Clinical trial NCT02626715: Reduced-Intensity Conditioning (RIC) and Myeloablative Conditioning (MAC) for HSCT in AML/MDS
Official title: A Phase II Study of Myeloablative and Reduced-Intensity Conditioning Regimens for Children and Young Adults With Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia (AML)
Myelodysplastic Syndrome (MDS)
Hematopoietic Stem Cell Transplant (HSCT)
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2015-12-10
Enrollment: 21
Sex: ALL
Minimum age (years): 0
Maximum age (years): 26
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: INCLUSION CRITERIA:

Individuals must meet all the following criteria to be eligible for this study.

* Subject, parent, or legal guardian, if applicable, must have given written informed consent. For patients ≤ 17 years of age who are developmentally able, assent or affirmation will be obtained.
* Age 0-26, inclusive, at time of consent.
* Diagnosis of myelodysplastic syndrome or acute myeloid leukemia, either high-risk (defined below), 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: RAM phenotype; adverse cytogenetic abnormalities of monosomy 5, monosomy 7, 5q deletion, or other unfavorable prognostic markers according to cytogenetics, FISH, or next generation sequencing (NGS); presence of FLT3 positive internal tandem duplication (FLT3/ITD+), particularly high allelic ratio; treatment-related AML; or positive minimal residual disease (MRD) at end of Induction I.
* Stem cell sources include bone marrow, peripheral blood stem cells, or umbilical cord blood. 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 DR-B1.
* Minimum pre-freezing cell dose for cord blood units: 3 x 10\^7 total nucleated cells/kg and 1.5 x 10\^5 CD34+ cells/kg. If this is not attainable, then double cord blood transplant should be considered.
* Subject must have adequate performance status: Lansky score ≥60% for patients \<16 years, Karnofsky score ≥60% for patients ≥16 years.
* Subject must have adequate pre-transplant organ function to undergo one of the two conditioning regimens, either the myeloablative conditioning (MAC) OR reduced-intensity conditioning (RIC) regimen. If a subject does not meet the following organ function criteria for the MAC regimen, the RIC regimen will be considered if eligibility criteria is met. The RIC regimen may also be considered, regardless of MAC eligibility, if deemed appropriate by the Principal Investigator and/or treating physician.

Pre-transplant organ function criteria for Myeloablative Conditioning regimen:

* 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.

OR

Pre-transplant organ function criteria for Reduced-Intensity Conditioning regimen:

* 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.

  * HIV and HTLV negative, by either PCR or serology.
  * Negative pregnancy test for females ≥10 years old or who have reached menarche.
  * All females of childbearing potential and sexually active males must agree to use an FDA approved method of birth control for up to 12 months after HSCT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect.

EXCLUSION CRITERIA:

Individuals who meet any of the following criteria are not eligible for this protocol.

* Uncontrolled bacterial, viral, fungal, or other infection at the time of cytoreduction, defined by positive blood cultures and/or fevers \>38.0 within 24 hours of start of conditioning therapy.
* Females who are pregnant or who are lactating.
* Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

Additional Exclusion Criteria for Myeloablative Conditioning (MAC) Only Individuals who meet any of the following criteria are not eligible for the MAC regimen.

* Recipient of either an autologous or allogeneic stem cell transplant within 3 months of the start of conditioning.
* Patients with any inherited bone marrow failure syndrome including, but not limited to, Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis congenita or Down syndrome (defined as either constitutional trisomy 21 or constitutional mosaicism of trisomy 21).

Primary outcomes:
measure: Number of Non-relapsed Deaths by 100 Days Post-transplant in Pediatric Patients Receiving a Myeloablative or Reduced-intensity Preparative Regimen Prior to HSCT for High-risk AML and MDS.
timeFrame: Day 100
measure: 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.
timeFrame: 6 months
measure: Number of Non-relapsed Deaths by 6 Months Post-transplant in Pediatric Patients Receiving a Myeloablative or Reduced-intensity Preparative Regimen Prior to HSCT for High-risk AML and MDS.
timeFrame: Day 180
Secondary outcomes:
measure: The Pace of Neutrophil Recovery
timeFrame: Day of transplant to end of study (Day 365)
measure: The Pace of Platelet Recovery
timeFrame: Day of transplant to end of study (Day 365)
measure: Number of Participants Developing Acute Graft Versus Host Disease (aGVHD) by Grade
timeFrame: Day of transplant to end of study (Day 365)
measure: Number of Participants Developing Chronic Graft Versus Host Disease (cGVHD) by Grade
timeFrame: Day of transplant to end of study (Day 365)
measure: Disease-free Survival (DFS)
timeFrame: Day 100 and 180 post-transplant
measure: Treatment-related Mortality (TRM)
timeFrame: Day 100 and 180 post-transplant
measure: The Number of Subjects With Overall Survival (OS)
timeFrame: Day 100 and 180 post-transplant
measure: Day 0 Campath (Alemtuzumab) Level
timeFrame: Day 0
measure: Pace of Immune Reconstitution
timeFrame: Day 180
measure: Incidence of Primary Graft Failure.
timeFrame: Post-transplant to 42 days post-transplant
measure: Incidence of Grades 4 and 5 Adverse Events
timeFrame: Day 180
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Randy Windreich, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8.
citation: Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, Cheng GS, Kerr H, Stratton P, Duarte RF, McDonald GB, Inamoto Y, Vigorito A, Arai S, Datiles MB, Jacobsohn D, Heller T, Kitko CL, Mitchell SA, Martin PJ, Shulman H, Wu RS, Cutler CS, Vogelsang GB, Lee SJ, Pavletic SZ, Flowers ME. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015 Mar;21(3):389-401.e1. doi: 10.1016/j.bbmt.2014.12.001. Epub 2014 Dec 18.