STUDY OF MAB 216 WITH CHEMOTHERAPY FOR THE TREATMENT OF PEDIATRIC PATIENTS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary Aims: 1. Estimate the maximum tolerable dose (MTD) of monoclonal antibody 216 (mAb 216), administered in two doses one week apart, to children with relapsed or refractory acute lymphoblastic leukemia (ALL). 2. Determine the dose-limiting toxicities (DLT) of mAb 216 given on this schedule, as a single agent and in combination with Vincristine. 3. Characterize the pharmacokinetic behavior of mAb 216 in children with relapsed or refractory ALL. Secondary Aims: 1. Preliminarily define the anti-tumor activity of mAb 216 within the confines of a Phase I study. 2. Assess the biologic activity of mAb 216 in patients with relapsed or refractory ALL. Goals ALL is the most common malignancy of childhood. Approximately 80% of childhood ALL is of B-cell lineage, and although with current therapy nearly 80% of children with ALL will be cured, for the remaining group of patients the need for new and different treatment strategies continues to be a therapeutic challenge. Agents that demonstrate specificity for leukemic blasts, but which do not share a toxicity profile with chemotherapy drugs, would be particularly advantageous for designing new strategies of anti-leukemia therapy. Our research has found that malignant B cells obtained from ALL, non-Hodgkin's lymphoma (NHL) patient biopsies, B-cell lines and normal human B-cells are killed in vitro by a subset of monoclonal antibodies (mAbs) encoded by the VH4-34 gene (variable heavy region), and that cytotoxicity of VH4-34 encoded Abs are highly specific for B cells. Because human mAb 216 was the most cytotoxic of the tested mAbs, it has been used for further study. Importantly, flow cytometry analysis of normal bone marrow stained with labeled mAb 216 and labeled anti CD34 showed that 216 does not react with stem cells, so although the normal peripheral B cells would be killed in vivo by mAb 216 treatment, they will repopulate. Furthermore, in vitro studies have demonstrated mAb 216's cytotoxicity on pre-B cells from children diagnosed with ALL. In vitro cytotoxicity of mAb 216 in combination with single chemotherapeutic agents has also been tested. Cell lines which have been derived from ALL blasts of different genotype and phenotype, were incubated with mAb 216 alone or in combination with vincristine, daunomycin, or L-asparaginase. All of these chemotherapeutic agents increased the degree of cytoxicity seen with either single agent chemotherapy or mAb 216 alone. However, the combination of vincristine with mAb 216 was particularly striking, resulting in enhanced cytoxicity an order of magnitude greater than that seen with either vincristine or mAb 216 alone. Through the RAID program, the NCI and its contractors have performed in rabbits, pharmacokinetic (PK) and toxicity studies of mAb 216 alone and when given in combination with Vincristine. On histopathologic examination, no drug-related changes were noted. By itself, three days after administration, mAb 216 produced a dose-related decrease in platelet count, and mean WBC counts were decreased at a 20 mg/kg dosage, primarily due to neutropenia. Both platelet and WBC counts recovered by Day 8, and there were no significant changes in serum chemistry parameters. Based on the results of toxicology studies, RAID investigators concluded that sustained systemic toxicity is not expected at the planned clinical doses (100-400 mg/m2/dose) of mAb 216 when given in combination with Vincristine. While this is the first Phase I trial of mAb 216 in pediatric patients, another VH4-34 derived antibody, HA-1A, has been tested in children. In those studies, there were no adverse events reported that were felt to be "definitely" or "probably related" to HA-1A. While not definitive, these results suggest that mAb 216 may be well tolerated in pediatric patients. Given the high risk nature of the patient population who will be eligible for treatment on this Phase I study, it is the intent of this trial design to: 1) allow testing of mAb 216 as a single agent in patients with relapsed ALL; 2) to determine the PK of mAb 216 when administered as a single agent; 3) to determine the toxicity profile of this antibody as a single agent; and 4) to assess the in vivo cytotoxicity of this antibody. The preclinical cytotoxicity data strongly suggest that mAb 216 may demonstrate clinical efficacy when used alone. However, there is compelling evidence that mAb 216, when used in combination with chemotherapy agents, particularly Vincristine, mediates a synergistic degree of cytoxicity against B-progenitor leukemic blasts. The study design of this clinical trial will therefore provide important information about the clinical impact of mAb 216 when used alone as well as in combination with chemotherapeutic agents.