Breast Cancer
Conditions
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.
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.
Interventions
DRUGTrastuzumab 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
Sponsors
Roche Pharma AG
Experior
MedSIR
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| 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. |
| 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. |
| 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 |
| 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 |
| 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 |
| Doxorubicinol - Tmax | Baseline (Cycle1Day1) and end of Cycle 2 (C2D21) | Maximum concentration of drug in plasma (Tmax) |
| Trastuzumab - Cmax | Baseline (Cycle1 Day1) | Pharmacokinetic parameters for trastuzumab |
| Trastuzumab - AUC | Baseline (Cycle1Day1) | Pharmacokinetic parameters for trastuzumab |
| Trastuzumab - Tmax | Baseline (Cycle1Day1) | Pharmacokinetic parameters for trastuzumab |
| DM-1 - Cmax | Baseline (Cycle1Day1) | Pharmacokinetic parameters for emtansine (DM1) by treatment dose level |
| DM-1 - AUC | Baseline (Cycle1Day1) | Pharmacokinetic parameters for DM1 by treatment dose level |
| DM-1 - Tmax | Baseline (Cycle1Day1) | Pharmacokinetic parameters for DM1 by treatment dose level |
| Doxorubicinol - Apparent Half-life (t1/2) | Baseline (Cycle1Day1) and end of Cycle 2 (C2D21) | Apparent half-life for doxorubicinol by treatment dose level. |
| 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) |
Countries
France, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) 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 | 3 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) 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 | 3 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) 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 | 9 |
| Total | 15 |
Baseline characteristics
| Characteristic | Total | Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) |
|---|---|---|---|---|
| Age, Continuous | 49.3 years STANDARD_DEVIATION 11.6 | 58.7 years STANDARD_DEVIATION 2.1 | 50.3 years STANDARD_DEVIATION 11.5 | 45.9 years STANDARD_DEVIATION 12.5 |
| Disease Stage at Initial Diagnostic I | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Disease Stage at Initial Diagnostic II | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Disease Stage at Initial Diagnostic III | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Disease Stage at Initial Diagnostic IV | 9 Participants | 3 Participants | 3 Participants | 3 Participants |
| ECOG Performance Status (ITT) ECOG score 0 (Fully active) | 13 participants | 3 participants | 3 participants | 7 participants |
| ECOG Performance Status (ITT) ECOG score 1 (Restricted physical activity) | 2 participants | 0 participants | 0 participants | 2 participants |
| Estrogen Receptor (ER) (ITT) Negative | 4 Participants | 0 Participants | 1 Participants | 3 Participants |
| Estrogen Receptor (ER) (ITT) Positive | 11 Participants | 3 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 3 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| HER2 detection method Chromogenic in situ hybridization (CISH) | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| HER2 detection method Fluorescence in situ hybridization (FISH) | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| HER2 detection method Immunohistochemistry (IHC) | 11 Participants | 2 Participants | 2 Participants | 7 Participants |
| Human Epidermal Growth Factor Receptor 2 (HER2) (ITT) | 15 Participants | 3 Participants | 3 Participants | 9 Participants |
| Metastasis sites (ITT) Bone | 10 participants | 3 participants | 3 participants | 4 participants |
| Metastasis sites (ITT) Brain | 2 participants | 0 participants | 1 participants | 1 participants |
| Metastasis sites (ITT) Liver | 6 participants | 2 participants | 0 participants | 4 participants |
| Metastasis sites (ITT) Lung | 5 participants | 1 participants | 0 participants | 4 participants |
| Metastasis sites (ITT) Lymph node | 10 participants | 1 participants | 2 participants | 7 participants |
| Metastasis sites (ITT) Metastasis | 15 participants | 3 participants | 3 participants | 9 participants |
| Metastasis sites (ITT) Other sites | 2 participants | 1 participants | 0 participants | 1 participants |
| Metastasis sites (ITT) Skin | 2 participants | 0 participants | 0 participants | 2 participants |
| Previous Treatment for Metastatic Breast Cancer 1 | 11 Participants | 3 Participants | 0 Participants | 8 Participants |
| Previous Treatment for Metastatic Breast Cancer 2 | 3 Participants | 0 Participants | 3 Participants | 0 Participants |
| Previous Treatment for Metastatic Breast Cancer 3 | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior Medication No | 5 Participants | 0 Participants | 0 Participants | 5 Participants |
| Prior Medication Yes | 10 Participants | 3 Participants | 3 Participants | 4 Participants |
| Progesterone Receptor (PgR) (ITT) Negative | 8 Participants | 1 Participants | 2 Participants | 5 Participants |
| Progesterone Receptor (PgR) (ITT) Positive | 7 Participants | 2 Participants | 1 Participants | 4 Participants |
| Region of Enrollment France | 3 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Slovenia | 2 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment Spain | 10 participants | 2 participants | 3 participants | 5 participants |
| Sex: Female, Male Female | 15 Participants | 3 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| TNM Staging (ITT) Core biopsy | 13 Participants | 3 Participants | 3 Participants | 7 Participants |
| TNM Staging (ITT) Fine needle aspiration | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| TNM Staging (ITT) Missing | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| TNM Staging M Category M0 | 4 Participants | 0 Participants | 0 Participants | 4 Participants |
| TNM Staging M Category M1 | 9 Participants | 3 Participants | 3 Participants | 3 Participants |
| TNM Staging M Category Mx | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| TNM Staging N Category N0 | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| TNM Staging N Category N1 | 6 Participants | 0 Participants | 0 Participants | 6 Participants |
| TNM Staging N Category N2 | 5 Participants | 2 Participants | 3 Participants | 0 Participants |
| TNM Staging N Category Nx | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| TNM Staging T Category T1 | 4 Participants | 0 Participants | 1 Participants | 3 Participants |
| TNM Staging T Category T2 | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| TNM Staging T Category T3 | 5 Participants | 1 Participants | 2 Participants | 2 Participants |
| TNM Staging T Category T4 | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| TNM Staging T Category Tx | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 3 | 0 / 9 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 9 / 9 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 1 / 9 |
Outcome results
Primary
Hematological - Dose Limiting Toxicities
Treatment-related adverse events (AEs) of any grade reported in ≥10% of patients.
Time frame: Baseline up to 6 weeks after patient entry (Cycle2Day21)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Hematological - Dose Limiting Toxicities | Thrombopenia | 1 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Hematological - Dose Limiting Toxicities | Lymphopenia | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Hematological - Dose Limiting Toxicities | Leukopenia | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Hematological - Dose Limiting Toxicities | Neutropenia | 1 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Hematological - Dose Limiting Toxicities | Decreased lymphocyte count | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Hematological - Dose Limiting Toxicities | Decreased hemoglobin | 1 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Hematological - Dose Limiting Toxicities | Anemia | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Hematological - Dose Limiting Toxicities | Leukopenia | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Hematological - Dose Limiting Toxicities | Neutropenia | 3 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Hematological - Dose Limiting Toxicities | Thrombopenia | 2 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Hematological - Dose Limiting Toxicities | Anemia | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Hematological - Dose Limiting Toxicities | Lymphopenia | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Hematological - Dose Limiting Toxicities | Decreased hemoglobin | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Hematological - Dose Limiting Toxicities | Decreased lymphocyte count | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Hematological - Dose Limiting Toxicities | Lymphopenia | 2 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Hematological - Dose Limiting Toxicities | Thrombopenia | 6 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Hematological - Dose Limiting Toxicities | Decreased lymphocyte count | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Hematological - Dose Limiting Toxicities | Decreased hemoglobin | 0 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Hematological - Dose Limiting Toxicities | Leukopenia | 2 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Hematological - Dose Limiting Toxicities | Anemia | 4 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Hematological - Dose Limiting Toxicities | Neutropenia | 7 participants |
Primary
Non-Hematological - Dose Limiting Toxicities
Treatment-related AEs of any grade reported in ≥10% of patients.
Time frame: Baseline up to 6 weeks after patient entry (Cycle2Day21)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Asthenia | 3 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Rash | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Alopecia | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Hypoalbuminemia | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Nausea | 2 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. aspartate aminotransferase | 1 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. alanine aminotransferase | 1 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. brain natriuretic peptide | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. gamma-glutamyl transferasehemoglobin | 2 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Increased troponin Ilymphocyte count | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Decreased appetite | 1 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Epistaxis | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Rhinorrhea | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Headache | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Fatigue | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Mucosal inflammation | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. blood alkaline phosphatase | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Aphthous ulcer | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Constipation | 1 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Diarrhea | 1 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Dry mouth | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Gingival bleeding | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Vomiting | 0 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. gamma-glutamyl transferasehemoglobin | 2 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Mucosal inflammation | 0 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Hypoalbuminemia | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Epistaxis | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Rash | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Constipation | 0 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Gingival bleeding | 0 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Rhinorrhea | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Dry mouth | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Asthenia | 2 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Decreased appetite | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. blood alkaline phosphatase | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Nausea | 3 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Diarrhea | 0 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Headache | 2 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. aspartate aminotransferase | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Vomiting | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Alopecia | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. alanine aminotransferase | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Fatigue | 0 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Aphthous ulcer | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. brain natriuretic peptide | 2 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Increased troponin Ilymphocyte count | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. brain natriuretic peptide | 4 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. gamma-glutamyl transferasehemoglobin | 2 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Increased troponin Ilymphocyte count | 4 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Decreased appetite | 3 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Alopecia | 3 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Constipation | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Epistaxis | 2 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Rhinorrhea | 2 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Headache | 0 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Diarrhea | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Fatigue | 2 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Gingival bleeding | 2 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Hypoalbuminemia | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Rash | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Mucosal inflammation | 2 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Vomiting | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Asthenia | 4 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Nausea | 4 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. blood alkaline phosphatase | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. aspartate aminotransferase | 6 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Dry mouth | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Inc. alanine aminotransferase | 4 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Non-Hematological - Dose Limiting Toxicities | Aphthous ulcer | 1 participants |
Secondary
Best Overall Response
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
Population: Best Overall Response, n (%)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Best Overall Response | Progressive disease | 1 Participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Best Overall Response | Stable disease <24 weeks | 0 Participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Best Overall Response | Partial response | 1 Participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Best Overall Response | Stable disease ≥24 weeks | 1 Participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Best Overall Response | Not evaluable | 0 Participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Best Overall Response | Stable disease <24 weeks | 1 Participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Best Overall Response | Partial response | 2 Participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Best Overall Response | Stable disease ≥24 weeks | 0 Participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Best Overall Response | Progressive disease | 0 Participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Best Overall Response | Not evaluable | 0 Participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Best Overall Response | Not evaluable | 1 Participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Best Overall Response | Progressive disease | 0 Participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Best Overall Response | Partial response | 3 Participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Best Overall Response | Stable disease <24 weeks | 2 Participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Best Overall Response | Stable disease ≥24 weeks | 3 Participants |
Secondary
Clinical Benefit Rate
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Clinical Benefit Rate | 66.7 percentage of participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Clinical Benefit Rate | 66.7 percentage of participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Clinical Benefit Rate | 66.7 percentage of participants |
Secondary
Discontinuation of the Study Drugs Due to Any Cardiotoxicity
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Discontinuation of the Study Drugs Due to Any Cardiotoxicity | 0 Participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Discontinuation of the Study Drugs Due to Any Cardiotoxicity | 0 Participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Discontinuation of the Study Drugs Due to Any Cardiotoxicity | 0 Participants |
Secondary
DM-1 - AUC
Pharmacokinetic parameters for DM1 by treatment dose level
Time frame: Baseline (Cycle1Day1)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | DM-1 - AUC | 23.1 μg x h/mL | Standard Deviation 143.1 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | DM-1 - AUC | 10.1 μg x h/mL | Standard Deviation 25 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | DM-1 - AUC | 5.63 μg x h/mL | Standard Deviation 24.9 |
Secondary
DM-1 - Cmax
Pharmacokinetic parameters for emtansine (DM1) by treatment dose level
Time frame: Baseline (Cycle1Day1)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | DM-1 - Cmax | 3.76 μg/mL | Standard Deviation 18.2 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | DM-1 - Cmax | 8.03 μg/mL | Standard Deviation 67.3 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | DM-1 - Cmax | 5.13 μg/mL | Standard Deviation 59.1 |
Secondary
DM-1 - Tmax
Pharmacokinetic parameters for DM1 by treatment dose level
Time frame: Baseline (Cycle1Day1)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | DM-1 - Tmax | 2.0 hours |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | DM-1 - Tmax | 1.83 hours |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | DM-1 - Tmax | 1.95 hours |
Secondary
Doxorubicinol - Apparent Half-life (t1/2)
Apparent half-life for doxorubicinol by treatment dose level.
Time frame: Baseline (Cycle1Day1) and end of Cycle 2 (C2D21)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Doxorubicinol - Apparent Half-life (t1/2) | Cycle 1 Day 1 | 93.4 days | Standard Deviation 37.9 |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Doxorubicinol - Apparent Half-life (t1/2) | Cycle 2 Day 21 | 51.91 days | Standard Deviation 0.5 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Doxorubicinol - Apparent Half-life (t1/2) | Cycle 1 Day 1 | 78.5 days | Standard Deviation 6 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Doxorubicinol - Apparent Half-life (t1/2) | Cycle 2 Day 21 | 64.01 days | Standard Deviation 23.6 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Doxorubicinol - Apparent Half-life (t1/2) | Cycle 1 Day 1 | 69.3 days | Standard Deviation 11.7 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Doxorubicinol - Apparent Half-life (t1/2) | Cycle 2 Day 21 | 49.41 days | Standard Deviation 1.9 |
Secondary
Doxorubicinol - Area Under Curve (AUC)
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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Doxorubicinol - Area Under Curve (AUC) | Cycle 1 Day 1- AUC | 982 ng x h/mL | Standard Deviation 28.4 |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Doxorubicinol - Area Under Curve (AUC) | Cycle 2 Day 21- AUC | 899 ng x h/mL | Standard Deviation 40.7 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Doxorubicinol - Area Under Curve (AUC) | Cycle 1 Day 1- AUC | 888 ng x h/mL | Standard Deviation 27.8 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Doxorubicinol - Area Under Curve (AUC) | Cycle 2 Day 21- AUC | 763 ng x h/mL | Standard Deviation 25.4 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Doxorubicinol - Area Under Curve (AUC) | Cycle 1 Day 1- AUC | 1340 ng x h/mL | Standard Deviation 65 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Doxorubicinol - Area Under Curve (AUC) | Cycle 2 Day 21- AUC | 1100 ng x h/mL | Standard Deviation 50.3 |
Secondary
Doxorubicinol - Concentration (Cmax)
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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Doxorubicinol - Concentration (Cmax) | Cycle 2 Day 21 | 16.0 μg/mL | Standard Deviation 25.2 |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Doxorubicinol - Concentration (Cmax) | Cycle 1 Day 1 | 14.8 μg/mL | Standard Deviation 8.4 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Doxorubicinol - Concentration (Cmax) | Cycle 2 Day 21 | 10.1 μg/mL | Standard Deviation 38.9 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Doxorubicinol - Concentration (Cmax) | Cycle 1 Day 1 | 9.19 μg/mL | Standard Deviation 42.1 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Doxorubicinol - Concentration (Cmax) | Cycle 1 Day 1 | 15.2 μg/mL | Standard Deviation 70.6 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Doxorubicinol - Concentration (Cmax) | Cycle 2 Day 21 | 15.6 μg/mL | Standard Deviation 54.5 |
Secondary
Doxorubicinol - Tmax
Maximum concentration of drug in plasma (Tmax)
Time frame: Baseline (Cycle1Day1) and end of Cycle 2 (C2D21)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Doxorubicinol - Tmax | Cycle 1 Day 1- Tmax | 3.75 hours |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Doxorubicinol - Tmax | Cycle 2 Day 21- Tmax | 4.02 hours |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Doxorubicinol - Tmax | Cycle 1 Day 1- Tmax | 3.58 hours |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Doxorubicinol - Tmax | Cycle 2 Day 21- Tmax | 3.58 hours |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Doxorubicinol - Tmax | Cycle 1 Day 1- Tmax | 3.63 hours |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Doxorubicinol - Tmax | Cycle 2 Day 21- Tmax | 3.78 hours |
Secondary
Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations
Patients with grade 3/4 adverse events, Serious Adverse Events (SAEs), deaths and discontinuations
Time frame: Baseline up to 24 months after patient entry
