Breast Cancer
Conditions
Keywords
stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIC breast cancer, stage IV breast cancer, breast cancer in situ, ductal breast carcinoma in situ
Brief summary
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. Giving chemotherapy in different ways, such as into the breast ducts, may kill more tumor cells. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase I trial is studying the side effects and best dose of liposomal doxorubicin when given before mastectomy in treating women with invasive breast cancer.
Detailed description
OBJECTIVES: Primary * Evaluate the feasibility, safety, and maximum tolerated dose of intraductal pegylated doxorubicin HCl liposome in women with invasive breast cancer awaiting mastectomy. Secondary * Determine the pharmacokinetics of intraductal pegylated doxorubicin HCl liposome, including serial plasma concentrations of doxorubicin and doxorubicinol and tissue concentrations in different portions of the breast at the time of surgery. OUTLINE: This is a dose-escalation study. Patients receive an intraductal injection of pegylated doxorubicin HCl liposome\* on day 1. Patients undergo mastectomy 2-4 weeks later. Cohorts of 3-6 patients receive escalating doses of pegylated doxorubicin HCl liposome\* until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. NOTE: \*The first cohort of 3 patients receive intraductal dextrose only followed by surgery as a feasibility study. An additional 3 patients receiving intravenous PLD will be enrolled in a pharmacokinetic control portion of the study.
Interventions
DRUGIntravenous arm
Blood samples and a breast tissue biopsy collected to look at levels of doxorubincol from patients receiving intravenous pegylated liposomal doxorubin to compare to the group receiving drug intraductally.
DRUGIntraductal arm
Patients will receive PLD intraductally according to the dose escalation schema (Dose Level -1=1 mg, Dose Level 1=2 mg, Dose Level 2= 5mg, Dose Level 3=10 mg). The PLD dose will be diluted in 5% dextrose in water and will be mixed for a total volume of 5 ml. The PLD will be administered via a breast duct (i.e., intraductally) using a microcatheter
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed infiltrating carcinoma of the breast meeting any of the following criteria: * T1-3, any N disease * Proven ductal carcinoma in situ * Unresected disease * Planned mastectomy as definitive surgical procedure * Known or suspected metastatic disease allowed provided mastectomy is planned * Nonpalpable tumor allowed (e.g., initial T2-3 tumor that responded to preoperative therapy) * No inflammatory breast cancer or other T4 features * Successful baseline ductogram * Baseline nipple aspiration procedure must identify a duct productive of nipple aspirate fluid * No severe nipple retraction * Hormone receptor status not specified PATIENT CHARACTERISTICS: * Female patients * Menopausal status not specified * ECOG performance status 0-2 * Absolute neutrophil count ≥1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin ≥ 9.0 g/dL * Creatinine ≤ 2 times upper limit of normal (ULN) * Bilirubin ≤ 2 times ULN * AST and ALT ≤ 2.5 times ULN * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No significant history of severe allergy to iodinated contrast material or debilitating anxiety that may not allow for a ductogram PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Prior preoperative chemotherapy, trastuzumab (Herceptin®), or hormonal therapy allowed provided it was completed 7-14 days prior to study treatment * No prior radiation therapy, excisional biopsy, breast reduction, areolar surgery, or breast implant (present or past history of implant that was removed) * No other prior procedure that may have altered the breast ductal system in the ipsilateral breast * No other concurrent chemotherapy, radiotherapy, endocrine therapy, or biologic agents for breast cancer * No other concurrent investigational drugs * Concurrent bisphosphonates allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Until up to 30 days after PLD administration | Maximum tolerated dose (MTD) of administering pegylated liposomal doxorubicin (PLD) into one duct of women with breast cancer awaiting mastectomy. MTD reflects highest dose of drug that did not cause Dose Limiting Toxicity (DLT) in more than 30% of patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Baseline, 4 hrs, day2/24 hrs, day 8, day of surgery/biopsy | Due to the limited number of samples and detectable levels, the maximum concentration of doxorubicin in blood (plasma) across all the participants in each group is reported. |
| Concentrations of Doxorubicin in Tissue at Definitive Surgery | Day of surgery/biopsy | Due to the limited number of samples and detectable levels, the maximum concentration of doxorubicin in tissue across all the participants in each group is reported. |
Countries
United States
Participant flow
Recruitment details
From February 2006 to October 2009, 19 women signed consent, and 17 women were enrolled in the intraductal portion of the study. An addition 3 women receiving standard intravenous PLD were enrolled in a pharmacokinetic contract portion.
