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)	Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
Measure Participants	3	3	9
Median (Full Range) [hours]	2.0	1.83	1.95

Adverse Events

Time Frame	Baseline up to 24 months after patient entry
Arm/Group Title	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)		Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)		Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
Arm/Group Description	Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (45 mg/m2) IV		Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (50 mg/m2) IV		Trastuzumab and non-pegylated liposomal doxorubicin: Trastuzumab 3.6 mg/kg IV on Day 1 every 3 weeks and non-pegylated liposomal doxorubicin (60 mg/m2) IV
All Cause Mortality
	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)		Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)		Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		1/3 (33.3%)		0/9 (0%)
Serious Adverse Events
	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)		Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)		Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		0/3 (0%)		1/9 (11.1%)
Blood and lymphatic system disorders
Investigations	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1
Gastrointestinal disorders
Infections and infestations	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1
Nervous system disorders
Nervous system disorders	1/3 (33.3%)	1	0/3 (0%)	0	0/9 (0%)	0
Nervous system disorder	1/3 (33.3%)	1	0/3 (0%)	0	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2)		Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2)		Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		9/9 (100%)
Blood and lymphatic system disorders
Neutrophil count decreased	1/3 (33.3%)	1	3/3 (100%)	3	7/9 (77.8%)	7
Platelet count decreased	1/3 (33.3%)	1	2/3 (66.7%)	2	6/9 (66.7%)	6
Aspartate aminotransferase (AST) increased	1/3 (33.3%)	1	1/3 (33.3%)	1	6/9 (66.7%)	6
Alanine aminotransferase (ALT) increased	1/3 (33.3%)	1	1/3 (33.3%)	1	4/9 (44.4%)	4
White blood cell count decreased	0/3 (0%)	0	1/3 (33.3%)	1	2/9 (22.2%)	2
Haemoglobin decreased	1/3 (33.3%)	1	1/3 (33.3%)	1	0/9 (0%)	0
Lymphocyte count decreased	0/3 (0%)	0	1/3 (33.3%)	1	1/9 (11.1%)	1
Platelet count abnormal	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1
Blood and lymphatic system disorders	0/3 (0%)	0	1/3 (33.3%)	1	5/9 (55.6%)	5
Anaemia	0/3 (0%)	0	0/3 (0%)	0	4/9 (44.4%)	4
Cardiac disorders
Brain natriuretic peptide increased	0/3 (0%)	0	2/3 (66.7%)	2	4/9 (44.4%)	4
Troponin increased	0/3 (0%)	0	1/3 (33.3%)	1	4/9 (44.4%)	4
Tachycardia	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1
Ear and labyrinth disorders
Hyperacusis	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1
Eye disorders
Eye disorders	0/3 (0%)	0	1/3 (33.3%)	1	3/9 (33.3%)	3
Gastrointestinal disorders
Gastrointestinal disorders	3/3 (100%)	3	3/3 (100%)	3	5/9 (55.6%)	5
General disorders
Asthenia	3/3 (100%)	3	2/3 (66.7%)	2	7/9 (77.8%)	7
Fatigue	0/3 (0%)	0	0/3 (0%)	0	2/9 (22.2%)	2
Mucosal inflammation	0/3 (0%)	0	0/3 (0%)	0	2/9 (22.2%)	2
Gait disturbance	1/3 (33.3%)	1	0/3 (0%)	0	0/9 (0%)	0
Pyrexia	0/3 (0%)	0	1/3 (33.3%)	1	0/9 (0%)	0
Hepatobiliary disorders
Gamma-glutamyltransferase increased	2/3 (66.7%)	2	2/3 (66.7%)	2	2/9 (22.2%)	2
Blood alkaline phosphatase increased	0/3 (0%)	0	1/3 (33.3%)	1	1/9 (11.1%)	1
Alanine aminotransferase abnormal	0/3 (0%)	0	1/3 (33.3%)	1	0/9 (0%)	0
Blood alkaline phosphatase abnormal	0/3 (0%)	0	1/3 (33.3%)	1	0/9 (0%)	0
Hepatobiliary disorders	1/3 (33.3%)	1	0/3 (0%)	0	1/9 (11.1%)	1
Metabolism and nutrition disorders
Blood albumin decreased	1/3 (33.3%)	1	0/3 (0%)	0	0/9 (0%)	0
Metabolism and nutrition disorders	1/3 (33.3%)	1	2/3 (66.7%)	2	4/9 (44.4%)	4
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/3 (0%)	0	1/3 (33.3%)	1	1/9 (11.1%)	1
Nervous system disorders
Nervous system disorders	1/3 (33.3%)	1	2/3 (66.7%)	2	1/9 (11.1%)	1
Headache	0/3 (0%)	0	2/3 (66.7%)	2	0/9 (0%)	0
Reproductive system and breast disorders
Vulvovaginal dryness	0/3 (0%)	0	1/3 (33.3%)	1	0/9 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders	0/3 (0%)	0	2/3 (66.7%)	2	2/9 (22.2%)	2
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders	0/3 (0%)	0	2/3 (66.7%)	2	5/9 (55.6%)	5
Vascular disorders
Hot flush	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.