Optimizing Cord Blood and Haploidentical Aplastic Anemia Transplantation (BMT CTN 1502) (CHAMP)

Study Description

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Brief Summary:

This study is a prospective, simultaneous, parallel phase II study with one arm receiving unrelated cord blood transplantation and the other arm receiving haploidentical transplantation for Severe Aplastic Anemia (SAA) patients. The primary objective is to assess overall survival (OS) separately in the 2 arms at 1 year post-hematopoietic stem cell transplantation (HSCT).

Condition or disease	Intervention/treatment	Phase
Severe Aplastic Anemia	Drug: Antithymocyte Globulin; Drug: Fludarabine; Drug: Cyclophosphamide; Radiation: Total Body Irradiation (TBI); Procedure: UCB HSCT; Procedure: Haplo HSCT; Drug: Tacrolimus; Drug: Mycophenolate mofetil (MMF); Drug: G-CSF	Phase 2

Detailed Description:

Acquired SAA is a rare bone marrow failure disorder with an estimated annual incidence of 2 cases per million and with over 600 new cases in the United States each year. A major challenge in treating acquired SAA is the management of patients who are refractory to immunosuppressant therapy (IST) or have relapsed after IST. HSCT is the only curative option for these patients but many are ineligible because they lack a suitable donor. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) seeks to increase options for these patients by using novel therapeutic strategies (optimized preparative regimens and targeted antithymocyte globulin (ATG) pharmacokinetics (PK)) to expand the donor pool utilizing UCB for transplantation. The goal of this protocol is to test whether optimized approaches using two alternative donor sources will achieve acceptable outcomes in SAA patients. Ideally, a direct comparison of the two approaches would allow us to determine a best approach. However, given 1) the rarity of the disease, 2) the fact that different centers often prefer different stem cell sources, and 3) the fact that most comparisons of alternative donor stem cell sources have shown very similar outcomes, this protocol allows both approaches to be performed, but there are no planned comparisons of outcomes between the two cohorts.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	60 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Optimizing Cord Blood and Haploidentical Aplastic Anemia Transplantation (CHAMP) (BMT CTN #1502)
Actual Study Start Date :	May 19, 2017
Estimated Primary Completion Date :	February 2021
Estimated Study Completion Date :	February 2022

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Unrelated Cord Blood HSCT; The unrelated cord blood arm will be treated with a preparative regimen of an individualized dose of Antithymocyte Globulin (ATG) (dose calculated based on actual weight and absolute lymphocyte count), fludarabine (150 mg/m^2), cyclophosphamide (100 mg/kg), and low dose total body irradiation (TBI) (200 cGy) before undergoing the UCB HSCT. GVHD prophylaxis will be tacrolimus combined with mycophenolate mofetil (MMF). G-CSF will be administered post-transplant.	Drug: Antithymocyte Globulin; Administration of ATG for the UCB arm should be over 8 hours IV daily for 4 days from Day -13 to Day -10. Administration of ATG for the haplo arm will be 0.5 mg/kg IV on Day -9 over 6 hours and 2 mg/kg IV on Days -8 and -7 over 4 hours.; Other Name: Thymoglobulin®, rATG; Drug: Fludarabine; Fludarabine dose will be 30 mg/m^2 IV daily for 5 days from Day -6 to Day -2 for both arms.; Other Name: Fludara®; Drug: Cyclophosphamide; Cyclophosphamide dose will be 50 mg/kg IV daily for 2 days on Day -3 and Day -2 for the UCB arm. Cyclophosphamide dose will be 14.5 mg/kg IV daily for 2 days (Day -6 to Day -5) prior to transplantation and 50 mg/kg IV daily for 2 days (Day +3 to Day +4) after transplantation for the haplo arm.; Other Name: Cytoxan®; Radiation: Total Body Irradiation (TBI); TBI is to be delivered in a single dose of 200 cGy on Day -1 for both arms.; Procedure: UCB HSCT; Eligible patients without a fully matched related or unrelated donor available will undergo unrelated umbilical cord blood hematopoietic stem cell transplant.; Drug: Tacrolimus; Tacrolimus should be started on Day -3 and administered to maintain a level of 10-15 ng/mL for the UCB arm. Tacrolimus should be started on Day +5 and administered to maintain a level of 10-15 ng/mL for the haplo arm.; Other Name: Prograf®; Drug: Mycophenolate mofetil (MMF); MMF dose will be 15 mg/kg PO three times a day (TID) up to 1 gm TID (or IV equivalent) starting on Day -3 for the UCB arm. MMF dose will be 15 mg/kg PO three times a day (TID) up to 1 gm TID (or IV equivalent) starting on Day +5 for the haplo arm.; Other Name: Cellcept®; Drug: G-CSF; G-CSF will be given IV or SQ starting on Day +1 at 5 mcg/kg/day until ANC is > 1500 for 3 days for the UCB arm. G-CSF will be given IV or SQ starting on Day +5 at 5 mcg/kg/day until ANC is > 1500 for 3 days for the haplo arm.; Other Name: Filgrastim, Neupogen®
Experimental: Haplo Bone Marrow HSCT; The haplo bone marrow arm will be treated with a preparative regimen of Antithymocyte Globulin (ATG) (4.5 mg/kg), fludarabine (150 mg/m^2), cyclophosphamide (29 mg/kg), and low dose total body irradiation (TBI) (200 cGy) before undergoing the haplo HSCT. GVHD prophylaxis will be with post-HSCT cyclophosphamide (100 mg/kg), tacrolimus, and mycophenolate mofetil (MMF). G-CSF will be administered post-transplant.	Drug: Antithymocyte Globulin; Administration of ATG for the UCB arm should be over 8 hours IV daily for 4 days from Day -13 to Day -10. Administration of ATG for the haplo arm will be 0.5 mg/kg IV on Day -9 over 6 hours and 2 mg/kg IV on Days -8 and -7 over 4 hours.; Other Name: Thymoglobulin®, rATG; Drug: Fludarabine; Fludarabine dose will be 30 mg/m^2 IV daily for 5 days from Day -6 to Day -2 for both arms.; Other Name: Fludara®; Drug: Cyclophosphamide; Cyclophosphamide dose will be 50 mg/kg IV daily for 2 days on Day -3 and Day -2 for the UCB arm. Cyclophosphamide dose will be 14.5 mg/kg IV daily for 2 days (Day -6 to Day -5) prior to transplantation and 50 mg/kg IV daily for 2 days (Day +3 to Day +4) after transplantation for the haplo arm.; Other Name: Cytoxan®; Radiation: Total Body Irradiation (TBI); TBI is to be delivered in a single dose of 200 cGy on Day -1 for both arms.; Procedure: Haplo HSCT; Eligible patients without a fully matched related or unrelated donor available will undergo haploidentical bone marrow transplant.; Drug: Tacrolimus; Tacrolimus should be started on Day -3 and administered to maintain a level of 10-15 ng/mL for the UCB arm. Tacrolimus should be started on Day +5 and administered to maintain a level of 10-15 ng/mL for the haplo arm.; Other Name: Prograf®; Drug: Mycophenolate mofetil (MMF); MMF dose will be 15 mg/kg PO three times a day (TID) up to 1 gm TID (or IV equivalent) starting on Day -3 for the UCB arm. MMF dose will be 15 mg/kg PO three times a day (TID) up to 1 gm TID (or IV equivalent) starting on Day +5 for the haplo arm.; Other Name: Cellcept®; Drug: G-CSF; G-CSF will be given IV or SQ starting on Day +1 at 5 mcg/kg/day until ANC is > 1500 for 3 days for the UCB arm. G-CSF will be given IV or SQ starting on Day +5 at 5 mcg/kg/day until ANC is > 1500 for 3 days for the haplo arm.; Other Name: Filgrastim, Neupogen®

