Phase 1/2 Study of ThermoDox With Approved Hyperthermia in Treatment of Breast Cancer Recurrence at the Chest Wall

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase II, Phase IBiomarker/Laboratory analysis, Treatment18 and over105-08-201
NCI-2010-01317, NCT00826085

Trial Description

Summary

This is a research study to evaluate the effects of ThermoDox in combination with

therapeutic heating of the chest wall in the treatment of recurrent regional breast cancer.

The purpose of this study is to evaluate the bioequivalence of ThermoDox and measure

efficacy in recurrent chest wall patients.

Further Study Information

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.

Eligibility Criteria

Inclusion Criteria:

Inclusion Criteria:

1. Histologically documented recurrent/metastatic adenocarcinoma of the breast with a

recurrence on the chest wall (or its overlying skin):

Subjects with ulcerative chest wall disease defined as non-healing wounds

consistent with cancer are eligible.

Subjects with prior skin changes consistent with inflammatory breast carcinoma

are eligible.

Breast carcinoma for medical reasons not being resected

2. Tumor thickness must be clinically indicated for hyperthermia therapy, as measured by

clinical exam or imaging studies (CT or MRI). The target local tumor lesion(s) must

be able to be covered within two hyperthermia fields of treatment.

3. Disease that has progressed despite other available standard treatment options, based

on what is clinically indicated according to the investigator's clinical and medical

judgment, including:

One or more radiation treatment(s) to the chest wall or breast up to a maximum

prior dose of 12,000 cGy in the hyperthermia field (not administered less than

28 days prior to enrollment).

4. Subjects who have previously received hyperthermia in conjunction with either

radiation therapy or chemotherapy are eligible.

5. Subjects may have distant metastasis, including brain metastases. Subjects with known

brain metastases are eligible if:

They have received standard anti-tumor treatment for their brain metastases

without encephalopathy;

Their neurological function is stable for at least 30 days and either off

steroid therapy or on a stable steroid regimen.

6. Non-pregnant female at least 18 years of age. If the subject is of child-bearing age,

must have a negative serum pregnancy test at baseline and must agree to practice an

acceptable form of birth control while on the study.

7. Provide written informed consent and willing to comply with protocol requirements.

Exclusion Criteria:

1. Requires any concomitant antineoplastic therapy. Prior chemotherapy should not be

administered within 5 half-lives or 28 days whichever is shorter. Subjects on a

current stable dose of hormonal treatments may continue on a stable dose during the

study (i.e. arimidex, amarosin, herceptin).

2. Prior confirmed allergic reaction (including moderate rash, dyspnea, wheezing,

urticaria or other symptoms) attributed to the administration of either

anthracyclines or other liposomally encapsulated drugs that required discontinuation

of prior therapy.

3. Prior therapy with anthracyclines exceeding the following doses (subjects will be

discontinued at 600 mg/m2 lifetime dose irrespective of the number of ThermoDox®

cycles received):

Free (i.e., non-liposomal) or liposomal doxorubicin > 450 mg/m2 Free epirubicin > 900

mg/m2.

4. Previous (required active treatment within 5 years) or concomitant malignancy except

basal cell cancer, in situ carcinoma of the cervix, or contralateral breast cancer.

Subjects with a prior contralateral breast malignancy can be included if they did not

receive any chemotherapy.

5. Baseline laboratories (repeat labs can be evaluated at baseline to establish

eligibility):

ANC Granulocytes < 1,500/ microliter

Platelets < 75,000/ microliter

Hemoglobin < 9 gm/dL

Total Bilirubin > 2 mg/dL

ALT and AST > 2.5 X upper limit of normal

Creatinine > 1.5 X upper limit of normal.

6. ECOG/Zubrod Performance Status > 2.

7. MUGA/Echocardiogram Left Ventricular Ejection Fraction < 50%.

8. Has a medical or psychiatric condition or other circumstances which would

significantly decrease the chances of obtaining reliable data, achieving study

objectives, or completing the study and/or post-dose follow-up examinations.

