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Reduced-Intensity Conditioning (RIC) and Myeloablative Conditioning (MAC) for HSCT in AML/MDS

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ClinicalTrials.gov Identifier: NCT02626715
Recruitment Status : Recruiting
First Posted : December 10, 2015
Last Update Posted : November 7, 2018
Sponsor:
Information provided by (Responsible Party):
Randy Windreich, University of Pittsburgh

Brief Summary:
The purpose of this study is to compare safety and efficacy of reduced-intensity conditioning and myeloablative conditioning regimens prior to HSCT in high-risk AML/MDS pediatric and young adult patients. This study investigates the use of two novel conditioning therapies for hematopoietic stem cell transplant (HSCT). The primary focus of both the investigators' myeloablative and reduced-intensity conditioning regimens is to reduce overall toxicity so that pediatric and young adult patients with high-risk AML/MDS with significant pretransplant comorbidities who would have been ineligible to proceed to HSCT previously can now receive potentially life-saving treatment.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS) Hematopoietic Stem Cell Transplant (HSCT) Drug: Reduced-Intensity Conditioning Regimen Drug: Myeloablative Conditioning Regimen Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Myeloablative and Reduced-Intensity Conditioning Regimens for Children With Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Actual Study Start Date : September 4, 2015
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2021


Arm Intervention/treatment
Active Comparator: Reduced-Intensity Conditioning

Campath (alemtuzumab), Droxia (hydroxyurea), Fludara (fludarabine), Alkeran (melphalan), Thiotepa (triethylenethiophosphoramide)

Trade Name (generic name)

Drug: Reduced-Intensity Conditioning Regimen
Campath (alemtuzumab) - drug class: monoclonal antibody Droxia (hydroxyurea) - drug class: antimetabolite Fludara (fludarabine) - drug class: antimetabolite Alkeran (melphalan) - drug class: alkylating agent Thiotepa (triethylenethiophosphoramide) - drug class: cytotoxic agent
Other Name: Campath, Droxia, Fludara, Alkeran, Thiotepa

Active Comparator: Myeloablative Conditioning

Campath (alemtuzumab), Thiotepa (triethylenethiophosphoramide) , Fludara (fludarabine), Busulfex (busulfan)

Trade Name (generic name)

Drug: Myeloablative Conditioning Regimen
Campath (alemtuzumab) - drug class: monoclonal antibody Thiotepa (triethylenethiophosphoramide) - drug class: cytotoxic agent Fludara (fludarabine) - drug class: antimetabolite Busulfex (busulfan) - drug class: alkylating agent
Other Name: Campath, Thiotepa, Fludara, Busulfex




Primary Outcome Measures :
  1. Safety in pediatric patients receiving a myeloablative or reduced-intensity preparative regimen prior to HSCT for high-risk AML and MDS. [ Time Frame: Day 100 ]
    Number of non-relapsed deaths that occur

  2. Preliminary efficacy (event-free survival at 6 months) in pediatric patients receiving a myeloablative or reduced-intensity preparative regimen prior to HSCT for high-risk AML and MDS. [ Time Frame: 6 months ]
  3. Safety in pediatric patients receiving a myeloablative or reduced-intensity preparative regimen prior to HSCT for high-risk AML and MDS. [ Time Frame: Day 180 ]
    Number of non-relapsed deaths that occur


Secondary Outcome Measures :
  1. The pace of neutrophil recovery [ Time Frame: Day of transplant to end of study (Day 365) ]
    The first of three consecutive days in which the absolute neutrophil count (ANC) exceeded 500/μL.

  2. The pace of platelet recovery [ Time Frame: Day of transplant to end of study (Day 365) ]
    The first of seven consecutive days in which the platelet count exceeded 20,000/mm3 without platelet transfusions.

  3. Incidence of Acute Graft Versus Host Disease (aGVHD) (II-IV, III-IV) [ Time Frame: Day of transplant to end of study (Day 365) ]
    Established by clinical and/or histological criteria

  4. Incidence of Chronic Graft Versus Host Disease (cGVHD) [ Time Frame: Day of transplant to end of study (Day 365) ]
    Established by clinical and/or histological criteria

  5. The number of subjects with disease-free survival (DFS) [ Time Frame: Day 100 and 180 post-transplant ]
    Adverse events assessed by CTCAE

  6. The number of subjects with treatment-related mortality (TRM) [ Time Frame: Day 100 and 180 post-transplant ]
    Adverse events assessed by CTCAE

  7. The number of subjects with overall survival (OS) [ Time Frame: Day 100 and 180 post-transplant ]
    Number of patients deceased

  8. The pace of immune reconstitution [ Time Frame: Post-transplant to end of study (365 days) ]
    Using lymphocyte subset panel

  9. Day 0 Campath (Alemtuzumab) level [ Time Frame: Day 0 ]
    Correlate with rate of relapse, rate of viral infections, and pace of immune reconstitution.

  10. Incidence of primary graft failure. [ Time Frame: Post-transplant to 42 days post-transplant ]
    The failure to achieve an ANC ≥500/μL after 42 days, determined by three consecutive measurements on different days, and not caused by recurrent leukemia.

  11. Incidence of Grades 4 and 5 adverse events [ Time Frame: Day 365 ]
    Adverse events as assessed by CTCAE

  12. Outcomes of Busulfan/Cyclophosphamide [ Time Frame: Conditioning to end of study (Day 365) ]
    Compare with historically-used "standard" conditioning regimens of Busulfan/Cyclophosphamide in terms of neutrophil recovery, platelet recovery, incidence of GVHD, TRM, OS, DFS, immune reconstitution, as well as short- and long-term complications.



