9.1 
Patients whose peripheral blood is not successfully marked with 
the MDR-1 retroviral vector, and whose peripheral blood cells do 
not exhibit an increase in the level of resistance to the non 
ablative dose chemotherapy with MDR drugs will not be continued 
on study unless there are preparations of marrow which contain 
elevated levels of hematopoietic cells which are resistant to MDR 
drugs above the levels which are encountered with unmodified 
cells . 
Patients with unacceptable toxicity will be taken off study. 
Patients exhibit two consecutive grade IV hematopoietic or other 
toxicities on post transplant Taxol despite dose reductions, will 
be removed from the study. Patients who refuse further 
participation in the study will also be discontinued from the 
study. All other patients will continued to be followed as 
described above. 
9.2 Patients with progressive disease will be removed from the study. 
10.0 STATISTICAL CONSIDERATIONS 
10.1 For this pilot trial, evaluation of the persistence of the 
functional state of the MDR sequences introduced into peripheral 
blood cells which are then transplanted will be conducted by 
aspiration of marrow cells following hematopoietic recovery from 
the transplant, and following each dose of post-transplantation 
therapy with Taxol for the first two years, or until the therapy 
is discontinued due to progression of disease, or until the death 
of the patient. PCR for MDR-1 will be used, and functional 
assays for the efficiency of efflux pumping by the marrow cells 
of dye rhodamine, and of the MDR drugs such adriamycin, and by 
study of in vitro resistance of the modified cells. The PCR 
assay will be done following the schedule outlined in Appendix F. 
The number of patients necessary to be entered for this program 
is between 10-2 0, so that a total of 10 evaluable patients can be 
transplanted and followed through at least 12 courses of Taxol. 
One patient per month will be evaluated and then study completed 
in one to two years. Success of the trial will be measured by 
decreases detactable in the duration and depth of the nadirs 
following Taxol chemotherapy during the dose escalation, which 
can be correlated with increases in the percentages of the cells 
which contain the MDR-1 viral transgene, by the statistical 
methods described in Appendix I. 
10.2 Evaluation of the response of the breast cancer to the therapy 
delivered as preparative therapy before bone marrow 
transplantation, and after the post-transplantation therapy of 
cyclical high dose Taxol, as outlined in the Treatment Plan. 
10.3 Stopping Rules: If three successive treatment deaths occur, or 
the mortality is >50% in the analyses of the cohorts at 6, 8 and 
10 patients, the trial will stop. In addition, if 3 successive 
patients fail to engraft (failure to reach 500 neutrophils/per mm 
in 30 days post transplant), and delayed hematopoietic recovery, 
the trial will be stopped. If the tumor progresses during the 
preparative therapy or during Taxol therapy in an individual 
patient, the therapy will be stopped for that patient. If 
unacceptable levels of non-hematopoietic toxicity is encoiintered , 
Recombinant DNA Research, Volume 19 [537] 
