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

• ClinicalTrials.gov Identifier: NCT02626715
• Recruitment Status: Recruiting
• First Posted: December 10, 2015
• Last Update Posted: January 10, 2022
• Sponsor: Randy Windreich
• Information provided by (Responsible Party): Randy Windreich, University of Pittsburgh

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 (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 and Young Adults With Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
• Actual Study Start Date: September 4, 2015
• Estimated Primary Completion Date: November 2022
• Estimated Study Completion Date: November 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 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

Outcome Measures

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.

Eligibility Criteria

• Ages Eligible for Study: up to 26 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Contacts

Contact: Randy Windreich, MD; 412-692-5055; randy.windreich@chp.edu

Locations

United States, Pennsylvania

UPMC Children's Hospital of Pittsburgh; Recruiting

Pittsburgh, Pennsylvania, United States, 15224

Contact: Randy Windreich, MD 412-692-5055 randy.windreich@chp.edu

Sponsors and Collaborators

Randy Windreich

Investigators

• Principal Investigator: Randy Windreich, MD; University of Pittsburgh

More Information

• Responsible Party: Randy Windreich, Assistant Professor of Medicine, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02626715
• Other Study ID Numbers: PRO14100126 / STUDY19030327
• First Posted: December 10, 2015
• Last Update Posted: January 10, 2022
• Last Verified: January 2022

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:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Vidarabine; Fludarabine phosphate; Fludarabine; Alemtuzumab; Thiotepa; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antiviral Agents; Anti-Infective Agents; Antineoplastic Agents, Immunological; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists