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.