Outcome Measures

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Primary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: 1 year ]
   Evaluated separately in the 2 arms, OS is defined as the time interval from date of transplant to death or to last follow-up.

Secondary Outcome Measures :

1. Neutrophil Recovery [ Time Frame: Day 28 and 56 ]
   Neutrophil recovery is achieving an absolute neutrophil count (ANC) > 0.5 x10^9/L for three consecutive measurements on different days, with the first of the three days being defined as the day of neutrophil engraftment.
2. Platelet Recovery [ Time Frame: Day 28 and 56 ]
   Platelet recovery is defined by achieving a platelet count > 20 x 10^9/L with no platelet transfusions in the preceding seven days. The first day of the sustained platelet count will be defined as the day of platelet engraftment.
3. Alive with Sustained Engraftment [ Time Frame: 1 year ]
   Being alive and engrafted is defined as not having experienced death, primary graft failure, or secondary graft failure.
4. Incidences of Graft Failure [ Time Frame: 1 year ]
   Primary graft failure is defined by the lack of neutrophil engraftment by Day +56 post-HSCT or < 5% donor chimerism on all measurements up to and including Day +56. Secondary graft failure is defined by initial neutrophil engraftment followed by sustained subsequent decline in ANC to < 0.5 x 10^9/L for three consecutive measurements on different days or initial whole blood or marrow donor chimerism more than 5%, but then declining to < 5% on subsequent measurements.
5. Incidences of graft-vs-host-disease (GVHD) [ Time Frame: 1 year ]
   Acute and chronic GVHD are graded according to the BMT CTN Manual of Procedures (MOP).
6. Immune Reconstitution [ Time Frame: Days 91, 180, and 365 ]
   Quantitative assessments of peripheral blood CD4, CD19, and CD56 positive lymphocytes will be done through flow cytometric analysis.
7. Incidences of Infection [ Time Frame: 1 year ]
   Number of participants that experienced at least one infection.
8. Health Related Quality of Life (HR-QoL) [ Time Frame: 1 year ]
   HR-QoL will be measured using patient reported surveys.

Eligibility Criteria

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Ages Eligible for Study:	up to 75 Years (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Patient is < 75 years of age at time of enrollment.

