Lintuzumab-Ac225 in Combination With Cladribine + Cytarabine + Filgastrim + Mitoxantrone (CLAG-M) for Relapsed/Refractory Acute Myeloid Leukemia

  • STATUS
    Recruiting
  • End date
    Oct 5, 2025
  • participants needed
    35
  • sponsor
    Medical College of Wisconsin
Updated on 5 May 2022
myeloproliferative disorder
cytarabine
flow cytometry
filgrastim
ejection fraction
granulocyte colony stimulating factor
mitoxantrone
refractory acute myeloid leukemia (aml)
secondary acute myeloid leukemia
blast cells
cladribine
colony stimulating factor

Summary

This is a prospective, single-center phase I clinical study aimed at determining the maximum-tolerated dose, recommended phase 2 dose and safety of Lintuzumab-Ac225 in combination with CLAG-M chemotherapy in the management of relapsed/refractory acute myeloid leukemia. This study uses a 3+3 design with a five-patient cohort at the recommended phase 2 dose.

Description

Relapsed/refractory acute myeloid leukemia (RR-AML) in adults is an important therapeutic challenge. Nearly 60% of AML patients ultimately relapse or have refractory disease, and failure to achieve remission in this population is almost universally fatal. Therefore, a critical need exists for the development of novel therapies.

Currently, for RR-AML, many institutions utilize the chemotherapy regimen of CLAG-M (cladribine, cytarabine, G-CSF, mitoxantrone) based on a reported morphological complete remission (CR) rate of 58% in prospective clinical trials. Because of this, and its favorable performance when compared with outcomes reported for other regimens utilized in RR-AML, we believe enhancing the efficacy of CLAG-M is a rational approach to improve therapy in RR-AML.

A promising approach that could enhance the clearance of leukemic blasts when added to CLAG-M chemotherapy is a monoclonal antibody radioconjugate directed against markers expressed in leukemic cells. Radiation has known cytotoxic properties in chemo-resistant AML. The benefit of an antibody radioconjugate would be leukemic specific delivery of potent radiotherapy with potentially minimal systemic off-target side-effects. One such antibody radioconjugate is Lintuzumab-Ac225, a highly cytotoxic alpha radiation emitter that targets the cluster of differentiation 33 (CD33) cell surface antigen, which is expressed on leukemic cells.

In this novel study, we aim to add the radioconjugated antibody Lintuzumab-Ac225 to salvage CLAG-M chemotherapy in order to improve the treatment response for patients with RR-AML.

Details
Condition Acute Myeloid Leukemia
Treatment G-CSF, cytarabine, Mitoxantrone, cladribine, Lintuzumab AC 225, Lintuzumab-Ac-225 (Dose 1: 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab), Lintuzumab-Ac-225 (Dose 2: 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab), Lintuzumab-Ac-225 (Dose 3: 0.75 μCi/kg with 4.7μg/kg lintuzumab), Lintuzumab-Ac-225 (Dose 4: 1.00 μCi/kg with 6.4 μg/kg lintuzumab), Lintuzumab-Ac-225 (Dose 5: 1.25 μCi/kg with 8.0 μg/kg lintuzumab), Lintuzumab-Ac-225 (Recommended Phase 2 Dose)
Clinical Study IdentifierNCT03441048
SponsorMedical College of Wisconsin
Last Modified on5 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Age ≥18 years at the time of informed consent
Morphologically documented primary AML or secondary AML [from prior conditions such as Myelodysplastic Syndrome (MDS), myeloproliferative neoplasm (MPN)] or therapy related AML (t-AML), as defined by World Health Organization (WHO) criteria
In first or subsequent relapse or refractory status after prior therapy, with or without prior hematopoietic stem cell transplant (HSCT). Patients with MDS and progression to AML on hypomethylating agents will also be included
Eastern Cooperative Oncology Group (ECOG) performance score 0-2
Greater than 25% of blasts must be CD33 positive on flow cytometry using Phycoerythrin (PE) labeled anti-CD33 antibody
Patients must meet the following clinical laboratory criteria
Total bilirubin ≤ 2 x the upper limit of the normal range (ULN)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN
Calculated creatinine clearance ≥ 50 mL/min
Resting left ventricular ejection fraction (LVEF) > 40%
Female patients must agree to avoid becoming pregnant, and male patients should avoid
impregnating a female partner

Exclusion Criteria

Acute Promyelocytic Leukemia
Active severe infection not well controlled by antibacterial or antiviral therapy
Known infection with human immunodeficiency virus
Patients with documented pulmonary disease, with a diffusing capacity of the lungs for carbon monoxide (DLCO) and/or forced expiratory volume in one second (FEV1) <65%, or history of dyspnea at rest, or requiring oxygen
Pregnant or breast feeding women
Prior chemotherapy or radiotherapy within 14 days of study entry unless fully recovered from adverse effects due to treatment, at investigator's discretion
Active malignancy within 2 years of 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 progressive disease based on prostate-specific antigen (PSA) levels and are not on active therapy. Active malignancy is malignancy receiving treatment
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