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Ages Eligible for Study:   up to 22 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Myeloablative Conditioning Transplant

  1. Patient must be between 0-22 years of age.
  2. Diagnosis of acute myeloid leukemia or myelodysplastic syndrome, either high-risk, relapsed or primary refractory, MRD-positive without circulating myeloblasts or active extramedullary disease at the time of transplant. Active marrow disease is permitted.

    ("High-risk" AML features are defined by the following: greater than 15% blasts in the bone marrow after the first course of Induction chemotherapy; adverse cytogenetic abnormalities of monosomy 5, monosomy 7, or 5q deletion; presence of FLT3 positive internal tandem duplication (FLT3/ITD+), particularly high allelic ratio; or treatment-related AML.)

  3. Stem cell sources include bone marrow, peripheral blood stem cells, or umbilical cord blood.
  4. Related bone marrow, peripheral blood stem cell, or cord blood unit: sibling should be HLA-matched at A, B, and DR-B1 loci. Unrelated cord blood unit should be at a minimum of 4/6 matched at antigen level on HLA A and B, and allele level at HLA DR-B1 loci. Unrelated bone marrow or peripheral blood stem cell donor should be HLA allele level matched at A, B, C, and DR-B1.
  5. Minimum prefreezing cell dose for cord blood units: 3 x 107 total nucleated cells/kg and 1.5 x 105 CD34+ cells/kg. If this is not attainable, then double cord blood transplant should be considered.
  6. Patient, parent, or legal guardian must have given written informed consent and/or assent.
  7. Patient must have adequate performance status (Lansky score ≥60% for patients <16 years; Karnofsky score ≥60% for patients ≥16 years).
  8. Patient must have adequate pre-transplant organ function as defined by:

    • Renal: creatinine clearance or radioisotope GFR ≥70 mL/min/1.73 m2.
    • Hepatic: total bilirubin ≤2.0 mg/dL unless the increase in bilirubin is attributable to Gilbert's syndrome; and SGOT (AST), SGPT (ALT), and Alkaline Phosphatase <4 x upper limit of normal (ULN) for age.
    • Cardiac: normal cardiac function by echocardiogram or radionuclide scan, as defined by left ventricular ejection fraction at rest >45%, or shortening fraction >26%.
    • Pulmonary: FEV1, FVC, and DLCO (corrected for hemoglobin) ≥50% of predicted; if unable to perform pulmonary function tests, then oxygen saturation ≥92% on room air.

Eligibility Criteria for Reduced-Intensity Conditioning Transplant

  1. Patient must be between 0 -22 years of age.
  2. Patient must meet criteria #2-7 in section 5.1.
  3. Patient is excluded from myeloablative conditioning transplant due to failure to meet any of the criteria outlined in #8 of section 5.1.
  4. Patient must have adequate pre-transplant organ function as defined by:

    • Renal: creatinine clearance or radioisotope GFR ≥70 mL/min/1.73 m2.
    • Hepatic: total bilirubin ≤2.5 mg/dL unless the increase in bilirubin is attributable to Gilbert's syndrome; and SGOT (AST), SGPT (ALT), and Alkaline Phosphatase <5 x upper limit of normal (ULN) for age.
    • Cardiac: normal cardiac function by echocardiogram or radionuclide scan, as defined by left ventricular ejection fraction at rest >40%, or shortening fraction >26%.
    • Pulmonary: FEV1, FVC, and DLCO (corrected for hemoglobin) ≥40% of predicted; if unable to perform pulmonary function tests, then oxygen saturation ≥92% on room air.

Exclusion Criteria:

Exclusion Criteria for Myeloablative Conditioning Transplant

  1. Recipient of an autologous stem cell transplant.
  2. Allogeneic hematopoietic stem cell transplant within the previous 3 months.
  3. Uncontrolled bacterial, viral, fungal, or other infection at the time of cytoreduction. Uncontrolled infection defined by positive blood cultures and fevers >38.0 within 24-48 hours of start of conditioning therapy.
  4. Evidence of HIV/HTLV infection or HIV/HTLV positive serology.
  5. Pregnancy or lactating. All females of 11 years of age or older and/or who have begun menstruating will be screened for HCG by either urinalysis or a blood sample in order to screen for pregnancy status.
  6. Patients with any inherited bone marrow failure syndrome (including, but not limited to, Fanconi anemia, Shwachman-Diamond syndrome, and dyskeratosis congenital) or Down syndrome (defined as either constitutional trisomy 21 or constitutional mosaicism of trisomy 21).

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): NCT02626715


Contacts
Contact: Randy Windreich, MD 412-692-5055

Locations
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Randy Windreich, MD    412-692-5055      
Sponsors and Collaborators
Randy Windreich
Investigators
Principal Investigator: Randy Windreich, MD University of Pittsburgh

Responsible Party: Randy Windreich, Assistant Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02626715     History of Changes
Other Study ID Numbers: PRO14100126
First Posted: December 10, 2015    Key Record Dates
Last Update Posted: November 7, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Fludarabine
Fludarabine phosphate
Alemtuzumab
Thiotepa
Melphalan
Busulfan
Vidarabine
Alkylating Agents
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Myeloablative Agonists