A Phase I/II Study Evaluating the Maximum Tolerated Dose, Bioequivalence/Pharmacokinetics, Safety, and Efficacy of Hyperthermia and ThermoDox (Lyso-Thermosensitive Liposomal Doxorubucin) in Patients With Local-Regional Recurrent Breast Cancer.
Breast cancer is the most common malignancy in women in both the United States and the
world. Despite a variety of hormonal, cytotoxic and biologic approaches, a significant
number of tumors will recur in the chest wall and axillary area following primary treatment.
Any local recurrence of breast cancer after mastectomy is generally regarded as a poor
prognostic indicator. However, it is also generally agreed that those who present without
measurable metastatic disease at the time of loco-regional recurrence (LRR) have a more
favorable disease and may experience long-term survival. Overall up to 35% of women with
operable breast cancer will experience an isolated LRR following their primary treatment.
Patients with LRR suffer from disfiguring tumors and other clinical signs and symptoms
including pain, lymphedema limiting range of motion in the affected extremity, foul-smelling
wounds, and a visual reminder of tumor progression. Up to 40% of patients undergoing a
mastectomy as their primary treatment will experience a recurrence at the chest wall or
overlying skin (RCW).
For initial curative intent in LRR, available interventions include surgical resection in
patients whose tumor and clinical status permits anesthesia and surgical removal, radiation
therapy in patients whose tumor and clinical status permits additional radiation, systemic
hormonal and/or cytotoxic chemotherapy in patients whose tumors are sensitive to such drugs
and combinations of the aforementioned. For unresectable LRR tumors, radiation and
chemotherapy are used to manage the disease. In this setting some success has been achieved;
however, a patient who reoccurs following these treatments is often treated with palliative
Diathermy refers to the therapeutic generation of local heat in body tissues by
high-frequency electromagnetic radiation, electric currents, or ultrasonic waves. In mild
hyperthermia local tissue temperatures are restricted to a range of 39-45°C. Two types of
external devices, microwave systems and ultrasound systems, have been approved by the FDA
for delivering mild hyperthermia to the chest wall.
Mild hyperthermia from either microwave or ultrasound devices has been used safely in breast
cancer treatment. In conjunction with external beam radiation, both types of devices have
been used to heat the chest wall and both devices have demonstrated enhanced effects when
compared to radiation therapy without additional hyperthermia.
Doxorubicin hydrochloride is a cytotoxic anthracycline antibiotic. The recommended
single-agent dose of doxorubicin HCl (Adriamycin®) for injection is 60 to 75 mg/m2
intravenously (IV) in three-week cycles. Acute myelosuppression and long term, cumulative,
cardiotoxicity (congestive heart failure) are dose-limiting. Doxorubicin is active against
breast cancer as a single agent and is used with other drugs in multi-agent chemotherapy
regimens. In LRR breast cancer, single agent doxorubicin achieves response rates comparable
to combination chemotherapy.
Lyso-thermosensitive liposomal doxorubicin (ThermoDox®) is a temperature sensitive liposomal
drug delivery system that selectively accumulates in tumors as a result of their leaky
vasculature. During ThermoDox/hyperthermia therapy, the tumor is heated locally while the
rest of the body remains at a normal temperature. When the liposomes encounter a temperature
of 39.5°C or above, they release doxorubicin locally into the heated area. Liposomal
doxorubicin is administered intravenously and, because it is particulate, will eventually be
removed from circulation by the reticuloendothelial system in the liver and spleen.
Pharmacokinetic data from liver cancer patients treated with radiofrequency ablation (RFA)
and ThermoDox show that the major portion of exposure to ThermoDox (about 95% of the
liposomal doxorubicin plasma AUC0-∞) occurs during the first six hours following the
infusion, establishing this time period as optimal for application of hyperthermia. Animal
studies have repeatedly shown higher tumor doxorubicin concentrations and enhanced tumor
cell killing when ThermoDox is combined with hyperthermia compared to doxorubicin without
Endpoint Classification: Bio-equivalence Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the bioequivalence of ThermoDox when used with hyperthermia among patients with RCW breast cancer.
PK collection at Cycle 1 and Cycle 2
Nicholas Borys, MD
United States: Food and Drug Administration
|University of California, San Francisco||San Francisco, California 94143|
|Northwestern University||Chicago, Illinois 60611|
|New York University||New York, New York 10016|
|Southwestern Regional Medical Center||Tulsa, Oklahoma 74133|
|Eastern Regional Medical Center||Philadelphia, Pennsylvania|