A Phase I, Dose Escalation and Pharmacokinetics Study of Temperature Sensitive Liposome Encapsulated Doxorubicin (ThermoDox™) and Hyperthermia in Patients With Local-Regionally Recurrent Breast Cancer
A Phase I, Dose Escalation and Pharmacokinetics Study of Temperature Sensitive Liposome Encapsulated Doxorubicin (ThermoDox™) and Hyperthermia in Patients With Local-Regionally Recurrent Breast Cancer
RATIONALE: Drugs used in chemotherapy, such as liposomal doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Hyperthermia therapy kills tumor cells by heating them to several degrees above normal body temperature. Giving temperature-sensitive liposomal doxorubicin together with hyperthermia may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of temperature-sensitive liposomal doxorubicin when given together with hyperthermia in treating women with locally recurrent breast cancer.
OBJECTIVES:
OUTLINE: This is a dose-escalation study of temperature-sensitive liposomal doxorubicin (ThermoDox™).
Patients receive ThermoDox™ IV over 30 minutes immediately followed by hyperthermia to the chest wall/axilla over 1-2 hours on day 1. Treatment repeats every 21-35 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of ThermoDox™ (with or without standard-dose granulocyte colony-stimulating factor [G-CSF] support) until the maximum tolerated dose (MTD) is determined. The MTD without G-CSF support is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT). At least 6 patients are treated at the MTD. If the only DLT is neutropenia in > 1 of 6 patients treated at any dose level, then additional cohorts of 3-6 patients receive escalating doses of ThermoDox™ with G-CSF support (standard-dose G-CSF or standard-dose pegfilgrastim) until the MTD is determined. The MTD with G-CSF support is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT after the addition of G-CSF support.
Quality of life and pain are assessed at baseline, prior to courses 3 and 5, and at 21-42 days after completion of therapy.
After completion of study treatment, patients are followed periodically for 5 years.
PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.
DISEASE CHARACTERISTICS:
Histologically confirmed adenocarcinoma of the breast
Locally recurrent disease involving the chest wall and/or its overlying skin
Distant metastasis (excluding known brain metastases) allowed
Must have undergone prior local radiotherapy to the chest wall or breast in the adjuvant or metastatic setting
Must have progressed on ≥ 1 course of hormonal therapy for metastatic disease (if tumor is estrogen receptor positive or progesterone receptor positive) AND ≥ 1 course of chemotherapy
Prior contralateral breast malignancy allowed provided not previously treated with chemotherapy
Hormone receptor status not specified
PATIENT CHARACTERISTICS:
Female
Menopausal status not specified
Zubrod performance status 0-1 OR Karnofsky performance status 90-100%
Not pregnant
Negative pregnancy test
Fertile patients must use effective contraception
Granulocyte count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 9 g/dL
Bilirubin normal
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN)
Creatinine ≤ 1.5 times ULN
left ventricular ejection fraction (LVEF) ≥ 50% by multiple gated acquisition scan (MUGA) or echocardiogram
No nonhealing wounds or active infection in the area of the chest wall
No clinically significant findings on baseline evaluations, including laboratory and physical examinations, vital signs, and ECG
No prior sensitivity (e.g., rash, dyspnea, wheezing, urticaria, or other symptoms) attributed to anthracyclines or other liposomally encapsulated drugs
No other prior or concurrent primary malignancy except for melanoma in situ, nonmelanoma skin cancer, squamous cell carcinoma, or noninvasive cervical carcinoma
No history of any of the following:
No other serious medical illness including, but not limited to, the following:
No major psychiatric illness that required inpatient treatment within the past 3 months or that would preclude obtaining informed consent
No concurrent devices or conditions that might interfere with the hyperthermia portion of the trial, including any of the following:
No known allergy to eggs or egg products
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
More than 3 months since prior major surgery
No prior therapy with anthracyclines exceeding the following doses:
More than 42 days since prior trastuzumab (Herceptin®)
More than 90 days since prior radiotherapy to the involved chest wall area
No other concurrent systemic anticancer therapy, including hormonal therapy, chemotherapy, or investigational anticancer therapy
No concurrent radiotherapy, including radiotherapy for pain control
No concurrent administration of any of the following drugs:
Concurrent bisphosphonates for palliation of bony metastasis allowed