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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03441048
Recruitment Status : Active, not recruiting
First Posted : February 22, 2018
Last Update Posted : October 20, 2022
Sponsor:
Information provided by (Responsible Party):
Sameem M. Abedin, MD, Medical College of Wisconsin

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Biological: Lintuzumab-Ac-225 (Dose 1: 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab) Drug: Cladribine Drug: Cytarabine Drug: Mitoxantrone Drug: G-CSF Biological: Lintuzumab-Ac-225 (Dose 2: 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab) Biological: Lintuzumab-Ac-225 (Dose 3: 0.75 μCi/kg with 4.7μg/kg lintuzumab) Biological: Lintuzumab-Ac-225 (Dose 4: 1.00 μCi/kg with 6.4 μg/kg lintuzumab) Biological: Lintuzumab-Ac-225 (Dose 5: 1.25 μCi/kg with 8.0 μg/kg lintuzumab) Biological: Lintuzumab-Ac-225 (Recommended Phase 2 Dose) Phase 1

Detailed 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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Lintuzumab-Ac225 in Combination With CLAG-M Chemotherapy in Patients With Relapsed/Refractory Acute Myeloid Leukemia
Actual Study Start Date : May 22, 2018
Estimated Primary Completion Date : October 2024
Estimated Study Completion Date : October 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: 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.
 Biological: Lintuzumab-Ac-225 (Dose 1: 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab)
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Other Names:
  • HuM195-Ac225
  • Actimab-A

Drug: Cladribine
Cladribine 5mg/m^2/day IV over two hours on days 2-6.
Other Names:
  • Leustatin
  • Mavenclad

Drug: Cytarabine
Cytarabine 2 gm/m^2/day IV over four hours on days 2-6.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)

Drug: Mitoxantrone
Mitoxantrone 10mg/m^2/day IV on days 2-4.
Other Names:
  • Mitozantrone
  • Novantrone

Drug: G-CSF
G-CSF at a dose of 300 µg on days 1-6.
Other Name: colony-stimulating factor 3 (CSF 3)
Experimental: 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.
 Drug: Cladribine
Cladribine 5mg/m^2/day IV over two hours on days 2-6.
Other Names:
  • Leustatin
  • Mavenclad

Drug: Cytarabine
Cytarabine 2 gm/m^2/day IV over four hours on days 2-6.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)

Drug: Mitoxantrone
Mitoxantrone 10mg/m^2/day IV on days 2-4.
Other Names:
  • Mitozantrone
  • Novantrone

Drug: G-CSF
G-CSF at a dose of 300 µg on days 1-6.
Other Name: colony-stimulating factor 3 (CSF 3)

Biological: Lintuzumab-Ac-225 (Dose 2: 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab)
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Other Names:
  • HuM195-Ac225
  • Actimab-A
Experimental: 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.
 Drug: Cladribine
Cladribine 5mg/m^2/day IV over two hours on days 2-6.
Other Names:
  • Leustatin
  • Mavenclad

Drug: Cytarabine
Cytarabine 2 gm/m^2/day IV over four hours on days 2-6.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)

Drug: Mitoxantrone
Mitoxantrone 10mg/m^2/day IV on days 2-4.
Other Names:
  • Mitozantrone
  • Novantrone

Drug: G-CSF
G-CSF at a dose of 300 µg on days 1-6.
Other Name: colony-stimulating factor 3 (CSF 3)

Biological: Lintuzumab-Ac-225 (Dose 3: 0.75 μCi/kg with 4.7μg/kg lintuzumab)
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Other Names:
  • HuM195-Ac225
  • Actimab-A
Experimental: 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.
 Drug: Cladribine
Cladribine 5mg/m^2/day IV over two hours on days 2-6.
Other Names:
  • Leustatin
  • Mavenclad

Drug: Cytarabine
Cytarabine 2 gm/m^2/day IV over four hours on days 2-6.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)

Drug: Mitoxantrone
Mitoxantrone 10mg/m^2/day IV on days 2-4.
Other Names:
  • Mitozantrone
  • Novantrone

Drug: G-CSF
G-CSF at a dose of 300 µg on days 1-6.
Other Name: colony-stimulating factor 3 (CSF 3)

Biological: Lintuzumab-Ac-225 (Dose 4: 1.00 μCi/kg with 6.4 μg/kg lintuzumab)
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Other Names:
  • HuM195-Ac225
  • Actimab-A
Experimental: 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.
 Drug: Cladribine
Cladribine 5mg/m^2/day IV over two hours on days 2-6.
Other Names:
  • Leustatin
  • Mavenclad

Drug: Cytarabine
Cytarabine 2 gm/m^2/day IV over four hours on days 2-6.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)

Drug: Mitoxantrone
Mitoxantrone 10mg/m^2/day IV on days 2-4.
Other Names:
  • Mitozantrone
  • Novantrone

Drug: G-CSF
G-CSF at a dose of 300 µg on days 1-6.
Other Name: colony-stimulating factor 3 (CSF 3)

Biological: Lintuzumab-Ac-225 (Dose 5: 1.25 μCi/kg with 8.0 μg/kg lintuzumab)
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Other Names:
  • HuM195-Ac225
  • Actimab-A
Experimental: 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.
 Drug: Cladribine
Cladribine 5mg/m^2/day IV over two hours on days 2-6.
Other Names:
  • Leustatin
  • Mavenclad

Drug: Cytarabine
Cytarabine 2 gm/m^2/day IV over four hours on days 2-6.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)

Drug: Mitoxantrone
Mitoxantrone 10mg/m^2/day IV on days 2-4.
Other Names:
  • Mitozantrone
  • Novantrone

Drug: G-CSF
G-CSF at a dose of 300 µg on days 1-6.
Other Name: colony-stimulating factor 3 (CSF 3)

Biological: Lintuzumab-Ac-225 (Recommended Phase 2 Dose)
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.
Other Names:
  • HuM195-Ac225
  • Actimab-A


Outcome Measures
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Primary Outcome Measures :
  1. The number of subjects with dose-limiting toxicities. [ Time Frame: 28 Days ]

    Dose-escalation will be conducted according to a 3+3 design with a five-patient expansion cohort at the recommended phase 2 dose. The initial dose of Lintuzumab-Ac225 will be 0.25 micro-Curie (μCi)/kg (Dose level 1), and the highest dose administered will be 1.25 μCi/kg.

    • if 0/3 pts have no dose-limiting toxicity (DLT), new patients enter next dose level.
    • if 1/3 pts has DLT, 3 pts treated at same dose level.
    • if 0/3 pts at that dose level has DLT, new pts enter higher level.
    • if 1 or more of the additional 3 pts has a DLT, no further pts started at dose level, preceding dose is the MTD.
    • if 2/3 of initially dosed patients have a DLT on first dose, study terminated.
    • if 0/3 have DLT at highest dose, additional 3 enrolled.

  2. Maximum-tolerated dose. [ Time Frame: 28 Days ]
    Defined as the dosage with the highest level at which no more than one subject experiences a DLT.

  3. The number of subjects who have at least one serious adverse event related to the study. [ Time Frame: 60 days ]
    All subjects who receive study drug will be closely monitored for serious adverse events (SAEs). The NCI's CTCAE (Common Toxicity Criteria for Adverse Effects) v4.03 will be used.

  4. Overall survival [ Time Frame: 2 years ]
    The number of subjects alive at two years from the first day of salvage therapy.


Secondary Outcome Measures :
  1. The number of subjects with a complete response (CR). [ Time Frame: Up to Day 60 ]
    A complete response will be defined as bone marrow blasts <5% with absolute neutrophil count ≥1000/μL and platelet ≥100,000/μL.

  2. The number of subjects with CR with incomplete hematologic recovery (CRi) [ Time Frame: Up to Day 60 ]
    CRi is defined as CR without platelet recovery or neutrophil recovery. This will be defined as bone marrow blasts <5% with absolute neutrophil count <1000/L and platelet <100,000/L.

  3. The number of subjects in a morphologic leukemia-free state (MLFS). [ Time Frame: Up to Day 60 ]
    MLFS is bone marrow blasts <5% with absolute neutrophil count <1000/μL AND platelet <100,000/μL.

  4. The number of subjects experiencing partial remission. [ Time Frame: Up to Day 60 ]
    Partial remission (PR) is defined by a decrease of at 50% or more in the percentage of blasts to less than 25% in the bone marrow. and normalized blood counts ( ANC>1000, Platelets>100,000/ml).

  5. Progression-free Survival [ Time Frame: 1 Year ]
    The number of subjects, who from the first day of remission until one year, do not relapse or progress.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03441048


Locations
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United States, Wisconsin
Froedtert Hospital and the Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Medical College of Wisconsin
Investigators
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Principal Investigator: Sameem Abedin, MD Medical College of Wisconsin
More Information
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Responsible Party: Sameem M. Abedin, MD, Assistant Professor, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT03441048    
Other Study ID Numbers: PRO00031633
First Posted: February 22, 2018    Key Record Dates
Last Update Posted: October 20, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sameem M. Abedin, MD, Medical College of Wisconsin:
Acute myeloid leukemia
Relapsed/refractory acute myeloid leukemia
CLAG-M
Lintuzumab
Additional relevant MeSH terms:
Layout table for MeSH terms
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Mitoxantrone
Cladribine
Lintuzumab
Lenograstim
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
 Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Immunological
Adjuvants, Immunologic