Clinical Trials /

Actinium-225-Lintuzumab in Patients With Acute Myeloid Leukemia

NCT03705858

Description:

The purpose of this study is to see what dose of 225Ac-lintuzumab is safest to give to acute myeloid leukemia (AML) patients who are in remission but still have minimal residual disease (MRD). About 12 subjects will be asked to take part in this phase 1, 3+3 dose-escalation study. In addition to confirming the safety profile of postremission therapy with 225Ac-lintuzumab, preliminary evidence of efficacy will be assessed by estimating progression-free survival (PFS) and overall survival (OS), and serially evaluating for MRD using cytogenetics, fluorescence in situ hybridization (FISH), or flow cytometric assays, as applicable.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Withdrawn

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Actinium-225-Lintuzumab in Patients With Acute Myeloid Leukemia
  • Official Title: Postremission Therapy With Actinium-225 (225Ac)-Lintuzumab (Actimab-A®) in Patients With Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: AAAR9075
  • NCT ID: NCT03705858

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Ac-LintuzumabActimab-A ®Ac-lintuzumab

Purpose

The purpose of this study is to see what dose of 225Ac-lintuzumab is safest to give to acute myeloid leukemia (AML) patients who are in remission but still have minimal residual disease (MRD). About 12 subjects will be asked to take part in this phase 1, 3+3 dose-escalation study. In addition to confirming the safety profile of postremission therapy with 225Ac-lintuzumab, preliminary evidence of efficacy will be assessed by estimating progression-free survival (PFS) and overall survival (OS), and serially evaluating for MRD using cytogenetics, fluorescence in situ hybridization (FISH), or flow cytometric assays, as applicable.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Ac-lintuzumabExperimentalSubjects with AML will receive Ac-lintuzumab.
  • Ac-Lintuzumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of postremission therapy
Time Frame:Up to 2 years
Safety Issue:
Description:The 3+3 dose-escalation is designed to establish the MTD of postremission therapy with 225Ac-lintuzumab in patients with AML in first, second, or third CR/CRp who have detectable minimal residual disease (MRD) and have completed all planned therapy.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description:The length of time during and after the treatment of AML that a subject lives with the disease but it does not get worse. It will be calculated from the time of study entry to relapse, death or last follow-up. That includes subjects with at least one cycle of therapy.
Measure:Overall Survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:The Length of time in days during and after the treatment of AML that a subject lives. It will be calculated from the time of entry onto study to death or last follow-up. That includes all subjects who receive at least one cycle of therapy.
Measure:Effectiveness of the therapy
Time Frame:Up to 3 years
Safety Issue:
Description:Evaluate the effectiveness on MRD using serial cytogenetic/fluorescence in situ hybridization (FISH) analysis and flow cytometric monitoring.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Joseph Jurcic

Trial Keywords

  • Acute Myeloid Leukemia
  • Actinium-225
  • Lintuzumab
  • Columbia
  • Post-remission
  • Phase I

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