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

NCT ID: NCT02626715

Last Updated: 2024-07-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-04
• Study Completion Date: 2023-04-12

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.

Conditions

Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); Hematopoietic Stem Cell Transplant (HSCT)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Reduced-Intensity Conditioning

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

Trade Name (generic name)

Group Type: ACTIVE_COMPARATOR

Reduced-Intensity Conditioning Regimen

Intervention Type: DRUG

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

Myeloablative Conditioning

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

Trade Name (generic name)

Group Type: ACTIVE_COMPARATOR

Myeloablative Conditioning Regimen

Intervention Type: DRUG

Campath (alemtuzumab) - drug class: monoclonal antibody Thiotepa (triethylenethiophosphoramide) - drug class: cytotoxic agent Fludara (fludarabine) - drug class: antimetabolite Busulfex (busulfan) - drug class: alkylating agent

Interventions

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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Campath, Droxia, Fludara, Alkeran, Thiotepa; Campath, Thiotepa, Fludara, Busulfex

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.

• 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).

• Minimum Eligible Age: 0 Months
• Maximum Eligible Age: 26 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Randy Windreich

OTHER

Sponsor Role: lead

Responsible Party

Randy Windreich

Assistant Professor of Medicine

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Randy Windreich, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

UPMC Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 7581076 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25529383 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

STUDY19030327

Identifier Type: -

Identifier Source: org_study_id