5.4 Maintenance Taxol Therapy: Following recovery from the autologous 
transplant, 12 courses of Taxol will be given, starting at a dose 
of 60 mg/m^, and escalating each course by the scheme outlined 
below (at 120, 180, 235, and 275 mg/m^ depending on the grade of 
hematopoietic toxicity in the previous cycle of therapy) as a 
single 24-hour continuous infusion each cycle, in the doses 
listed below, every three to four weeks following recovery of 
hematopoietic function after transplantation of the MDR-1 virally 
modified peripheral blood stem cells, when the platelet count, 
hemoglobin, white cell count and ANC are greater or equal to the 
following values respectively: 100,000/cu mm, 8 g/dl, 4,000/cu 
mm, and 1800/cu mm. Each dose of Taxol will be preceded by 
Dexamethasone (20 mg po or IV at 12 hrs and 6 hrs prior to 
Taxol) , Cimetidine (300 mg IV 30 min prior to Taxol) , and 
diphenhydramine (50 mg IV 3 0 min prior to Taxol) , to reduce the 
probability of analyphylaxis from Taxol. A total of 12 doses of 
Taxol will be given post transplant unless the events listed in 
Section 10.0 as stopping rules occur. 
We have described below the algorithms used to adjust downwards 
the dose of Taxol if Grade IV toxicity is encountered following 
60 mg/m^ for the initial dose of Taxol. 
We have proposed a starting dose of Taxol post autologous 
transplant of 60 mg/m^. This dose is below the MTD, but was 
chosen because patients have decreased stem cell reserve 
immediately following transplant on the basis of decreased bone 
marrow cellular ity. No one has given Taxol immediately following 
bone marrow transplant, and therefore we do not know if the MTD 
is the same for Taxol in these sensitive post transplant patients 
as it is in patients not just recovered from an autologous 
transplant. The discussions within our own center, and during 
the approval process before the NIH RAC led to the selection of 
the low starting dose of Taxol post transplant. As shown below, 
a dose escalation scheme which is rapid, and provides adjustments 
on the basis of the tolerance of the patient to the Taxol, is 
provided. This dose escalation scheme will provide for dose 
reductions in the case of grade IV toxicity, and dose escalations 
in case of the relative absence of toxicity (Grade I/II 
hematopoietic toxicity) . 
This low starting dose will not compromise the selection of 
genetically modified cells post transplant, since the dose 
escalation of the Taxol is so rapid. The studies in the mouse 
show that the frequency of the genetically-modified cells is 
quite high following bone marrow transplant, even before the 
administration of the first dose of Taxol (see Appendix C) . This 
starting dose will not compromise the comparability of the 
recovery curves in patients transplanted with genetically- 
modified cells, with those breast cancer patients receiving 
comparable doses of Taxol, since the doses of Taxol which are 
comparable to those being administered to comparable breast 
cancer patients who have not had transplants with genetically- 
modified cells, will be reached through the dose escalation 
scheme very rapidly. 
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Recombinant DNA Research, Volume 19 
