Phase 1/2 Study of ThermoDox With Approved Hyperthermia in Treatment of Breast Cancer Recurrence at the Chest Wall (DIGNITY)
Drug: ThermoDox in combination with Microwave Hyperthermia (heat)
|Study Design:||Endpoint Classification: Bio-equivalence Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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.|
- To determine the bioequivalence of ThermoDox when used with hyperthermia among patients with RCW breast cancer. [ Time Frame: PK collection at Cycle 1 and Cycle 2 ] [ Designated as safety issue: No ]
- To determine efficacy of ThermoDox in combination with Hyperthermia [ Time Frame: Efficacy assessed at Cycle 3, Cycle 5 and End of Treatment ] [ Designated as safety issue: No ]
- To evaluate the safety of ThermoDox in combination with Hyperthermia [ Time Frame: Through 6 treatment Cycles ] [ Designated as safety issue: Yes ]
|Study Start Date:||February 2013|
|Study Completion Date:||December 2015|
|Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
Experimental: Thermodox in combination with hyperthermia
Single arm study
Drug: ThermoDox in combination with Microwave Hyperthermia (heat)
ThermoDox is a 30 minute intravenous infusion followed by hyperthermia within 60 minutes of infusion completion.
Hyperthermia is a therapy used to heat tumors for 60 minutes. Using heat energy, the tumor is heated to a certain temperature. The heat can damage cancer cells at levels that are usually safe for normal cells and can be used to attack cancer in four major ways: 1) heat damages or weakens the cells of the tumor; 2) heat increase blood flow through the weakened tumor; 3) increased blood flow raises oxygen levels in tumors; and 4) when the body senses fever it can stimulate the nature immune system.
All patients will receive up to six ThermoDox/hyperthermia treatments at 21-day intervals.
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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 intent.
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 hyperthermia.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00826085
|United States, California|
|University of California, San Francisco|
|San Francisco, California, United States, 94143|
|United States, Georgia|
|Southeastern Regional Medical Center|
|Newnan, Georgia, United States, 30265|
|United States, Maryland|
|University of Maryland|
|Baltimore, Maryland, United States, 21201|
|United States, Missouri|
|Washington University in St. Louis|
|St. Louis, Missouri, United States, 63110|
|United States, Oklahoma|
|Southwestern Regional Medical Center|
|Tulsa, Oklahoma, United States, 74133|
|United States, Pennsylvania|
|Eastern Regional Medical Center|
|Philadelphia, Pennsylvania, United States, 19124|
|Study Director:||Nicholas Borys, MD||Celsion|