Pre-assignment details
Participants were not included after consent if eligibility criteria were not met (eg, lab values, performance status); an additional 2 subjects were consented but not included in the study population.
Participants by arm
| Arm | Count |
|---|---|
| Intraductal Arm Participants received intraductal administration of dextrose or dextrose with pegylated liposomal doxorubicin hydrochloride (or PLD) prior to conventional surgery for breast cancer. | 17 |
| Intravenous Arm Participants receiving standard intravenous administration of pegylated liposomal doxorubicin prior to breast biopsy for drug concentrations. | 3 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Inability to instill drug intraductally. | 0 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Intraductal Arm | Intravenous Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 3 Participants | 18 Participants |
| Region of Enrollment United States | 17 participants | 3 participants | 20 participants |
| Sex: Female, Male Female | 17 Participants | 3 Participants | 20 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 | 0 / 0 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 1 / 6 | 0 / 0 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
Maximum tolerated dose (MTD) of administering pegylated liposomal doxorubicin (PLD) into one duct of women with breast cancer awaiting mastectomy. MTD reflects highest dose of drug that did not cause Dose Limiting Toxicity (DLT) in more than 30% of patients.
Time frame: Until up to 30 days after PLD administration
Population: Participants received intraductal administration of dextrose prior to conventional surgery for breast cancer.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intraductal Arm | Maximum Tolerated Dose (MTD) | 10 milligrams |
Secondary
Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery
Due to the limited number of samples and detectable levels, the maximum concentration of doxorubicin in blood (plasma) across all the participants in each group is reported.
Time frame: Baseline, 4 hrs, day2/24 hrs, day 8, day of surgery/biopsy
Population: Participants in whom blood and/or tissue samples were collected at surgery or breast biopsy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intraductal Arm | Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Doxorubicin, max | 0 nM |
| Intraductal Arm | Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Doxorubicinol, max | 0 nM |
| Intraductal Arm- 2 mg PLD | Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Doxorubicin, max | 28.5 nM |
| Intraductal Arm- 2 mg PLD | Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Doxorubicinol, max | 0 nM |
| Intraductal Arm- 5 mg PLD | Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Doxorubicin, max | 18.3 nM |
| Intraductal Arm- 5 mg PLD | Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Doxorubicinol, max | 0 nM |
| Intraductal Arm- 10 mg PLD | Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Doxorubicinol, max | 36.9 nM |
| Intraductal Arm- 10 mg PLD | Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Doxorubicin, max | 902.0 nM |
| Intravenous Arm | Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Doxorubicin, max | 79300 nM |
| Intravenous Arm | Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Doxorubicinol, max | 8090 nM |
Secondary
Concentrations of Doxorubicin in Tissue at Definitive Surgery
Due to the limited number of samples and detectable levels, the maximum concentration of doxorubicin in tissue across all the participants in each group is reported.
Time frame: Day of surgery/biopsy
Population: Participants in whom blood and/or tissue samples were collected at surgery or breast biopsy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intraductal Arm | Concentrations of Doxorubicin in Tissue at Definitive Surgery | Doxorubicinol, max | 0 nmol/g |
| Intraductal Arm | Concentrations of Doxorubicin in Tissue at Definitive Surgery | Doxorubicin, max | 0 nmol/g |
| Intraductal Arm- 2 mg PLD | Concentrations of Doxorubicin in Tissue at Definitive Surgery | Doxorubicin, max | 0 nmol/g |
| Intraductal Arm- 2 mg PLD | Concentrations of Doxorubicin in Tissue at Definitive Surgery | Doxorubicinol, max | 0 nmol/g |
| Intraductal Arm- 5 mg PLD | Concentrations of Doxorubicin in Tissue at Definitive Surgery | Doxorubicinol, max | 0.09 nmol/g |
| Intraductal Arm- 5 mg PLD | Concentrations of Doxorubicin in Tissue at Definitive Surgery | Doxorubicin, max | 1.73 nmol/g |
| Intraductal Arm- 10 mg PLD | Concentrations of Doxorubicin in Tissue at Definitive Surgery | Doxorubicin, max | 10.82 nmol/g |
| Intraductal Arm- 10 mg PLD | Concentrations of Doxorubicin in Tissue at Definitive Surgery | Doxorubicinol, max | 5.26 nmol/g |
| Intravenous Arm | Concentrations of Doxorubicin in Tissue at Definitive Surgery | Doxorubicinol, max | 0 nmol/g |
| Intravenous Arm | Concentrations of Doxorubicin in Tissue at Definitive Surgery | Doxorubicin, max | 0.21 nmol/g |