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

Medical College of Wisconsin

Status and phase: Completed; Phase 1

Conditions: Acute Myeloid Leukemia

Treatments: Drug: Mitoxantrone; Biological: Lintuzumab-Ac-225; Drug: Cladribine; Drug: Cytarabine; Drug: G-CSF

Study type: Interventional

Funder types: Other

Identifiers

NCT03441048

PRO00031633

Details and patient eligibility

About

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.

Full 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.

Enrollment: 26 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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26 participants in 6 patient groups

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

Experimental group

Description:

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.

Treatment:

Drug: G-CSF

Drug: Cytarabine

Drug: Cladribine

Biological: Lintuzumab-Ac-225

Drug: Mitoxantrone

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

Experimental group

Description:

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.

Treatment:

Drug: G-CSF

Drug: Cytarabine

Drug: Cladribine

Biological: Lintuzumab-Ac-225

Drug: Mitoxantrone

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

Experimental group

Description:

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.

Treatment:

Drug: G-CSF

Drug: Cytarabine

Drug: Cladribine

Biological: Lintuzumab-Ac-225

Drug: Mitoxantrone

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

Experimental group

Description:

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.

Treatment:

Drug: G-CSF

Drug: Cytarabine

Drug: Cladribine

Biological: Lintuzumab-Ac-225

Drug: Mitoxantrone

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

Experimental group

Description:

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.

Treatment:

Drug: G-CSF

Drug: Cytarabine

Drug: Cladribine

Biological: Lintuzumab-Ac-225

Drug: Mitoxantrone

Lintuzumab Ac225 Recommended Phase 2 Dose (RP2D)

Experimental group

Description:

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.

Treatment:

Drug: G-CSF

Drug: Cytarabine

Drug: Cladribine

Biological: Lintuzumab-Ac-225

Drug: Mitoxantrone