Trial Information

Antimetabolite Induction, High-Dose Alkylating Agent Consolidation and Retroviral Transduction of the MDR1 Gene Into Peripheral Blood Progenitor Cells Followed by Intensification Therapy With Sequential Paclitaxel and Doxorubicin for Stage 4 Breast Cance

This pilot trial will determine whether retroviral-transduced peripheral blood progenitor
cells (PBPCs) can be selected and expanded in vivo after non-ablative chemotherapy in
patients with metastatic breast cancer. It will also examine the feasibility of
administering induction high-dose therapy with antimetabolites, followed with consolidation
using high-dose single alkylating agent therapy and finally intensification therapy with
sequential cycles of very high doses of the natural product breast cancer chemotherapeutic
agents (paclitaxel followed by doxorubicin).

Patients will receive induction therapy with antimetabolite agents (methotrexate, leucovorin
and 5-fluorouracil) for two to four cycles. Patients will then receive consolidation
therapy with two cycles of high-dose alkylating agents. First, patients will receive one
cycle of high-dose cyclophosphamide administered with growth factor support. PBPCs will be
harvested during the recovery phase of the cyclophosphamide cycle.

One-half of the cells to be reinfused will be transduced with a retroviral vector containing
the gene for the multidrug resistance protein (MDRI in vector G1MD) and the other half will
be transduced with a vector containing the neomycin resistance gene (NeoR in vector
G1Na.40). Both of these vectors have previously been approved by the Recombinant DNA
Advisory Committee for PBPC transduction in Medicine Branch protocols.

The next cycle will consist of high-dose single agent thiotepa. Hematopoietic stem cells
mobilized and collected during the previous cyclophosphamide cycle and transduced with the
retroviral vectors will be reinfused following treatment with thiotepa to augment recovery
of bone marrow function. After recovery, intensification with natural product chemotherapy
will be administered, consisting of four cycles of paclitaxel given as a 24-hour infusion
followed by four cycles of single agent doxorubicin. Peripheral blood mononuclear cells
will be monitored following each cycle of paclitaxel and doxorubicin for the presence of the
MDRI and NeoR transgenes. The ration of the levels of MDRI to NeoR transgenes in peripheral
blood will determine whether in vivo expansion of the PBPCs containing the selectable MDRI
marker has been achieved.

This protocol combines several highly active chemotherapeutic agents in an attempt to
improve upon response rates achieved with current combinations. Patients who do not wish to
participate in the gene therapy procedures will be offered identical chemotherapy in a
different protocol.