Clinical trial NCT00126646: BL22 Immunotoxin in Treating Patients With Refractory Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, or Non-Hodgkin's Lymphoma
Official title: Phase I Study of BL22, A Recombinant Immunotoxin for Chronic Lymphocytic Leukemia and CD22+ Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia
Lymphoma
Keywords: B-cell chronic lymphocytic leukemia
refractory chronic lymphocytic leukemia
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
recurrent marginal zone lymphoma
splenic marginal zone lymphoma
stage III marginal zone lymphoma
stage IV marginal zone lymphoma
recurrent mantle cell lymphoma
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
recurrent small lymphocytic lymphoma
stage III small lymphocytic lymphoma
stage IV small lymphocytic lymphoma
recurrent adult diffuse small cleaved cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
Waldenstrom macroglobulinemia
prolymphocytic leukemia
Lead sponsor: MedImmune LLC
Sponsor class: INDUSTRY
First posted: 2005-08-04
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: BL22 immunotoxin can find tumor cells and kill them without harming normal cells.

PURPOSE: This phase I trial is studying the side effects and best dose of BL22 immunotoxin in treating patients with refractory B-cell chronic lymphocytic leukemia, prolymphocytic leukemia, or non-Hodgkin's lymphoma.

Detailed description: OBJECTIVES:

* Determine the maximum tolerated dose of recombinant BL22 immunotoxin in patients with CD22-positive refractory B-cell chronic lymphocytic leukemia, prolymphocytic leukemia, or indolent non-Hodgkin's lymphoma.
* Determine the safety and efficacy of this drug in these patients.
* Determine the pharmacokinetics of this drug in these patients.
* Determine the immunogenicity of this drug in these patients.
* Determine the effect of this drug on various components of the circulating cellular immune system in these patients.

OUTLINE: This is a nonrandomized, dose-escalation study. Patients are stratified according to disease type (chronic lymphocytic leukemia vs non-Hodgkin's lymphoma).

Patients receive recombinant BL22 immunotoxin IV over 30 minutes on days 1, 3, and 5. Treatment repeats ≥ every 27 days for up to 6 courses in the absence of neutralizing antibodies to BL22 or PE38, disease progression, or unacceptable toxicity. Patients achieving a complete response (CR) receive 2 additional courses beyond CR. Patients who relapse from a CR lasting ≥ 6 months may receive additional courses.

Cohorts of 3-6 patients per stratum receive escalating doses of recombinant BL22 immunotoxin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: A total of 24 patients (12 per stratum) will be accrued for this study within 1-2 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of B-cell leukemia or lymphoma of 1 of the following types:

  * Chronic lymphocytic leukemia

    * Failed standard chemotherapy
  * Prolymphocytic leukemia

    * Failed standard chemotherapy
  * Indolent non-Hodgkin's lymphoma, including mantle cell lymphoma

    * Stage III or IV disease
    * Failed ≥ 1 prior doxorubicin- or fludarabine-containing standard therapy
* CD22-positive disease, as evidenced by 1 of the following:

  * More than 15% malignant cells react with anti-CD22 by immunohistochemistry
  * More than 30% malignant cells are CD22-positive by fluorescence-activated cell sorting analysis
  * More than 400 CD22 sites per malignant cell (average) by radiolabeled anti-CD22 binding
* Treatment is medically indicated, as evidenced by any of the following:

  * Progressive disease-related symptoms
  * Progressive cytopenias due to marrow involvement
  * Progressive or painful splenomegaly or adenopathy
  * Rapidly increasing lymphocytosis
  * Autoimmune hemolytic anemia or thrombocytopenia
  * Increased frequency of infections
* No neutralizing anti-toxin or anti-mouse immunoglobulin G (IgG) antibodies to BL22 or PE38

  * No serum neutralization of \> 75% of the activity of 1 μg/mL of BL22
* No CNS disease requiring treatment
* No hairy cell leukemia

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* ECOG 0-2

Life expectancy

* More than 6 months

Hematopoietic

* Absolute neutrophil count \> 1,000/mm\^3\*
* Platelet count \> 40,000/mm\^3 NOTE: \*Patients with leukemia are eligible regardless of absolute neutrophil count; Grade III-IV pancytopenia or growth factor dependence allowed if due to disease

Hepatic

* Bilirubin \< 1.5 times upper limit of normal (ULN)
* ALT and AST \< 2.5 times ULN

Renal

* Creatinine ≤ 1.5 mg/dL

Pulmonary

* FEV1 ≥ 60% of predicted
* DLCO ≥ 55% of predicted

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

* Prior bone marrow transplantation allowed
* More than 3 weeks since prior biologic therapy, including interferon, denileukin diftitox, or LMB-2 immunotoxin
* More than 3 months since prior monoclonal antibody therapy (e.g., rituximab)

Chemotherapy

* See Disease Characteristics
* More than 3 weeks since prior cytotoxic chemotherapy

Endocrine therapy

* More than 1 week since prior steriods

  * Less than 5 doses for non-treatment reasons (e.g., allergy prophylaxis)
  * No evidence of disease response

Radiotherapy

* More than 3 weeks since prior whole-body electron beam radiotherapy

  * Radiotherapy within the past 3 weeks allowed provided the volume of bone marrow treated is \< 10% AND the patient has measurable disease located outside the radiation port

Surgery

* Not specified

Other

* More than 3 weeks since prior retinoids
* More than 3 weeks since other prior systemic therapy for this malignancy

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Robert Kreitman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kreitman RJ, Squires DR, Stetler-Stevenson M, Noel P, FitzGerald DJ, Wilson WH, Pastan I. Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-cell malignancies. J Clin Oncol. 2005 Sep 20;23(27):6719-29. doi: 10.1200/JCO.2005.11.437. Epub 2005 Aug 1.