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

Study Overview
=================
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.

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

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Trastuzumab and non-pegylated liposomal doxorubicin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm<br>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<br>* 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<br>* Other names: T-DM1 and non-pegylated liposomal doxorubicin;|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Baseline up to 24 months after patient entry | 
| 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) | Baseline up to 24 months after patient entry | 
| 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 | Baseline up to 24 months after patient entry | 
| 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 | Baseline up to 24 months after patient entry | 
| Grade 3/4 Adverse Events, SAEs, Deaths and Discontinuations | Patients with grade 3/4 adverse events, Serious Adverse Events (SAEs), deaths and discontinuations | Baseline up to 24 months after patient entry | 
| Discontinuation of the Study Drugs Due to Any Cardiotoxicity | Rate of patients who discontinued treatment due to Cardiac Function or Due to Cardiac Cause | Baseline up to 24 months after patient entry | 
| 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. | Baseline up to 24 months after patient entry | 
| 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. | Baseline and after 4 cycles of treatment (Cycle4Day21) | 
| Doxorubicinol - Concentration (Cmax) | Plasma concentration of Doxorubicinol using a validated liquid chromatography electrospray tandem mass spectrometry (LC-MS/MS) method | Baseline (Cycle1Day1) and end of Cycle 2 (C2D21) | 
| Doxorubicinol - Area Under Curve (AUC) | Area under the plasma concentration versus time curve for the pharmacokinetic parameters for doxorubicinol by treatment dose level | Baseline (Cycle1Day1) and end of Cycle 2 (C2D21) | 
| Doxorubicinol - Apparent Half-life (t1/2) | Apparent half-life for doxorubicinol by treatment dose level. | Baseline (Cycle1Day1) and end of Cycle 2 (C2D21) | 
| Doxorubicinol - Tmax | Maximum concentration of drug in plasma (Tmax) | Baseline (Cycle1Day1) and end of Cycle 2 (C2D21) | 
| Trastuzumab - Cmax | Pharmacokinetic parameters for trastuzumab | Baseline (Cycle1 Day1) | 
| Trastuzumab - AUC | Pharmacokinetic parameters for trastuzumab | Baseline (Cycle1Day1) | 
| Trastuzumab - Tmax | Pharmacokinetic parameters for trastuzumab | Baseline (Cycle1Day1) | 
| DM-1 - Cmax | Pharmacokinetic parameters for emtansine (DM1) by treatment dose level | Baseline (Cycle1Day1) | 
| DM-1 - AUC | Pharmacokinetic parameters for DM1 by treatment dose level | Baseline (Cycle1Day1) | 
| DM-1 - Tmax | Pharmacokinetic parameters for DM1 by treatment dose level | Baseline (Cycle1Day1) |