Immunotoxin Therapy and Cytarabine in Treating Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To define the maximum tolerated dose (MTD) of Combotox (deglycosylated ricin A
chain-conjugated anti-CD19/anti-CD22 immunotoxins) when added to high-dose cytarabine during
salvage therapy for adult patients with relapsed or refractory B-lineage acute lymphoblastic
leukemia.

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of this regimen. II. To assess for the presence of a postulated
CD34+/CD38-/low/CD19+ leukemic stem cell phenotype in the bone marrow at time of relapse and
to assess its association with treatment outcome.

III. To determine the development of human mouse or ricin antibodies (human anti-mouse
antibodies [HAMA]/human anti-ricin antibodies [HARA]).

IV. To determine the pharmacokinetic characteristics of Combotox. V. To evaluate the value
of fractional excretion of sodium (FeNa) as early marker of toxicity.

OUTLINE: This is a dose-escalation study of deglycosylated ricin A chain-conjugated
anti-CD19/anti-CD22 immunotoxins.

Patients receive high-dose cytarabine intravenously (IV) over 2-3 hours every 12 hours on
days 1-3 and deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 immunotoxins IV
over 4 hours on days 8, 10, and 12. Treatment repeats every 28 days for up to 4 courses in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 weeks.

Inclusion Criteria:

- Patients must have histologically confirmed B-lineage acute lymphoblastic leukemia
(ALL) at diagnosis and either evidence of relapse/refractory disease based on a bone
marrow/peripheral blood examination or evidence by cytogenetic studies or polymerase
chain reaction (PCR) amplification; patients with only extramedullary disease in the
absence of bone marrow or blood involvement are not eligible; patients with L3
(Burkitt's) are not eligible; for ALL in marrow or peripheral blood,
immunophenotyping of the blood or marrow lymphoblasts must be performed to determine
lineage (B cell, T-cell, or mixed B/T cell); NOTE: appropriate marker studies
including CD19 (B cell), CD10, CD5, and CD7 (T cell) must be performed; co-expression
of myeloid antigens (CD13 and CD33) will not exclude patients; if possible, the
lineage specific markers cytoplasmic CD22 or CD79a (B cells), cytoplasmic CD3 (T
cells) and cytoplasmic myeloperoxidase (MPO) (myeloid cells) must be determined;
patients with mixed lineage ALL (ML-ALL) as defined by a lack of cytochemical markers
of myeloid differentiation, and by the presence of immunophenotypic markers
suggesting both lymphoid and myeloid differentiation, are allowed

- CD19 and/or CD22 must be expressed on at least 50% of the lymphoblasts

- Disease must be refractory to conventional induction therapy or relapsed after
initial standard therapy for ALL; any number of prior therapies is permitted and
including allogeneic and/or autologous stem cell transplant

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 2 months

- Total bilirubin =< 1.5 x institutional upper limit of normal, unless related to
leukemic infiltration or hemolysis

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal, unless related to leukemic infiltration
or hemolysis

- Creatinine within normal institutional limits OR

- Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal

- Patients must have recovered from effects of prior therapy; at least 2 weeks should
have elapsed since the last dose of high dose chemotherapy; hydroxyurea, steroids and
vincristine are allowed to control counts until eligibility is confirmed and study
treatment can be initiated

- Adequate cardiac function defined as an ejection fraction of >= 50% by multi gated
acquisition scan (MUGA) scan or echocardiogram and a corrected QT (QTc) interval of
=< 450 ms for men and =< 460 ms for women

- Adequate pulmonary function defined as no evidence of dyspnea at rest

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation; should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks (4 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 2 weeks earlier

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Combotox or other agents used in study agents

- Presence of a significant pleural effusion by chest x-ray

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic

- Presence of active untreated central nervous system (CNS) leukemia

- Presence of graft-versus-host disease (GVHD) more than grade 2

- History of documented seizure disorder, presence of cerebellar dysfunction, dysphasia
or altered mental status on neurological examination

- Human anti-mouse antibody (HAMA) levels of > 100 ug/ml or human ricin antibodies
(HARA) > 100 ug/ml HARA after cycle 1

- Impaired liver function defined as a total bilirubin > 1.5 x normal range and AST or
ALT > 2.5 x normal range unless secondary to Gilbert's disease, hemolysis or leukemic
involvement of the liver

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with Combotox

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible