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

Sponsor

Randy Windreich (Other)

Overall Status

Recruiting

CT.gov ID

NCT02626715

Collaborator

(none)

Enrollment

Location

Arms

85.9

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

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 Design

Study Type:

Interventional

Anticipated 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 and Young Adults With Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Actual Study Start Date :

Sep 4, 2015

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Nov 1, 2022

Arms and Interventions

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 Names: 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 Names: Campath, Thiotepa, Fludara, Busulfex

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 Names:

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 Names:

Campath, Thiotepa, Fludara, Busulfex

Outcome Measures

Primary Outcome Measures

Safety in pediatric patients receiving a myeloablative or reduced-intensity preparative regimen prior to HSCT for high-risk AML and MDS. [Day 100]
Number of non-relapsed deaths that occur
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. [6 months]
Safety in pediatric patients receiving a myeloablative or reduced-intensity preparative regimen prior to HSCT for high-risk AML and MDS. [Day 180]
Number of non-relapsed deaths that occur

Secondary Outcome Measures

The pace of neutrophil recovery [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.
The pace of platelet recovery [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.
Incidence of Acute Graft Versus Host Disease (aGVHD) (II-IV, III-IV) [Day of transplant to end of study (Day 365)]
Established by clinical and/or histological criteria
Incidence of Chronic Graft Versus Host Disease (cGVHD) [Day of transplant to end of study (Day 365)]
Established by clinical and/or histological criteria
The number of subjects with disease-free survival (DFS) [Day 100 and 180 post-transplant]
Adverse events assessed by CTCAE
The number of subjects with treatment-related mortality (TRM) [Day 100 and 180 post-transplant]
Adverse events assessed by CTCAE
The number of subjects with overall survival (OS) [Day 100 and 180 post-transplant]
Number of patients deceased
The pace of immune reconstitution [Post-transplant to end of study (365 days)]
Using lymphocyte subset panel
Day 0 Campath (Alemtuzumab) level [Day 0]
Correlate with rate of relapse, rate of viral infections, and pace of immune reconstitution.
Incidence of primary graft failure. [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.
Incidence of Grades 4 and 5 adverse events [Day 365]
Adverse events as assessed by CTCAE
Outcomes of Busulfan/Cyclophosphamide [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Months to 26 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

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).