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Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Busulfan Conditioning for Allogeneic Transplantation in High Risk AML and Myelodysplastic Syndromes

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ClinicalTrials.gov Identifier: NCT03121014
Recruitment Status : Recruiting
First Posted : April 19, 2017
Last Update Posted : September 6, 2019
Sponsor:
Information provided by (Responsible Party):
Damiano Rondelli, MD, University of Illinois at Chicago

Brief Summary:
The study is a Phase II clinical trial. Patients will receive intensity modulated total marrow irradiation (TMI) at a dose of 9 Gy with standard myeloablative fludarabine/ i.v. targeted busulfan (FluBu) conditioning prior to allogeneic hematopoietic stem cell transplant (HSCT).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndromes Drug: Fludarabine Drug: Busulfan Drug: ATG Radiation: Total Marrow Irradiation Procedure: Stem Cell Product Infusion Drug: Tacrolimus Drug: Methotrexate Phase 2

Detailed Description:
Patients will receive the following conditioning regimen: fludarabine 40 mg/m2 IVBP daily for day -5 (5 days before stem cell infusion) through Day -2, IV busulfan targeting a 4800μM/min/ day from day -5 through day -2, and ATG (Thymoglobulin®) at 0.5 mg/kg IV on day -3, and 2 mg/kg on days -2 and day -1 (Only for recipients of stem cells from unrelated or mismatched donors). In addition to the above conditioning regimen all patients will receive TMI at a dose of 3Gy on days -3, -2 and -1. On day 0, the stem cell product will be infused according to BMT unit policy. Graft versus host disease (GVHD) prophylaxis will consist of administration of tacrolimus and methotrexate (see Section 8). Post-transplant evaluation will be done as per standard care with study data collected at day 30, 60, 90, 180, 365 and 2 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Busulfan Conditioning for Allogeneic Transplantation in High Risk AML and Myelodysplastic Syndromes
Actual Study Start Date : April 24, 2017
Estimated Primary Completion Date : April 24, 2023
Estimated Study Completion Date : April 24, 2024


Arm Intervention/treatment
Experimental: Patient Treatment
Patients will receive fludarabine 40 mg/m2 IVBP daily for day -5 (5 days before stem cell infusion) through Day -2, IV busulfan targeting a 4800μM/min/ day from day -5 through day -2, and ATG (Thymoglobulin®) at 0.5 mg/kg IV on day -3, and 2 mg/kg on days -2 and day -1 (Only for recipients of stem cells from unrelated or mismatched donors). In addition to the above conditioning regimen all patients will receive TMI at a dose of 3Gy on days -3, -2 and -1. On day 0, the stem cell product will be infused according to BMT unit policy. Graft versus host disease (GVHD) prophylaxis will consist of administration of tacrolimus and methotrexate. Post-transplant evaluation will be done as per standard care with study data collected at day 30, 60, 90, 180, 365 and 2 years.
Drug: Fludarabine
40 mg/m^2 IVBP daily for day -5 (5 days before stem cell infusion) through Day -2
Other Name: Fludara®

Drug: Busulfan
targeting a 4800μM/min/ day from day -5 through day -2
Other Name: Busulfex®

Drug: ATG
0.5 mg/kg IV on day -3, and 2 mg/kg on days -2 and day -1
Other Name: Thymoglobulin®

Radiation: Total Marrow Irradiation
dose of 3Gy on days -3, -2 and -1

Procedure: Stem Cell Product Infusion
Day 0 according to BMT unit policy

Drug: Tacrolimus
The starting dose is at 0.03 mg/kg/day IV continuous infusion over 24 hr from 4 PM on day -2. Dose will be adjusted to target trough levels of 5-15 ng/mL. More information is available in the protocol document.
Other Name: FK-506, Prograf®

Drug: Methotrexate
10 mg/m^2 on Day 1, 8 mg/m^2 on Days 3, 6 and 11
Other Name: Trexall®




Primary Outcome Measures :
  1. Relapse free survival of approximately 30% in high-risk patients conditioned with the Fludarabine/ Busulfan regimen [ Time Frame: Up to 1 year ]
    Using a Simon 2 stage optimal design with α of 0.05 and power of 0.8, 15 patients will be enrolled in the first stage. If greater than 5 patients survive to 1 year without relapse the study will continue into stage 2. Recruitment will then continue to a total of 46 patients. In this expanded cohort, if a total of 18 or more patients survive to 1 year without relapse, the treatment will be judged efficacious and worthy of further study.


Secondary Outcome Measures :
  1. Relapse free survival [ Time Frame: Up to 1 year ]
    It will be estimated and reported with 90% confidence intervals. The proportion of patients who are alive at 1-year will also be estimated with a 90% exact binomial confidence interval.

  2. Overall survival [ Time Frame: Up to 1 year ]
    It will be estimated and reported with 90% confidence intervals. The proportion of patients who are alive at 1-year will also be estimated with a 90% exact binomial confidence interval.

  3. Transplant related mortality rate [ Time Frame: Up to 1 year ]
    After accrual of 10 patients, analysis will be performed to ensure that the mortality rate does not exceed 30%. By calculation of confidence intervals to ensure the TRM not exceed 30%, accrual would be halted if n= 6 of 10 (lower bound of the exact, one-sided 90% CI is 35.4%).



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.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18-65 years
  2. Patients with AML or MDS who meet the following criteria:

    1. Relapsed or refractory AML (including AML in CR2)
    2. Poor-risk AML in first remission, with remission defined as <5% bone marrow blasts morphologically:

      • AML arising from MDS or a myeloproliferative disorder, or secondary AML
      • Poor risk molecular features including presence of FLT3 internal tandem duplication mutation.
      • Poor-risk cytogenetics: Monosomal karyotype, complex karyotype (> 3 abnormalities), inv(3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7
    3. Primary refractory disease
    4. MDS with at least one of the following poor-risk features:

      • Poor-risk cytogenetics including 3q abnormalities, 7/7q minus or complex cytogenetics (>3 abnormalities)
      • Current or previous INT-2 or high IPSS score
      • Treatment-related MDS
      • MDS diagnosed before age 21 years
      • Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy
      • Life-threatening cytopenias, including those requiring regular PRBC or platelet transfusions
  3. Patients must have a related or unrelated peripheral blood stem cell donor as follows:

    1. Sibling donor must be a 6/6 match for HLA-A, -B at intermediate (or higher) resolution and -DRB1 at high resolution using DNA based typing
    2. Unrelated donors must be at least 7/8 match at HLA-A, -B, -C and DRB1 at high resolution using DNA-based typing

Exclusion criteria:

  1. Presence of significant co morbidity as shown by:

    1. Left ventricular ejection fraction < 50%
    2. Bilirubin > 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST > 5 x ULN
    3. FEV1 and FVC < 50% of predicted or DLCO <50% of predicted once corrected for anemia
    4. Karnofsky score <70 (appendix C)
    5. Hematopoietic cell transplantation comorbidity index >3
    6. Active viral hepatitis or HIV infection
    7. Cirrhosis
  2. Pregnancy
  3. Patients unable to sign informed consent
  4. Patient who have previously received radiation to >20% of bone marrow containing areas.

4. DONOR ELIGIBILITY AND SELECTION

4.1. Donor Selection

Donor evaluation and selection is by standard for normal clinical practice. No study procedures are to be performed on donors. All donors must be willing to donate peripheral blood stem cells and meet institutional or NMDP criteria for donation.

The following prioritization will be used when selecting donors:

  1. When possible, an HLA compatible sibling will be used as a donor.
  2. For patients who do not have an HLA compatible sibling, an unrelated donor will be used
  3. 8/8 matched unrelated donors are preferred over single antigen mismatched donors.

If more than one potential volunteer unrelated donor is considered suitable further selection of the most suitable donor is at the discretion of the treating physician. The following serves only as a guide for prioritization:

  1. Age of donor (18-24 > 25-34 > 35-44 > 45+)
  2. Sex and parity of donor (male > female, nulliparous female > parous, multiparous female)
  3. Cytomegalovirus (CMV) status, if recipient is CMV seronegative (CMV- > CMV+)

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): NCT03121014


Contacts
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Contact: Damiano Rondelli, MD 312-413-3547 drond@uic.edu

Locations
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United States, Illinois
University of Illinois at Chicago Recruiting
Chicago, Illinois, United States, 60612
Contact: Damiano Rondelli, MD    312-413-3547    drond@uic.edu   
Sponsors and Collaborators
University of Illinois at Chicago
Investigators
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Principal Investigator: Damiano Rondelli, MD University of Illinois at Chicago

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Responsible Party: Damiano Rondelli, MD, Professor, Hematology, University of Illinois at Chicago
ClinicalTrials.gov Identifier: NCT03121014     History of Changes
Other Study ID Numbers: 2017-0001
2017-0001 ( Other Identifier: UIC, Office for the Protection of Research Subjects )
First Posted: April 19, 2017    Key Record Dates
Last Update Posted: September 6, 2019
Last Verified: September 2019

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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
Additional relevant MeSH terms:
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Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Vidarabine
Methotrexate
Fludarabine phosphate
Fludarabine
Busulfan
Tacrolimus
Thymoglobulin
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents