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Efficacy and Pharmacogenomics of Salvage CLAG-M Chemotherapy in Patients With Relapse/Refractory and Secondary Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT03150004
Recruitment Status : Recruiting
First Posted : May 11, 2017
Last Update Posted : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Ehab L Atallah, Medical College of Wisconsin

Brief Summary:
This is a prospective phase II clinical study to be conducted at the Medical College of Wisconsin. After meeting the study criteria and enrollment, patients will be treated with CLAG-M chemotherapy and followed at periodic intervals to determine the primary and secondary objectives.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: CLAG-M regimen Phase 2

Detailed Description:

STUDY RATIONALE:

The optimal treatment regimen for relapsed/refractory acute myeloid leukemia (AML) is unknown. Although several chemotherapy options are available, there is no universally accepted regimen to date. One such regimen is CLAG-M (Cladribine, Cytarabine, Mitoxantrone, G-CSF) that has been frequently used at our center. However, it is difficult to predict which patients are likely to respond to CLAG-M or experience treatment-related toxicities. In patients with newly diagnosed AML, studies have demonstrated that achievement of minimal residual disease negative CR is associated with a better overall survival. However, this has not been clearly studied in patients with relapsed-refractory AML. Through this study, we aim to demonstrate the influence of achieving MRD negative CR on survival of patients with relapsed/refractory AML treated with CLAG-M. In addition to the conventionally used predictive factors, we aim to incorporate pharmacogenomics to assess the efficacy and toxicity of therapy.

PRIMARY OBJECTIVE:

To determine the complete remission (CR) rate and achievement of minimal residual disease (MRD) negativity after treatment with salvage CLAG-M chemotherapy regimen in patients with relapse/refractory and secondary AML.

SECONDARY OBJECTIVES:

  1. To determine the progression free survival (PFS) and overall survival (OS) of patients treated with CLAG-M chemotherapy regimen.
  2. To study the pharmacogenomics of patients receiving CLAG-M chemotherapy and determine its influence on survival, CR rate and MRD negativity.
  3. Determination of disease- or patient-related factors that predict MRD negativity and survival with CLAG-M.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy and Pharmacogenomics of Salvage CLAG-M Chemotherapy in Patients With Relapse/Refractory and Secondary Acute Myeloid Leukemia
Actual Study Start Date : June 14, 2017
Estimated Primary Completion Date : October 1, 2020
Estimated Study Completion Date : October 1, 2021


Arm Intervention/treatment
Experimental: CLAG-M regimen
Patients treatment cycle is 30 days.
Drug: CLAG-M regimen

Patients will be started on CLAG-M regimen, which consists of the following:

  • Cladribine 5mg/m2 IV over two hours on days 1-5;
  • Cytarabine 2 gm/m2 IV over four hours on days 1-5, starting two hours after the Cladribine infusion is complete;
  • Mitoxantrone 10mg/m2 IV on days 1-3;
  • G-CSF at a dose of 300 μg on days 0-5.




Primary Outcome Measures :
  1. Minimal residual disease (MRD) complete remission (CR) rate after CLAG-M chemotherapy, using bone marrow aspirate/biopsy. [ Time Frame: Day 30 (+/- 5 days) ]
    Repeat bone marrow study will be obtained after the completion of CLAG-M therapy at day 30 or when absolute neutrophil count (ANC) recovers to >1000 cells/cu.mm.

  2. Minimal residual disease (MRD) complete remission (CR) rate after CLAG-M chemotherapy using flow cytometery. [ Time Frame: Day 30 (+/- 5 days) ]
    MRD assessment by flow cytometry will be done on patients achieving CR or CRp at the Wisconsin Diagnostic Laboratory. The test is performed using 8-color flow cytometry (FC). Briefly, EDTA-anticoagulated bone marrow aspirates are lysed and cell suspensions are prepared for incubation with 8 different, fluorochrome-labeled antibodies per tube. Antibodies analyzed across multiple tubes include: CD7, CD11b, CD13, CD14, CD15, CD22, CD33, CD34, CD36, CD38, CD45, CD56, CD64, CD117, and HLA-DR.

  3. Pharmacogenomics assessment through affimetry DMET assay. [ Time Frame: Day -30 to day 0 ]
    Genotyping with the DMET Plus array (Drug Metabolizing Enzymes and Transporters) will be performed using the DNA extracted from blood through Qiagen Blood and Cell Culture DNA extraction kit.



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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 Acute Myeloid Leukemia (AML) or AML secondary to Myelodysplastic Syndrome (MDS) or therapy related AML (t-AML), as defined by World Health Organization (WHO) criteria.
  3. Patients must meet one of the following criteria:

    • In first or subsequent relapse or refractory status, with or without prior hematopoietic stem cell transplant (HSCT) OR
    • Patients with MDS transformed to AML will be eligible even if they had not received prior therapy for AML.
  4. Eastern Cooperative Oncology Group (ECOG) performance score 0-2.
  5. Patients must meet the following clinical laboratory criteria: Direct bilirubin ≤ 1.5 X the upper limit of the normal range (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN unless related to AML or Gilbert syndrome or hemolysis. Calculated creatinine clearance ≥30 mL/min
  6. LVEF ≥ 45%

Exclusion Criteria:

  1. Acute Promyelocytic Leukemia.
  2. Pregnant or breast feeding women.
  3. Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.

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): NCT03150004


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

Locations
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United States, Wisconsin
Froedtert & the Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Medical College of Wisconsin Clinical Cancer Center    414-805-8900    cccto@mcw.edu   
Sponsors and Collaborators
Medical College of Wisconsin
Investigators
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Principal Investigator: Ehab Atallah, MD Medical College of Wisconsin

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Responsible Party: Ehab L Atallah, Associate Professor, Department of Medicine, Division of Hematology/Oncology, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT03150004     History of Changes
Other Study ID Numbers: PRO29327
First Posted: May 11, 2017    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Ehab L Atallah, Medical College of Wisconsin:
Acute myeloid leukemia
AML
salvage chemotherapy
CLAG-M
relapse acute myeloid leukemia
secondary acute myeloid leukemia
phase II
pharmacogenomics
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Recurrence
Neoplasms by Histologic Type
Neoplasms
Pathologic Processes
Disease Attributes