Phase I Multicenter Clinical Trial Evaluating the Combination of Trastuzumab Emtansine (T-DM1) and Non-pegylated Liposomal Doxorubicin in HER2-positive Metastatic Breast Cancer
Phase I Multicenter Clinical Trial Evaluating the Combination of Trastuzumab Emtansine (T-DM1) and Non-pegylated Liposomal Doxorubicin in HER2-positive Metastatic Breast Cancer
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.
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:
Secondary objectives:
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.
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:
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:
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