High-Dose Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Breast Cancer

Phase I-II Study of Dose Intense Doxorubicin, Paclitaxel And Cyclophosphamide With Peripheral Blood Progenitor Cells (PBPC) And Cytokine Support In Patients With Metastatic Breast Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining peripheral stem cell transplantation with chemotherapy may kill more tumor cells.

PURPOSE: Phase I/II trial to study the effectiveness of high-dose combination chemotherapy and peripheral stem cell transplantation in treating patients with recurrent or metastatic breast cancer.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Paclitaxel; Biological: Filgrastim (G-CSF); Drug: Doxorubicin Hydrochloride; Procedure: Peripheral Blood Stem Cell Transplantation

Detailed Description

OBJECTIVES: I. Define the maximum tolerated doses of four courses of doxorubicin (DOX), paclitaxel (TAX), and cyclophosphamide (CTX) followed by peripheral blood stem cell (PBSC) and granulocyte colony-stimulating factor support given in an out-patient setting in patients with metastatic breast cancer. II. Evaluate the cardiotoxicity of the combination of bolus DOX, a 3-hour infusion of TAX, and CTX. III. Determine the clinical response rate and time to progression associated with this regimen. IV. Determine Cmax, AUC and the drug:metabolite ratio of TAX and DOX when given with CTX, a known p450 inducer.

OUTLINE: Patients without prior doxorubicin (DOX) or paclitaxel (TAX) receive two courses of induction chemotherapy with DOX/TAX with G-CSF support given 3 weeks apart. Peripheral blood stem cells (PBSC) are harvested during the recovery phase following the second course. Patients who previous received DOX or TAX and responded receive cyclophosphamide (CTX) with G-CSF for stem cell mobilization followed by PBSC harvest. Back-up bone marrow may be harvested from patients without marrow involvement for whom PBSC collection is inadequate. Patients with responding or stable disease who have adequate PBSC available receive dose-intensive chemotherapy with DOX, CTX, and TAX given on day 1, with PBSC infused on day 3 and G-CSF given from day 3 until neutrophil recovery. Four courses of dose-intensive chemotherapy with PBSC and G-CSF support are given every 3-4 weeks. During the phase I portion of the study, groups of 3-6 patients are treated at increasing doses of DOX, TAX, and CTX until the maximum tolerated dose (MTD) is determined; during the phase II portion, additional patients are treated at the MTD. Patients who progress after 2 courses of induction or 2 courses of dose-intensive chemotherapy are given the option of receiving their PBSC after conditioning with a different regimen (e.g., CTX, etoposide, and cisplatin). Patients who receive induction on protocol but who choose not to receive dose-intensive chemotherapy continue DOX/TAX for a total of 6 courses. Patients are followed 3, 6, 12, 18, and 24 months after therapy, then as clinically indicated.

PROJECTED ACCRUAL: During the phase I portion of the study, groups of 3-6 patients will be entered at each dose level studied. During the phase II portion of the study, 25 patients will be treated at the maximum tolerated dose.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas - MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS: Histologically confirmed breast cancer that is metastatic or recurrent Poor-prognosis status required for Phase I portion of the study, i.e.: Estrogen receptor and progesterone receptor-negative tumor OR Failed hormonal therapy and with bulky disease or liver metastasis Bone marrow involvement less than 15% No active CNS metastases

PATIENT CHARACTERISTICS: Age: 15 to 60 Sex: Not specified Performance status: Zubrod 0 or 1 Hematopoietic: WBC greater than 3,500/mm3 Absolute granulocyte count greater than 2,000/mm3 Platelet count greater than 100,000/mm3 Hepatic: Liver function tests less than twice normal Renal: Creatinine clearance (calculated) at least 60 mL/min Cardiovascular: Left ventricular ejection fraction greater than 50% No symptomatic cardiac disease requiring antiarrhythmic or inotropic therapy Pulmonary: DLCO greater than 50% of predicted Other: No pre-existing peripheral neuropathy greater than grade 1 No severe concomitant medical or psychiatric disease

PRIOR CONCURRENT THERAPY: Biologic therapy: More than 3 weeks since any immunotherapy Chemotherapy: No prior doxorubicin or paclitaxel Patients with up to 150 mg per square meter doxorubicin or up to 4 courses of paclitaxel and who have responding disease are eligible for dose-intensive portion of protocol therapy Endocrine therapy: Not specified Radiotherapy: More than 3 weeks since any radiotherapy Surgery: Not specified

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doxorubicin, Paclitaxel + Cyclophosphamide with PBPC	Drug: Cyclophosphamide; Other Names: Cytoxan; Neosar; Drug: Paclitaxel; Other Names: Taxol; Biological: Filgrastim (G-CSF); Other Names: Neupogen; Drug: Doxorubicin Hydrochloride; Other Names: Adriamycin PFS; Adriamycin RDF; Procedure: Peripheral Blood Stem Cell Transplantation; Other Names: PBSCT; Stem Cell Transplant; SCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum Tolerated Doses (MTD) of 4 courses Doxorubicin, Paclitaxel, + Cyclophosphamide followed by PBSC and G-CSF Support	Evaluated with each 3-4 week course

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: Bristol-Myers Squibb; National Cancer Institute (NCI)
• Investigators: Study Chair: Michele L. Donato, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• UT MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start: September 1, 1995
• Primary Completion (Actual): January 1, 2002
• Study Completion (Actual): January 1, 2002

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: June 30, 2004
• First Posted (Estimate): July 1, 2004

Study Record Updates

• Last Update Posted (Estimate): July 31, 2012
• Last Update Submitted That Met QC Criteria: July 27, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: stage IV breast cancer; recurrent breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Paclitaxel; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: DM95-156; P30CA016672 (U.S. NIH Grant/Contract); MDA-DM-95156 (Other Identifier: UT MD Anderson Cancer Center); NCI-V96-1017; CDR0000065052 (Registry Identifier: NCI PDQ)