Yttrium Y 90 Anti-CD45 Monoclonal Antibody AHN-12 in Treating Patients With Advanced Leukemia

MT2005-13R - Phase I Open Label, Single Arm, Dose Escalation Trial to Evaluate the Biodistribution and Safety of AHN-12 in Patients With Advanced Leukemia

RATIONALE: Monoclonal antibodies can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Radioactive monoclonal antibodies, such as yttrium Y 90 monoclonal antibody, can find cancer cells and either kill them or carry cancer-killing substances to them without harming normal cells.

PURPOSE: This phase I trial is studying the side effects and best dose of a yttrium Y 90 monoclonal antibody and how much radiation is taken in by the organs in the body in treating patients with advanced leukemia or other hematologic disorder.

OBJECTIVES:

Primary

• To establish that a dose of 150 mg/m² of nonradiolabeled anti-CD45 monoclonal antibody AHN-12 results in normal biodistribution, normal-organ estimated radiation-absorbed dose of less than 20 Gy, and estimated radiation-absorbed dose of no more than 13 Gy to the red marrow.

Secondary

• To determine the maximum tolerated dose of yttrium Y 90 anti-CD45 monoclonal antibody AHN-12 (^90Y-AHN-12).
• To determine the human anti-mouse antibody (HAMA) response.
• To define, preliminarily, the antitumor activity of ^90Y-AHN-12.

OUTLINE: This is a dose-escalation study of yttrium Y 90 anti-CD45 monoclonal antibody AHN-12 (^90Y-AHN-12).

• Biodistribution: Patients receive nonradiolabeled monoclonal antibody AHN-12 IV and an imaging dose of indium Y 111 monoclonal antibody AHN-12 (^111In-AHN-12) IV over 10 minutes on day 0. Patients undergo whole-body gamma-camera imaging immediately following infusion, at 4-6 hours, and on days 1, 3, 4, and 7. Blood samples are collected prior to each imaging for dosimetry calculations and pharmacokinetics.

Patients also undergo bone marrow biopsy 16-24 hours after infusion for dosimetry calculations. Patients with the expected biodistribution of ^111In-AHN-12, an estimated radiation-absorbed dose to the normal organ of < 20 Gy, an estimated radiation-absorbed dose to the red marrow of ≤ 13 Gy, and a negative human anti-mouse antibody at day 7 proceed to the therapy portion.

• Treatment: Patients receive nonradiolabeled anti-CD45 monoclonal antibody AHN-12 IV over 60 minutes and escalating therapy doses of yttrium Y 90 anti-CD45 monoclonal antibody AHN-12 (^90Y-AHN-12) IV over 10 minutes on day 7 or 8.

After completion of study treatment, patients are followed periodically for 1 year.

Inclusion Criteria:

• Histologically confirmed CD45+ diseases:

  • Acute lymphoblastic leukemia or acute myeloid leukemia (AML), meeting any of the following criteria:

    • Primary refractory disease
    • Relapsed disease, defined as persistent disease following a minimum of 2 different standard chemotherapy induction attempts at time of diagnosis or at relapse

  • Acute myelogenous leukemia (AML), primary refractory or relapsed disease - defined as persistent disease after a minimum of two different standard chemotherapy induction attempts at time of diagnosis or relapse

  • Advanced myelodysplastic syndrome (MDS) defined as > or = 15% bone marrow blasts following a minimum of one standard chemotherapy induction attempt

  • AML arising from preexisting MDS, refractory - defined as persistent disease following a minimum of one standard chemotherapy induction attempt

  • Chronic myelogenous leukemia (CML) following blast crisis (> or = 15% marrow blasts following a minimum of one standard chemotherapy induction attempt

• Peripheral leukemic blasts (by morphology) must be < 5,000/μL (hydroxyurea to control peripheral blast count allowed)

• Must have source of allogeneic stem cells (sibling, unrelated cord[s], or donor) identified prior to initiation of protocol therapy

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 or Karnofsky PS 60-100%

• Life expectancy > 12 weeks

• Total bilirubin ≤ 2.5 times upper limit of normal (ULN)

• aspartate aminotransferase (AST) and Alanine transaminase (ALT) ≤ 2.5 times upper limit of normal (ULN)

• Creatinine ≤ 1.3 mg/dL OR creatinine clearance ≥ 60 mL/min

• Left ventricular ejection fraction (LVEF) ≥ 45% by Multi Gated Acquisition Scan (MUGA) or echocardiogram (ECHO)

• Carbon Monoxide Diffusing Capacity (DLCO) (corrected) ≥ 50% of predicted

• Human anti-mouse antibody (HAMA) must be negative

• Not pregnant or nursing

• Fertile patients must use effective contraception

• Human immunodeficiency virus (HIV) negative

• Recovered from all prior therapy

• At least 7 days since prior biologic agents

Exclusion Criteria:

• Bone marrow cellularity < 15%

• Known brain metastases or active central nervous system (CNS) disease

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ^90Y-AHN-12 or other agents used in study

• Uncontrolled illness, including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic or congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situations that would limit compliance with study requirements

• Other concurrent investigational agents

• Prior allogeneic transplantation

• Less than 60 days since prior autologous transplantation with relapsed disease