The main goal of LABORATORY PROGRAM II is to generate pharmacokinetic and pharmacodynamic data in support of the clinical trials outlined in CLINICAL PROGRAM I & II. In the proposed studies, we will employ (a) carefully developed and validated analytical methods for quantitating drugs and metabolites in serum samples chained from experiments in the SCID mouse model of human B-lineage ALL and from children with relapsed B-lineage ALL enrolled on clinical trials (b) biomedical modeling and pharmacokinetic/dynamic parameter estimation for both individual subjects and study populations, as well as (c) quantitative and qualitative linkage between drug disposition and exposure in the SCID mouse model and children with B-lineage ALL.
Under SPECIFIC AIM 1, we will study the disposition of B43-PAP immunotoxin in children with B-lineage ALL to define the relationship between the level of systemic exposure to B43-PAP and the antileukemic efficacy, toxicity, and immunogenicity of B43-PAP.
Under SPECIFIC AIM 2, we will perform pharmacokinetic and pharmacodynamic studies in SCID mice and children with B-lineage ALL receiving B43-PAP in combination with one of four chemotherapeutic agents (viz., cyclophosphamide, topotecan, etoposide, or cytosine arabinoside). We will interface pharmacokinetic and pharmacodynamic data from the SCID mouse model and from relapsed ALL patients treated according to the proposed combinative immunochemotherapy regimens outlined in CLINICAL PROGRAM II. Our primary goal is to determine whether systemic exposure levels of chemotherapeutic agents capable of enhancing the anti-leukemic activity of B43-PAP immunotoxin without significant added toxicity can be achieved in ALL patients. The integration of the laboratory data generated by LABORATORY PROGRAM II with the clinical outcome data of patients will (a) enable us to test specific hypotheses listed in the INTRODUCTORY SECTION, (b) expand our knowledge of the clinical potential of B43-PAP immunotoxin as a new anti-B-lineage ALL agent, and (c) likely provide the foundation for the design of novel and effective combinative immunochemotherapy regimens against poor prognosis B-lineage ALL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA061549-04
Application #
2339092
Study Section
Project Start
Project End
Budget Start
1995-10-01
Budget End
1996-09-30
Support Year
4
Fiscal Year
1996
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ek, O; Reaman, G H; Crankshaw, D L et al. (1998) Combined therapeutic efficacy of the thymidylate synthase inhibitor ZD1694 (Tomudex) and the immunotoxin B43(anti-CD19)-PAP in a SCID mouse model of human B-lineage acute lymphoblastic leukemia. Leuk Lymphoma 28:509-14
Uckun, F M; Yanishevski, Y; Tumer, N et al. (1997) Pharmacokinetic features, immunogenicity, and toxicity of B43(anti-CD19)-pokeweed antiviral protein immunotoxin in cynomolgus monkeys. Clin Cancer Res 3:325-37
Waurzyniak, B; Schneider, E A; Tumer, N et al. (1997) In vivo toxicity, pharmacokinetics, and antileukemic activity of TXU (anti-CD7)-pokeweed antiviral protein immunotoxin. Clin Cancer Res 3:881-90
Messinger, Y; Yanishevski, Y; Avramis, V I et al. (1996) Treatment of human B-cell precursor leukemia in SCID mice using a combination of the investigational biotherapeutic agent B43-PAP with cytosine arabinoside. Clin Cancer Res 2:1533-42
Gunther, R; Chelstrom, L M; Wendorf, H R et al. (1996) Toxicity profile of the investigational new biotherapeutic agent, B43 (anti-CD19)-pokeweed antiviral protein immunotoxin. Leuk Lymphoma 22:61-70, follow.186, color plate
Uckun, F M; Reaman, G H (1995) Immunotoxins for treatment of leukemia and lymphoma. Leuk Lymphoma 18:195-201
Myers, D E; Yanishevski, Y; Masson, E et al. (1995) Favorable pharmacodynamic features and superior anti-leukemic activity of B43 (anti-CD19) immunotoxins containing two pokeweed antiviral protein molecules covalently linked to each monoclonal antibody molecule. Leuk Lymphoma 18:93-102
Uckun, F M; Myers, D E (1993) Allograft and autograft purging using immunotoxins in clinical bone marrow transplantation for hematologic malignancies. J Hematother 2:155-63