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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

26 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-05-22

Study Completion Date

2024-05-22

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Acute Myeloid Leukemia

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

SEQUENTIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Lintuzumab Ac225 (Dose 1 - 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab)

Dose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m\^2/day IV over two hours on days 2-6; cytarabine 2 gm/m\^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m\^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.

Group Type EXPERIMENTAL

Lintuzumab-Ac-225

Intervention Type BIOLOGICAL

Lintuzumab-Ac225 is an immunoconjugate \[antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)\] for the treatment of relapsed/refractory acute myeloid leukemia.

Cladribine

Intervention Type DRUG

Cladribine is a purine antimetabolite.

Cytarabine

Intervention Type DRUG

Cytarabine is an antineoplastic anti-metabolite.

Mitoxantrone

Intervention Type DRUG

Mitoxantrone is an anthracenedione antineoplastic agent.

G-CSF

Intervention Type DRUG

G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.

Lintuzumab Ac225 (Dose 2 - 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab)

Dose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m\^2/day IV over two hours on days 2-6; cytarabine 2 gm/m\^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m\^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.

Group Type EXPERIMENTAL

Lintuzumab-Ac-225

Intervention Type BIOLOGICAL

Lintuzumab-Ac225 is an immunoconjugate \[antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)\] for the treatment of relapsed/refractory acute myeloid leukemia.

Cladribine

Intervention Type DRUG

Cladribine is a purine antimetabolite.

Cytarabine

Intervention Type DRUG

Cytarabine is an antineoplastic anti-metabolite.

Mitoxantrone

Intervention Type DRUG

Mitoxantrone is an anthracenedione antineoplastic agent.

G-CSF

Intervention Type DRUG

G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.

Lintuzumab Ac225 (Dose 3 - 0.75 μCi/kg Ac-225 with 4.7μg/kg lintuzumab)

Dose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m\^2/day IV over two hours on days 2-6; cytarabine 2 gm/m\^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m\^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.

Group Type EXPERIMENTAL

Lintuzumab-Ac-225

Intervention Type BIOLOGICAL

Lintuzumab-Ac225 is an immunoconjugate \[antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)\] for the treatment of relapsed/refractory acute myeloid leukemia.

Cladribine

Intervention Type DRUG

Cladribine is a purine antimetabolite.

Cytarabine

Intervention Type DRUG

Cytarabine is an antineoplastic anti-metabolite.

Mitoxantrone

Intervention Type DRUG

Mitoxantrone is an anthracenedione antineoplastic agent.

G-CSF

Intervention Type DRUG

G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.

Lintuzumab Ac225 (Dose 4 - 1.00 μCi/kg Ac-225 with 6.4 μg/kg lintuzumab)

Dose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m\^2/day IV over two hours on days 2-6; cytarabine 2 gm/m\^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m\^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.

Group Type EXPERIMENTAL

Lintuzumab-Ac-225

Intervention Type BIOLOGICAL

Lintuzumab-Ac225 is an immunoconjugate \[antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)\] for the treatment of relapsed/refractory acute myeloid leukemia.

Cladribine

Intervention Type DRUG

Cladribine is a purine antimetabolite.

Cytarabine

Intervention Type DRUG

Cytarabine is an antineoplastic anti-metabolite.

Mitoxantrone

Intervention Type DRUG

Mitoxantrone is an anthracenedione antineoplastic agent.

G-CSF

Intervention Type DRUG

G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.

Lintuzumab Ac225 (Dose 5 - 1.25 μCi/kg Ac-225 with 8.0 μg/kg lintuzumab)

Dose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m\^2/day IV over two hours on days 2-6; cytarabine 2 gm/m\^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m\^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.

Group Type EXPERIMENTAL

Lintuzumab-Ac-225

Intervention Type BIOLOGICAL

Lintuzumab-Ac225 is an immunoconjugate \[antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)\] for the treatment of relapsed/refractory acute myeloid leukemia.

Cladribine

Intervention Type DRUG

Cladribine is a purine antimetabolite.

Cytarabine

Intervention Type DRUG

Cytarabine is an antineoplastic anti-metabolite.

Mitoxantrone

Intervention Type DRUG

Mitoxantrone is an anthracenedione antineoplastic agent.

G-CSF

Intervention Type DRUG

G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.

Lintuzumab Ac225 Recommended Phase 2 Dose (RP2D)

The maximum-tolerated dose for lintuzumab-Ac225 is defined as the highest level at which no more than one patient experiences a dose-limiting toxicity. The RP2D is defined as the dose level below the dose where two or more dose-limiting toxicities were observed. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m\^2/day IV over two hours on days 2-6; cytarabine 2 gm/m\^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m\^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.

Group Type EXPERIMENTAL

Lintuzumab-Ac-225

Intervention Type BIOLOGICAL

Lintuzumab-Ac225 is an immunoconjugate \[antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)\] for the treatment of relapsed/refractory acute myeloid leukemia.

Cladribine

Intervention Type DRUG

Cladribine is a purine antimetabolite.

Cytarabine

Intervention Type DRUG

Cytarabine is an antineoplastic anti-metabolite.

Mitoxantrone

Intervention Type DRUG

Mitoxantrone is an anthracenedione antineoplastic agent.

G-CSF

Intervention Type DRUG

G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.

Interventions

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Lintuzumab-Ac-225

Lintuzumab-Ac225 is an immunoconjugate \[antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)\] for the treatment of relapsed/refractory acute myeloid leukemia.

Intervention Type BIOLOGICAL

Cladribine

Cladribine is a purine antimetabolite.

Intervention Type DRUG

Cytarabine

Cytarabine is an antineoplastic anti-metabolite.

Intervention Type DRUG

Mitoxantrone

Mitoxantrone is an anthracenedione antineoplastic agent.

Intervention Type DRUG

G-CSF

G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.

Intervention Type DRUG

Other Intervention Names

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HuM195-Ac225 Actimab-A Leustatin Mavenclad Cytosar-U Depocyt cytosine arabinoside (ara-C) Mitozantrone Novantrone colony-stimulating factor 3 (CSF 3)

Eligibility Criteria

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Inclusion Criteria

1. Age ≥18 years at the time of informed consent.
2. 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.
3. 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.
4. Eastern Cooperative Oncology Group (ECOG) performance score 0-2.
5. Greater than 25% of blasts must be CD33 positive on flow cytometry using Phycoerythrin (PE) labeled anti-CD33 antibody.
6. 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%
7. Female patients must agree to avoid becoming pregnant, and male patients should avoid impregnating a female partner.

Exclusion Criteria

1. Acute Promyelocytic Leukemia.
2. Active severe infection not well controlled by antibacterial or antiviral therapy.
3. Known infection with human immunodeficiency virus.
4. 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.
5. Pregnant or breast feeding women.
6. Prior chemotherapy or radiotherapy within 14 days of study entry unless fully recovered from adverse effects due to treatment, at investigator's discretion.
7. 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.

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No