Yttrium Y 90 Anti-CD19 Antibody BU-12 in Patients With Advanced Relapsed or Refractory Acute Lymphoblastic Leukemia or Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Radiolabeled monoclonal antibodies can find cancer cells and carry cancer-killing substances to them without harming normal cells. This may be effective treatment for leukemia. PURPOSE: This phase I trial is studying the best dose of yttrium Y 90-labeled monoclonal antibody BU-12 in treating patients with advanced relapsed or refractory acute lymphoblastic leukemia or chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: Primary To determine the biodistribution of indium-111 BU-12 in patients with refractory CD19+ leukemia. Secondary To determine the maximum tolerated dose of yttrium Y 90 anti-CD19 antibody BU-12 Determine the human anti-mouse antibody (HAMA) response. To define, preliminarily, the antitumor activity of yttrium Y 90 anti-CD19 antibody BU-12. OUTLINE: Patients receive yttrium Y 90 anti-CD19 antibody BU-12/indium-111 BU-12 IV over 60 minutes on day 0 and undergo whole-body imaging on days 0, 1, 3, 4, and 7. Patients also undergo blood collection and bone marrow biopsy periodically for dosimetry calculations and pharmacokinetics. After completion of study treatment, patients are followed periodically for 2 years.

Official Title
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Phase I Open Label, Single Arm Escalation Trial to Evaluate the Biodistribution and Safety of BU-12 in Patients With Advanced Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Radiation: yttrium Y 90 anti-CD19 monoclonal antibody BU12
* Radiation: 111In-BU-12


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed CD19-positive (> 25% by flow cytometry evaluation of bone marrow blasts) disease of 1 of the following types: Primary refractory or relapsed acute lymphoblastic leukemia (ALL) defined as persistent disease following a minimum of two different standard effective chemotherapy induction attempts at time of diagnosis or at relapse Chronic Lymphocytic leukemia (CLL) following blast crisis (≥15% bone marrow blasts following a minimum of one standard effective chemotherapy induction attempt) Human anti-mouse antibody (HAMA) must be negative Patients who have relapsed ≥ 60 days following an autologous or allogeneic transplant are eligible if all other eligibility criteria are met No active central nervous system (CNS) disease ECOG performance status (PS) 0-2 or Karnofsky PS 60-100% Life expectancy > 8 weeks Total bilirubin ≤ 2.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN Creatinine normal OR creatinine clearance ≥ 60 mL/min LVEF ≥ 45% by MUGA/ECHO Oxygen saturation on room air > 92% and no oxygen requirement Not pregnant or nursing Negative pregnancy test Fertile patients mus use effective contraception Exclusion criteria: History of allergic reactions attributed to compounds of similar chemical or biologic composition to of yttrium Y 90 anti-CD19 antibody BU-12 or other agents used in study Uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situations that would limit compliance with study requirements HIV-positive Active graft-vs-host disease Less than 4 weeks since prior agents and recovered Less than 7 days since prior therapy with any biologic agent, defined as a growth factor or cytokine Less than 3 months since prior antibody or biologic anticancer therapy (e.g., alemtuzumab or epratuzumab) Other concurrent investigational agents Patients with peripheral blasts > 5,000/uL may receive concurrent hydroxyurea

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 111 In-BU-12<br>111In-BU-12 is the 111Indium-labeled murine monoclonal antibody used for imaging and dosimetry. | Radiation: yttrium Y 90 anti-CD19 monoclonal antibody BU12<br>* Patients in whom the biodistribution is as expected (unaltered) AND a HAMA response does not develop will receive a single dose of 90Y-BU-12 in a dose escalated manner to establish the maximum tolerated dose (MTD) of 90Y-BU-12 over 60 minutes on Day 0. A single course of BU-12 includes the imaging dose of 111In-BU-12 followed 7-8 days later by the therapy dose of 90YBU- 12.<br>* Other names: 90Y-BU-12;Radiation: 111In-BU-12<br>* Patients receive indium-111 BU-12 IV over 60 minutes on day 0<br>* Other names: indium-111 BU-12;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biodistribution of indium-111 BU-12 | Perform a whole body scan acquiring both anterior and posterior images at a speed of 10 cm/min (20 minute scan) using a medium energy collimator, a 256 x 1024 computer acquisition matrix and acquisition photo peak settings of 172 and 247 keV with 15% windows. | Immediately post infusion, 4-6 hours after infusion and Days 1, 3, 4 and 7 after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of yttrium Y 90 anti-CD19 antibody BU-12 | DLT will be defined as bone marrow aplasia > 6 weeks duration from the first treatment day; specifically, failure to recover peripheral ANC > 500/μL and platelets > 20,000/μL documented by bone marrow aplasia, not malignant infiltration - Any NCI CTCAE v 3.0 grade 3 non-hematologic toxicity except for allergic reactions to radiolabeled BU-12 will be dose limiting. If the BU-12 antibody is very allergenic, then ≥ grade 3 allergic reactions will be dose limiting. | Beginning Day 1 of treatment | 
| Presence or absence of a human antibody to murine antibody | Presence or absence of a human antibody to murine antibody at baseline, 28 and 60 days post therapy, and at 6 months post therapy | baseline, 28 and 60 days post therapy, and at 6 months post therapy | 
| Number of Patients by Clinical Response | Patients evaluable for DLT will be assessed for response at day 28 and day 60 post therapy dose (event is whether or not the patient has a Complete Remission, Partial Remission, Stable Disease, Refractory Disease, Relapsed Disease). The proportion of patients by disease status will be reported. | day 28 and day 60 | 
| Time to Clinical Response | Time-to-event will be measured from date of therapy dose. | Day 28, 60, 6 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia, refractory chronic lymphocytic leukemia