Clinical Trials /

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

NCT03441048

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Lintuzumab-Ac225 in Combination With CLAG-M Chemotherapy in Patients With Relapsed/Refractory Acute Myeloid Leukemia
  • Official Title: A Phase I Study of Lintuzumab-Ac225 in Combination With CLAG-M Chemotherapy in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: ABEDIN-IIT
  • NCT ID: NCT03441048

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Lintuzumab AC 225IV infusion of Lintuzumab AC225 following CLAG-M chemotherapy
CladribineIV infusion of Lintuzumab AC225 following CLAG-M chemotherapy
CytarabineIV infusion of Lintuzumab AC225 following CLAG-M chemotherapy
MitoxantroneIV infusion of Lintuzumab AC225 following CLAG-M chemotherapy
G-csfIV infusion of Lintuzumab AC225 following CLAG-M chemotherapy

Purpose

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).

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.
    

Trial Arms

NameTypeDescriptionInterventions
IV infusion of Lintuzumab AC225 following CLAG-M chemotherapyExperimentalCLAG-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.
  • Lintuzumab AC 225
  • Cladribine
  • Cytarabine
  • Mitoxantrone
  • G-csf

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum-Tolerated Dose of Lintuzumab-AC225
Time Frame:Through primary study completion, 1 year
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Response Rates
Time Frame:Through study completion, 2 years
Safety Issue:
Description: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.
Measure:Progression-free Survival
Time Frame:Through study completion, 2 years
Safety Issue:
Description:Progression-free survival (PFS) will be calculated from the first day of remission until documentation of relapse/progression.
Measure:Overall Survival
Time Frame:Through study completion, 2 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Medical College of Wisconsin

Trial Keywords

  • Acute myeloid leukemia
  • Relapsed/refractory acute myeloid leukemia
  • CLAG-M
  • Lintuzumab

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