Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information

Alternate Title

High-Dose Chemotherapy, Peripheral Stem Cell Transplantation, and Gene Therapy in Treating Women With Stage IV Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	18 and over	NCI	NCI-96-C-0007K NCI-MB-361, NCI-T95-0096N, T95-0096

Objectives

I.  Evaluate the feasibility of retroviral transfer of the multidrug 
resistance (MDR1) and neomycin resistance (NeoR) genes into peripheral blood 
progenitor cells and the reconstitution of gene-marked cells following 
nonablative chemotherapy in the initial treatment of patients with metastatic 
breast cancer.

II.  Determine whether the transduced MDR1 gene affects in vivo expansion of 
MDR1-transduced cells relative to NeoR cells after treatment with the 
noncross-resistant drugs paclitaxel (TAX) and doxorubicin (DOX).

III.  Evaluate the feasibility of sequential administration of 4 courses of 
antimetabolite chemotherapy (methotrexate/fluorouracil) followed by 3 courses 
of high-dose single-agent alkylator chemotherapy (cyclophosphamide and 
thiotepa) followed by multiple courses of TAX and DOX in these patients.

IV.  Assess the toxicity of this regimen, and determine whether evidence of in 
vivo expansion of MDR1-transduced cells can be correlated with decreased 
myelotoxicity.

V.  Study the pattern of T-cell depletion and recovery and T-cell signal 
transduction and function following dose-intensive chemotherapy.

Entry Criteria

Disease Characteristics:

Histologically diagnosed stage IV breast cancer
  No CNS metastases (CT or MRI required)

Hormone receptor status:
  Not specified

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  No prior chemotherapy for metastatic disease
  Prior adjuvant chemotherapy allowed
  At least 3 weeks since chemotherapy and recovered

Endocrine therapy:
  No chronic steroids

Radiotherapy:
  At least 3 weeks since radiotherapy and recovered
  No more than 25% of bone marrow previously irradiated

Surgery:
  Not specified

Patient Characteristics:

Age:
  18 and over

Sex:
  Female

Menopausal status:
  Any status

Performance status:
  ECOG 0-2

Hematopoietic:
  (in absence of bone marrow metastases)
  Absolute neutrophil count greater than 1,200/mm3
  Platelet count greater than 100,000/mm3

Hepatic:
  (in absence of liver metastases)
  Bilirubin less than 1.8 mg/dL
  Transaminases less than 2 times normal

Renal:
  (unless due to metastases)
  Creatinine less than 2.0 mg/dL
  Creatinine clearance (12 to 24-hour) greater than 50 mL/min

Cardiovascular:
  Left ventricular ejection fraction at least 40% on MUGA OR
  Left ventricular function normal on echocardiogram
  No clinically significant cardiovascular disease, e.g.:
     Arrhythmia
     Congestive heart failure
     Coronary artery disease

Other:
  No HIV antibody or hepatitis B antibody/antigen
  No requirement for anticoagulants
  No nonmalignant medical or psychiatric condition that precludes entry
  No second malignancy within 10 years except:
     In situ cervical cancer
     Basal cell carcinoma
     Prior breast cancer
  Not pregnant or nursing

Expected Enrollment

A maximum of 25 patients will be treated.

Outline

Patients with undrainable pleural effusions or ascites proceed directly to 
consolidation therapy.  Other patients receive induction chemotherapy with 
methotrexate, fluorouracil, and leucovorin every 2 weeks for 2-4 courses.

Patients then receive one 3-week course of consolidation therapy with 
cyclophosphamide followed by daily filgrastim (granulocyte colony-stimulating 
factor; G-CSF) and leukapheresis.  Of the cells collected, one half are 
transduced with the multidrug resistance gene, and one half with the neomycin 
resistance gene.

Patients receive myeloablative doses of thiotepa followed by G-CSF and stem 
cells transduced with the multidrug resistance and neomycin resistance genes.
Patients who did not have the minimum number of peripheral cells collected do 
not receive thiotepa.

After hematopoietic reconstitution, patients receive 24-hour infusions of 
paclitaxel every 3 weeks for four doses, followed by doxorubicin or 
vinblastine every 3 weeks for 4 doses.

Patients are followed monthly for 3 months, then q 3 months for 9 months and 
every 6 months thereafter.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Kenneth Cowan, MD, PhD, Protocol chair		Ph: 402-559-4238 Email: kcowan@unmc.edu