9. History of:

Acute coronary syndrome

Cerebral vascular accident

Abnormal cardiac stress testing within last 6 months

Symptomatic coronary artery disease

Uncontrolled hypertension or cardiomyopathy

Cardiac valvular surgery or open heart surgery

Known structural heart disease.

10. Has a condition which may interfere with the hyperthermia portion of the trial such

as: functioning cardiac pacemak

Exclusion Criteria:

Inclusion Criteria:

1. Histologically documented recurrent/metastatic adenocarcinoma of the breast with a

recurrence on the chest wall (or its overlying skin):

Subjects with ulcerative chest wall disease defined as non-healing wounds

consistent with cancer are eligible.

Subjects with prior skin changes consistent with inflammatory breast carcinoma

are eligible.

Breast carcinoma for medical reasons not being resected

2. Tumor thickness must be clinically indicated for hyperthermia therapy, as measured by

clinical exam or imaging studies (CT or MRI). The target local tumor lesion(s) must

be able to be covered within two hyperthermia fields of treatment.

3. Disease that has progressed despite other available standard treatment options, based

on what is clinically indicated according to the investigator's clinical and medical

judgment, including:

One or more radiation treatment(s) to the chest wall or breast up to a maximum

prior dose of 12,000 cGy in the hyperthermia field (not administered less than

28 days prior to enrollment).

4. Subjects who have previously received hyperthermia in conjunction with either

radiation therapy or chemotherapy are eligible.

5. Subjects may have distant metastasis, including brain metastases. Subjects with known

brain metastases are eligible if:

They have received standard anti-tumor treatment for their brain metastases

without encephalopathy;

Their neurological function is stable for at least 30 days and either off

steroid therapy or on a stable steroid regimen.

6. Non-pregnant female at least 18 years of age. If the subject is of child-bearing age,

must have a negative serum pregnancy test at baseline and must agree to practice an

acceptable form of birth control while on the study.

7. Provide written informed consent and willing to comply with protocol requirements.

Exclusion Criteria:

1. Requires any concomitant antineoplastic therapy. Prior chemotherapy should not be

administered within 5 half-lives or 28 days whichever is shorter. Subjects on a

current stable dose of hormonal treatments may continue on a stable dose during the

study (i.e. arimidex, amarosin, herceptin).

2. Prior confirmed allergic reaction (including moderate rash, dyspnea, wheezing,

urticaria or other symptoms) attributed to the administration of either

anthracyclines or other liposomally encapsulated drugs that required discontinuation

of prior therapy.

3. Prior therapy with anthracyclines exceeding the following doses (subjects will be

discontinued at 600 mg/m2 lifetime dose irrespective of the number of ThermoDox®

cycles received):

Free (i.e., non-liposomal) or liposomal doxorubicin > 450 mg/m2 Free epirubicin > 900

mg/m2.

4. Previous (required active treatment within 5 years) or concomitant malignancy except

basal cell cancer, in situ carcinoma of the cervix, or contralateral breast cancer.

Subjects with a prior contralateral breast malignancy can be included if they did not

receive any chemotherapy.

5. Baseline laboratories (repeat labs can be evaluated at baseline to establish

eligibility):

ANC Granulocytes < 1,500/ microliter

Platelets < 75,000/ microliter

Hemoglobin < 9 gm/dL

Total Bilirubin > 2 mg/dL

ALT and AST > 2.5 X upper limit of normal

Creatinine > 1.5 X upper limit of normal.

6. ECOG/Zubrod Performance Status > 2.

7. MUGA/Echocardiogram Left Ventricular Ejection Fraction < 50%.

8. Has a medical or psychiatric condition or other circumstances which would

significantly decrease the chances of obtaining reliable data, achieving study

objectives, or completing the study and/or post-dose follow-up examinations.

9. History of:

Acute coronary syndrome

Cerebral vascular accident

Abnormal cardiac stress testing within last 6 months

Symptomatic coronary artery disease

Uncontrolled hypertension or cardiomyopathy

Cardiac valvular surgery or open heart surgery

Known structural heart disease.

10. Has a condition which may interfere with the hyperthermia portion of the trial such

as: functioning cardiac pacemak

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Celsion Corporation

    Link to the current ClinicalTrials.gov record.
    NLM Identifer NCT00826085

    Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.