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Thrombopenia | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Neutropenia | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Leukopenia | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Lymphopenia | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Increase in aspartate aminotransferase (AST) | 0 participants |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Fatigue | 0 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Fatigue | 0 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Thrombopenia | 0 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Lymphopenia | 1 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Increase in aspartate aminotransferase (AST) | 0 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Neutropenia | 2 participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Leukopenia | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Neutropenia | 6 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Leukopenia | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Fatigue | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Lymphopenia | 1 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Thrombopenia | 2 participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Increase in aspartate aminotransferase (AST) | 2 participants |
Secondary
Left Ventricular Dysfunction Class IV
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Left Ventricular Dysfunction Class IV | 0 Participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Left Ventricular Dysfunction Class IV | 1 Participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Left Ventricular Dysfunction Class IV | 2 Participants |
Secondary
Overall Response Rate
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Overall Response Rate | 33.3 percentage of participants |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Overall Response Rate | 66.7 percentage of participants |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Overall Response Rate | 33.3 percentage of participants |
Secondary
Progression-free Survival
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Progression-free Survival | 8.2 months |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Progression-free Survival | 7.0 months |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Progression-free Survival | 7.2 months |
Secondary
Serum HER-2 Levels
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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Serum HER-2 Levels | Cycle 4 Day 21, Serum HER-2 (ng/mL) | 7.4 ng/mL | Standard Deviation 0 |
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Serum HER-2 Levels | Baseline, Serum HER-2 (ng/mL) | 12.7 ng/mL | Standard Deviation 5.8 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Serum HER-2 Levels | Cycle 4 Day 21, Serum HER-2 (ng/mL) | 15.2 ng/mL | Standard Deviation 0.6 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Serum HER-2 Levels | Baseline, Serum HER-2 (ng/mL) | 38.1 ng/mL | Standard Deviation 35.7 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Serum HER-2 Levels | Baseline, Serum HER-2 (ng/mL) | 17.5 ng/mL | Standard Deviation 6 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Serum HER-2 Levels | Cycle 4 Day 21, Serum HER-2 (ng/mL) | 18.8 ng/mL | Standard Deviation 5.4 |
Secondary
Trastuzumab - AUC
Pharmacokinetic parameters for trastuzumab
Time frame: Baseline (Cycle1Day1)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Trastuzumab - AUC | 348 μg x h/mL | Standard Deviation 14.4 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Trastuzumab - AUC | 372 μg x h/mL | Standard Deviation 30.3 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Trastuzumab - AUC | 317 μg x h/mL | Standard Deviation 18.9 |
Secondary
Trastuzumab - Cmax
Pharmacokinetic parameters for trastuzumab
Time frame: Baseline (Cycle1 Day1)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Trastuzumab - Cmax | 94.6 μg/mL | Standard Deviation 16.8 |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Trastuzumab - Cmax | 114 μg/mL | Standard Deviation 2.8 |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Trastuzumab - Cmax | 78.3 μg/mL | Standard Deviation 7.6 |
Secondary
Trastuzumab - Tmax
Pharmacokinetic parameters for trastuzumab
Time frame: Baseline (Cycle1Day1)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1, Trastuzumab + Doxorubicin (45 mg/m2) | Trastuzumab - Tmax | 1.95 hours |
| Cohort 2, Trastuzumab + Doxorubicin (50 mg/m2) | Trastuzumab - Tmax | 1.83 hours |
| Cohort 3, Trastuzumab + Doxorubicin (60 mg/m2) | Trastuzumab - Tmax | 1.95 hours |