Liposomal Doxorubicin Before Mastectomy in Treating Women With Invasive Breast Cancer

A Phase I Study Assessing the Feasibility and Safety of Intraductal Administration of Pegylated Liposomal Doxorubicin (Doxil) in Women With 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. 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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Intraductal arm; Drug: Intravenous arm

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intraductal arm; Participants received intraductal administration of dextrose or dextrose with pegylated liposomal doxorubicin hydrochloride (or PLD) prior to conventional surgery for breast cancer.	Drug: Intraductal 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; Other Names: Doxorubicin HCl Liposome Injection, Dox-SL, Doxil TM
Active Comparator: Intravenous arm; Participants receiving standard intravenous administration of pegylated liposomal doxorubicin prior to breast biopsy for drug concentrations.	Drug: Intravenous 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.; Other Names: Doxorubicin HCl Liposome Injection, Dox-SL, Doxil TM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Until up to 30 days after PLD administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 4 hrs, day2/24 hrs, day 8, day of surgery/biopsy
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.	Day of surgery/biopsy

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Vered Stearns, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications and helpful links

General Publications

• Stearns V, Mori T, Jacobs LK, Khouri NF, Gabrielson E, Yoshida T, Kominsky SL, Huso DL, Jeter S, Powers P, Tarpinian K, Brown RJ, Lange JR, Rudek MA, Zhang Z, Tsangaris TN, Sukumar S. Preclinical and clinical evaluation of intraductally administered agents in early breast cancer. Sci Transl Med. 2011 Oct 26;3(106):106ra108. doi: 10.1126/scitranslmed.3002368.

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: February 9, 2006
• First Submitted That Met QC Criteria: February 9, 2006
• First Posted (Estimate): February 13, 2006

Study Record Updates

• Last Update Posted (Estimate): October 31, 2013
• Last Update Submitted That Met QC Criteria: October 7, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: stage IV breast cancer; stage IIIA breast cancer; stage II breast cancer; stage IIIC breast cancer; stage I breast cancer; breast cancer in situ; ductal breast carcinoma in situ
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: J0503 CDR0000459502; P30CA006973 (U.S. NIH Grant/Contract); JHOC-J0503 (Other Identifier: SKCCC at Johns Hopkins)