DOSE ADJUSTMENT SCHEMA FOR PATIENTS 
POST-TRANSPLANT WITH MDR-1 MODIFIED MARROW 
* 
Starting Dose of Taxol* 
(60 mg/m^) 
i 
Enter 3 patients and await 
hematopoietic recovery 
I 
Grade I/II Grade III Grade IV 
i • 4 4 
Escalate dose** Same dose Reduce dose 
4 4 
120 mg/m^ 40 mg/m^ 
4 4 
180 mg/m^ Grade IV 
4 Off study 
225 mg/m^ 
4 
275 mg/m^ 
For the initial dose only, if greater or equal to 2/3 of the first 
three patients have Grade IV toxicity, then start next cohort of three 
patients at 4 0 mg/m^; otherwise, all patients will start at 60 mg/m^. ! 
Rule for all subsequent courses after the first course for escalation 
or reduction: 
. . ! 
Grade I/II toxicity leads to an increased dose level ( 
Grade III same dose level I 
Grade IV reduce dose level 
I 
Patients will be followed for signs of a toxic effect of the ! 
transduction on the hematopoietic cells used to generate hematopoietic j 
recovery following infusion of the modified marrow. Our data in J 
transplants of eight CML and eight breast cancer patients reconstituted | 
with the CD34 peripheral blood (breast) or peripheral blood and marrow 
(CML) hematopoietic cells suggests that the time required for recovery 
to 500 PMN/cu mm is in the range of 10-2 3 days. Any delay beyond 40 
days, if it occurs in three successive patients, will be considered a 
sign that the retroviral modification has had a toxic effect on the 
autologous cells used for transplant. 
The time to recovery after each dose of Taxol will be monitored by ; 
measuring the time required to reach 500 neutrophils/cu mm, 1000 
neutrophils/cu mm, and the depth of the nadir will be measured after : 
each cycle by Taxol. We will compare duration and depth of each nadir ; 
(time to recover to 500 and 1000 PMN/cu mm, and the depth of each j 
nadir) encountered after the different doses of Taxol summarized above } 
in breast cancer patients who have been transplanted with MDR-1 ; 
transduced marrow, with duration and depth of neutropenia encountered i 
in breast cancer patients whose marrow is not MDR-1 transduced. This 
will tell us if the MDR-1 transduction is protecting the marrow. 
RT PCR will be conducted to determine the percentage of cells which j 
contain the MDR-1 retroviral vector to measure the frequency 
distribution of the level of the MDR-1 within the cells of the | 
[532] Recombinant DNA Research, Volume 19 I 
