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Lintuzumab-Ac225 in Combination With CLAG-M Chemotherapy in Patients With Relapsed/Refractory Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT03441048
Recruitment Status : Recruiting
First Posted : February 21, 2018
Last Update Posted : May 24, 2018
Sponsor:
Information provided by (Responsible Party):
Sameem M. Abedin, MD, Medical College of Wisconsin

Brief Summary:
This is a prospective, single-center phase I clinical study aimed at determining the maximum-tolerated 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 to estimate the maximum-tolerated dose (MTD).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Lintuzumab AC 225 Drug: Cladribine Drug: Cytarabine Drug: Mitoxantrone Drug: G-csf 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 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group 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 : April 1, 2019
Estimated Study Completion Date : April 1, 2020


Arm Intervention/treatment
Experimental: IV infusion of Lintuzumab AC225 following CLAG-M chemotherapy
CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m2/day IV over two hours on days 2-6; cytarabine 2 gm/m2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m2/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. Dose-escalation will be conducted according to a 3+3 design. The initial dose of Lintuzumab-Ac225 will be 0.25 uCi/kg (Dose level 1), and the highest dose administered will be 0.75uCi/kg.
Drug: 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. Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.

Drug: Cladribine
Cladribine 5mg/m2/day IV over two hours on days 2-6.

Drug: Cytarabine
Cytarabine 2 gm/m2/day IV over four hours on days 2-6.

Drug: Mitoxantrone
Mitoxantrone 10mg/m2/day IV on days 2-4.

Drug: G-csf
G-CSF at a dose of 300 µg on days 1-6.




Primary Outcome Measures :
  1. Maximum-Tolerated Dose of Lintuzumab-AC225 [ Time Frame: Through primary study completion, 1 year ]

    Dose-escalation will be conducted according to a 3+3 design. The initial dose of Lintuzumab-Ac225 will be 0.25 uCi/kg (Dose level 1), and the highest dose administered will be 0.75uCi/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.
    • MTD = highest level at which no more than 1/6 experience a DLT.

  2. Toxicities of the Combination [ Time Frame: Through study completion, 2 years ]
    All patients who receive study drug will be closely monitored for adverse events (AEs). All AEs that occur during study period will be reported and the investigator will determine the severity and relationship to study drug (unrelated, unlikely, possibly, probably, or definitely related). The NCI's CTCAE(Common Toxicity Criteria for Adverse Effects)v4.03 will be used for grading AEs, in addition to a modified criteria for hematologic adverse events.


Secondary Outcome Measures :
  1. Response Rates [ Time Frame: Through study completion, 2 years ]
    Assessment of response rates (complete, complete without platelet recovery, complete without platelet recovery or neutrophil recovery, partial and nonresponse) determined through bone marrow aspirate/biopsy and multi-color flow cytometry.

  2. Progression-free Survival [ Time Frame: Through study completion, 2 years ]
    Progression-free survival (PFS) will be calculated from the first day of remission until documentation of relapse/progression.

  3. Overall Survival [ Time Frame: Through study completion, 2 years ]


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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 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 DLCO and/or 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 PSA levels and are not on active therapy. Active malignancy is malignancy receiving treatment.

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


Contacts
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Contact: Medical College of Wisconsin Cancer Center Clinical Trials Office 414-805-8900 cccto@mcw.edu

Locations
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United States, Wisconsin
Froedtert Hospital and the Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Cancer Center Clinical Trials Office    866-680-0505 ext 8900    cccto@mcw.edu   
Principal Investigator: Sameem Abedin, MD         
Sponsors and Collaborators
Medical College of Wisconsin
Investigators
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Principal Investigator: Sameem Abedin, MD Medical College of Wisconsin

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Responsible Party: Sameem M. Abedin, MD, Assistant Professor, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT03441048     History of Changes
Other Study ID Numbers: ABEDIN-IIT
First Posted: February 21, 2018    Key Record Dates
Last Update Posted: May 24, 2018
Last Verified: May 2018

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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:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Cladribine
Mitoxantrone
Lintuzumab
Antibodies, Monoclonal
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