Temperature-Sensitive Liposomal Doxorubicin and Hyperthermia in Treating Women With Locally 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.
Study Overview
Status
Conditions
Detailed Description
OBJECTIVES:
- Determine the maximum tolerated dose of temperature-sensitive liposomal doxorubicin (ThermoDox™) when used in combination with local-regional hyperthermia in women with locally recurrent breast cancer.
- Determine the pharmacokinetic profile of ThermoDox™ when used in multiple-course dosing.
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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North Carolina
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Durham, North Carolina, United States, 27710
- Duke Cancer Institute
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
DISEASE CHARACTERISTICS:
Histologically confirmed adenocarcinoma of the breast
Locally recurrent disease involving the chest wall and/or its overlying skin
- Clinically and biopsy proven disease on the chest wall area measuring ≥ 1 cm
- Overall surface extent of tumor ≤ two 16 x 16 cm fields
- Tumor thickness ≤ 3 cm by clinical exam and CT scan or MRI
- Disease extent on the chest wall that exceeds the above criteria allowed provided no other local therapies are available
- Patients with axillary disease involvement only must meet the above criteria in order to be eligible
- Prior skin changes consistent with inflammatory breast cancer are allowed
Distant metastasis (excluding known brain metastases) allowed
- No resectable chest wall recurrence as the only site of metastatic disease
- No refractory pain secondary to metastatic disease
- 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:
- Cardiac ischemia or acute coronary artery syndrome, myocardial infarction (MI), cerebral vascular accident, or abnormal cardiac stress testing within the last 6 months
- Coronary artery disease (including non-Q wave MI)
- Uncontrolled hypertension or cardiomyopathy
- Cardiac valvular surgery or open heart surgery
- Known structural heart disease
No other serious medical illness including, but not limited to, the following:
- Congestive heart failure
- Life-threatening cardiac arrhythmias
- Acute or chronic liver disease
- 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:
- Functioning cardiac pacemaker
- Metal plates, rods, or prosthesis of the chest wall
- Severe numbness and/or tingling of the chest wall or breast
- Skin grafts and/or flaps on the breast or chest wall
- Unstable cardiovascular or pulmonary status
- 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:
- Doxorubicin hydrochloride > 450 mg/m^2
- Epirubicin hydrochloride > 900 mg/m^2
- 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:
- Amphotericin B by injection
- Antithyroid agents
- Azathioprine
- Chloramphenicol
- Colchicine
- Flucytosine
- Ganciclovir
- Interferon
- Plicamycin
- Zidovudine
- Sulfinpyrazone
- Probenecid
- Cyclosporine
- Phenobarbital
- Phenytoin
- Streptozocin
- Live vaccines
- Concurrent bisphosphonates for palliation of bony metastasis allowed
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Thermodox
ThermoDox20-40mg/m2 every 21-35 days followed by Chest Wall Hyperthermia
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Maximum tolerated dose of temperature-sensitive liposomal doxorubicin (ThermoDox™) in combination with hyperthermia
Time Frame: 4 years
|
4 years
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Pharmacokinetics
Time Frame: 4 years
|
4 years
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Kimberly L. Blackwell, MD, Duke Cancer Institute
Publications and helpful links
General Publications
- Zagar TM, Vujaskovic Z, Formenti S, Rugo H, Muggia F, O'Connor B, Myerson R, Stauffer P, Hsu IC, Diederich C, Straube W, Boss MK, Boico A, Craciunescu O, Maccarini P, Needham D, Borys N, Blackwell KL, Dewhirst MW. Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer. Int J Hyperthermia. 2014 Aug;30(5):285-94. doi: 10.3109/02656736.2014.936049.
- Nolen BM, Marks JR, Ta'san S, Rand A, Luong TM, Wang Y, Blackwell K, Lokshin AE. Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer. Breast Cancer Res. 2008;10(3):R45. doi: 10.1186/bcr2096. Epub 2008 May 12.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Skin Diseases
- Neoplasms
- Neoplasms by Site
- Wounds and Injuries
- Breast Diseases
- Body Temperature Changes
- Heat Stress Disorders
- Breast Neoplasms
- Hyperthermia
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Antibiotics, Antineoplastic
- Doxorubicin
- Liposomal doxorubicin
Other Study ID Numbers
- Pro00014340
- DUMC-6883-06-2R1
- DUMC-06068
- CDR0000482411 (Other Identifier: Secondary ID)
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