Actinium-225-Lintuzumab in Patients With Acute Myeloid Leukemia

Therapy with α particle-emitting constructs of the anti-CD33 monoclonal antibody lintuzumab
has demonstrated significant tumor effects in AML. Because therapy is selectively targeted to
leukemic blasts, it has the potential advantage of less extramedullary toxicity than
conventional systemic agents. Moreover, the unique radiobiological features of α particle
emissions may permit more efficient tumor cell kill with greater specificity than treatment
with β particle-emitting radioisotopes. Objective responses in AML following treatment with
225Ac-lintuzumab have been seen in cytoreduced disease, either following chemotherapy or
using a fractionated dosing scheme.

The presence of MRD detectable by cytogenetic techniques and flow cytometric assays indicates
a high risk of relapse for AML patients, despite achieving a clinical complete remission. The
high linear energy and short range of α emissions make them ideally suited to eradicate MRD,
as suggested by the clinical responses observed in earlier studies. To date, 225Ac-lintuzumab
has only been studied in patients with overt leukemia. The aim of this phase 1 study is to
identify the maximum tolerated dose (MTD) of 225Ac-lintuzumab that can be given safely to AML
patients in the postremission setting in order to eliminate detectable MRD and ultimately
prolong PFS and OS.

Inclusion Criteria:

1. Subjects must have histologically confirmed AML in first, second, or third clinical
CR/CRp after any standard or investigational therapy.

2. Subjects must have detectable MRD by cytogenetics, FISH, or flow cytometry after the
completion of all planned therapy. Detectable MRD by flow cytometry is defined by the
presence of a myeloid blast population with an atypical immunophenotype, constituting
less than 5% of all events. Examples of planned therapy courses include induction
chemotherapy with cytarabine and an anthracycline followed by consolidation
chemotherapy or 4-6 cycles of a hypomethylating agent-based regimen.

3. At the time of diagnosis or most recent relapse, greater than 25% of bone marrow
blasts must have been CD33 positive.

4. Age ≥18 years. Because no dosing or adverse event data are currently available on the
use of 225Ac-lintuzumab in patients <18 years of age, children are excluded from this
study.

5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

6. Subjects must have adequate bone marrow and organ function documented within 14 days
of study entry as follows:

1. Absolute neutrophil count (ANC) ≥ 1,000/μL;

2. Platelet count ≥ 50,000/μL;

3. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or estimated glomerular
filtration rate of > 50 mL/min;

4. Serum total bilirubin ≤ 1.5 × ULN (unless attributable to Gilbert's disease);

5. Alkaline phosphatase, serum aspartate aminotransferase (AST), and serum alanine
aminotransferase (ALT) ≤ 2.5 × ULN.

7. The effects of 225Ac-lintuzumab on the developing human fetus are unknown. Since
radiation exposure, however, is known to be teratogenic, 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 treatment
on study. Men treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, for the duration of study participation, and 4
months after completion of 225Ac-lintuzumab administration.

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

Exclusion Criteria:

1. Subjects with acute promyelocytic leukemia or BCR-ABL-positive leukemia.

2. Subjects who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier. Prior clofarabine is not allowed due to risk
of liver dysfunction.

3. Subjects who have previously received 225Ac-lintuzumab.

4. Subjects with an human leukocyte antigen (HLA)-compatible donor or stem cell source
who are immediate candidates for allogeneic hematopoietic cell transplantation (HCT).

5. Subjects who are receiving any other investigational agents concurrently.

6. Subjects with active central nervous system (CNS) involvement by AML.

7. Uncontrolled intercurrent illness including, but not limited to, active serious
infections uncontrolled by antibiotics, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, documented liver cirrhosis, or psychiatric
illness/social situations that would limit compliance with study requirements.

8. Active malignancy within 3 years of study entry, except previously treated melanoma
grade 2 or less, non-melanoma skin cancer, carcinoma in situ or cervical
intraepithelial neoplasia, and organ confined prostate cancer with no evidence of
recurrent or progressive disease based on prostate-specific antigen (PSA) levels and
are not on active therapy.

9. Prior organ transplant, including allogeneic HCT.

10. Pregnant or nursing women.

11. Subjects with known human immunodeficiency virus (HIV) infection, active hepatitis B,
or active hepatitis C.