Treosulfan/Fludarabine/Low Dose TBI as a Preparative Regimen for Children With AML/MDS Undergoing Allo HCT

NCT01772953 | Completed Phase 2 DMC

• 1 other identifier: 11-TREO
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 23

Brief Summary

This is a prospective, open-label, nonrandomized, prospective clinical trial evaluating a fixed regimen of treosulfan, fludarabine and low-dose total body irradiation (TBI) in children with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). The primary hypothesis is that HCT with a preparative regimen consisting of treosulfan, fludarabine and low-dose TBI will result in overall survival (OS) comparable to historical rates observed with conventional myeloablative regimens in the pediatric population. The preparative regimen will result in adequate incidence of neutrophil and platelet engraftment, and acceptable rates of graft-versus-host disease (GVHD), relapse and survival. The pharmacokinetic (PK) profile of treosulfan in children will be comparable to that of adults previously studied.

Conditions

Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS)

Keywords

AML; MDS; Treosulfan

Outcome Measures

Primary Outcomes (1)

• The primary endpoint will be overall survival (OS) at one year

  The primary objective of this study is to determine the safety and preliminary efficacy of a transplant preparative regimen consisting of treosulfan, fludarabine and low-dose TBI for children with AML and MDS. The primary endpoint will be overall survival (OS) at one year.

  1 year

Secondary Outcomes (12)

• Pharmacokinetic (PK) profile of Treosulfan in children < 40 kg

  1 year

• Non-Relapse Mortality

  1 year

• Disease-Free Survival

  1 year

• Neutrophil Engraftment

  1 year

• Donor Chimerism

  1 year

Study Arms (1)

treosulfan, fludarabine and low-dose TBI prep regimen

EXPERIMENTAL

Treosulfan: 10-14 g/m2/day IV over 120 minutes on days -6, -5 and -4. Treosulfan will be administered prior to fludarabine on days -6 to -4 to facilitate PK testing. Fludarabine: 30 mg/m2 IV for patients \> 10 kg (or 1 mg/kg IV for patients \< 10 kg) once daily per institutional infusion standards on days -6 through -2 for a total dose of 150 mg/m2 (or 5 mg/kg). A single fraction of 200 cGy TBI will be administered on day -1. Stem cell infusion on day 0

Drug: Treosulfan

Interventions

Treosulfan DRUG

This is a phase II, open-label, nonrandomized, prospective study of a preparative regimen consisting of treosulfan, fludarabine and low-dose total body irradiation (TBI) for children with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT).

treosulfan, fludarabine and low-dose TBI prep regimen

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age \< 21 years.
• Disease and disease status:
• Acute myeloid leukemia (AML) in morphologic remission (defined as \< 5% blasts in a bone marrow aspirate of adequate cellularity performed within 28 days from start of conditioning).
• Myelodysplastic syndrome (MDS): Any 2008 WHO classification subtype (Appendix I). RAEB-2 patients may proceed directly to transplant, but may also be considered for induction chemotherapy before transplant. Patients with ≥20% morphologic marrow blasts will require induction therapy to reduce morphologic marrow blasts below 5% before transplant.
• Karnofsky Index or Lansky Play-Performance Scale \> 70 % on pre-transplant evaluation. Karnofsky scores must be used for patients \> 16 years of age and Lansky scores for patients \< 16 years of age.
• Able to give informed consent if \> 18 years, or with a legal guardian capable of giving informed consent if \< 18 years.
• Negative pregnancy test (serum, urine β-HCG, or other test per institutional guidelines) for females of childbearing potential.
• A single previous autologous or allogeneic HCT is allowed as long as the time from first to second transplant hematopoietic cell infusion is no less than 6 months.
• With a suitable allogeneic hematopoietic cell donor including, as available:
• HLA-identical related donor matched for HLA-A, and -B at the serologic level at minimum and -DRB1 at high resolution by molecular typing. A single locus mismatched related donor (7/8 matched) is permitted only if there are no 8/8 matched unrelated donors available.
• Unrelated volunteer donor matched for HLA-A, -B, -C and -DRB1 defined by high resolution molecular typing. A single HLA antigen or allele mismatch (7/8 matched) is permitted.
• Unrelated cord blood (UCB) matched to the recipient at a minimum of 4 of 6 loci at HLA-A, and -B by intermediate resolution and -DRB1 by high resolution. Cord blood unit(s) will be selected using the following criteria:
• Unit selection is based on the cryopreserved total nucleated cell (TNC) dose and matching at HLA-A, -B intermediate resolution and -DRB1 high resolution typing. While HLA-C antigen/allele level typing is not considered in the matching criteria, if available, it may be used to optimize unit selection.
• Selection of two UCB units is required if a single UCB unit will not provide a sufficient cell dose (see Table 1 below). When two UCB units are not required per Table 1, two UCB units may be used with approval of the study chair or designee. When two units are selected, the following rules apply:
• The UCB unit with the least HLA disparity with the patient, followed by the larger cell dose for equivalently matched units, will be considered unit #1 (selection priority is 6/6 match \>5/6 match\>4/6 match).

You may not qualify if:

• Pregnant or lactating females are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants.
• Patients with HIV or uncontrolled fungal, bacterial or viral infections are excluded. Patients with history of fungal disease during induction therapy may proceed if they have a significant response to antifungal therapy with no or minimal evidence of disease remaining by CT evaluation.
• Patients with active CNS leukemia or any other active site of extramedullary disease at the time of enrollment are not permitted. Note: Those with prior history of CNS or extramedullary disease, but with no active disease at the time of pre-transplant workup, are eligible.
• Patients undergoing a course of chemotherapy using another investigational drug.
• Patients diagnosed with Fanconi Anemia.

Sponsors & Collaborators

• Center for International Blood and Marrow Transplant Research: lead
• National Marrow Donor Program: collaborator
• Resource for Clinical Investigation in Blood and Marrow Transplantation (RCI BMT): collaborator
• Pediatric Blood and Marrow Transplant Consortium: collaborator
• St. Baldrick's Foundation: collaborator
• medac GmbH: collaborator

Study Sites (23)

Children's Hospital of Alabama/UAB

Birmingham, Alabama, 35233, United States

Location

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

City of Hope

Duarte, California, 91010, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 99027, United States

Location

Children's Hospital of Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

All Children's Hospital

St. Petersburg, Florida, 33701, United States

Location

Riley Hospital for Children/Indiana University

Indianapolis, Indiana, 46202, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Washington University, St. Louis Children's

St Louis, Missouri, 63130, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

OHSU/Doernbecher Children's Hospital

Portland, Oregon, 97239, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

St. Jude's Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Methodist Children's Hospital of South Texas

San Antonio, Texas, 78229, United States

Location

Primary Children's Medical Center - University of Utah

Salt Lake City, Utah, 84111, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

University of Wisconsin - Madison

Madison, Wisconsin, 53705, United States

Location

Medical College of Wisconsin/Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

treosulfan

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Study Officials

• Eneida Nemecek, MD

  Doernbecher Children's Hospital, Oregon Health & Science University

  STUDY CHAIR

• Colleen Delaney, MD

  Seattle Children's Hospital, Fred Hutchinson Cancer Research Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 6, 2012
• First Posted: January 21, 2013
• Study Start: September 1, 2013
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: October 12, 2016

Record last verified: 2016-10

Locations

US (23)