2. Confirmed diagnosis of SAA, either from initial diagnosis or follow-up assessments, defined as:

   1. Bone marrow cellularity < 25% or marrow cellularity < 50% but with < 30% residual hematopoietic cells.
   2. Two out of three of the following (in peripheral blood): Neutrophils < 0.5 x10^9/L, Platelets < 20 x10^9/L, or Reticulocyte count < 20 x10^9/L
3. No suitable fully matched related (6/6 match for human leukocyte antigen (HLA)-A and B at intermediate or high resolution and DRB1 at high resolution using DNA-based typing) or unrelated donor (8/8 match for HLA-A, B, C, and DRB1 at high resolution using DNA-based typing) available. Search for an unrelated donor and enrollment on this protocol may be abandoned if the clinical situation dictates an urgent transplant in the best medical judgment of the treating provider. The definition of clinical urgency may include a low likelihood of identifying a suitable matched unrelated donor within 6-8 weeks from referral and the medical need to choose a donor without further delay beyond that time.
4. Failed at least one trial of immunosuppressive therapy (IST) by being refractory or having relapsed. IST could have included ATG based regimens, calcineurin inhibitors and/or other higher dose therapy directed at the treatment of primary SAA.

5. Available alternative donor:

   1. Cord blood unit(s) must be matched at a minimum of 4/6 to the recipient at HLA-A and B at low resolution using DNA-based typing and HLA-DRB1 at high resolution using DNA-based typing. Based on a published report from Eurocord, for single unit transplantation, the single unit pre-cryopreserved total nucleated cell (TNC) dose must be a minimum of 4.0 x10^7/kg recipient weight. For double cord transplants, each unit must have a minimum of 1.5 x10^7/kg pre-cryopreserved TNC and a minimum total of 4.0 x10^7/kg (sum of unit 1 and unit 2). For non-red blood cell depleted units, the minimum pre-cryopreserved TNC dose is 2.0 x10^7/kg recipient weight.

      or

   2. HLA haplo first degree relatives of the patient including biological parents, siblings or half siblings, or children with 2, 3, or 4 mismatches using DNA-based typing. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be identical at a minimum of one allele (at high resolution DNA-based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1.
6. Patient and/or legal guardian must sign informed consent for HSCT.
7. In the haplo cohort, the donor and/or legal guardian must be able to sign informed consent documents.
8. In the haplo cohort, the potential donor must be willing to donate bone marrow.
9. In the haplo cohort, the weight of the haplo donor must be ≥ 20 kg.

10. Adequate organ function defined as:

    1. Cardiac: Left ventricular ejection fraction (LVEF) at rest ≥ 40%. For patients aged < 13 years, shortening fraction (SF) ≥ 26% by echocardiogram or Multi Gated Acquisition Scan (MUGA) may be substituted for LVEF.
    2. Hepatic: Total bilirubin < 3.0 x the upper limit of normal (ULN) for age (patients who have been diagnosed with Gilbert's Disease are allowed to exceed this limit) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5.0 x ULN for age.
    3. Renal: For patients > 13.0 years of age at the time of enrollment: estimated creatinine clearance > 50 mL/minute (using the Cockcroft-Gault formula and actual body weight). For patients < 13.0 years of age at enrollment: Glomerular Filtration Rate (GFR) estimated by the updated Schwartz formula ≥ 90 mL/min/1.73 m2. If the estimated GFR is < 90 mL/min/1.73 m^2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be > 50 mL/min/1.73 m^2.
    4. Pulmonary: For patients > 13.0 years of age: Diffusing capacity of the lung for carbon monoxide (DLCO) (corrected/adjusted for hemoglobin) > 40% and forced expiratory volume in one second (FEV1) > 50% predicted (without administration of bronchodilator) and forced vital capacity (FVC) > 50% predicted. For patients < 13.0 years of age unable to perform pulmonary function tests (PFT) due to age or developmental ability: (1) no evidence of dyspnea at rest and (2) no need for supplemental oxygen and (3) O2 saturation > 92% on room air at sea level (with lower levels allowed at higher elevations per established center standard of care (e.g., Utah, 4,200 feet above sea level, does not give supplemental oxygen unless below 90%)).
11. Karnofsky or Lansky performance status ≥ 60%.
12. Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time or agree to abstinence.

Exclusion Criteria:

1. Inherited bone marrow failure syndromes. At minimum, the diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow.
2. Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination (e.g. Monosomy 7).
3. Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as a positive cross-match test of any titer by complement-dependent cytotoxicity or flow cytometric testing or the presence of anti-donor HLA antibody to the high expression loci HLA-A, B, C, DRB1, or DPB1 with mean fluorescence intensity (MFI) > 1000 by solid phase immunoassay).
4. Prior allogeneic stem cell transplant.
5. Prior solid organ transplant.
6. Known life-threatening reaction (i.e., anaphylaxis) to Thymoglobulin® that would prohibit use for the patient as this study requires use of the Thymoglobulin® preparation of ATG.
7. Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment.
8. Seropositive for the human immunodeficiency virus (HIV).
9. Active Hepatitis B or C determined by a detectable viral load of HBV or HCV.
10. Female patients who are pregnant (per institutional practice) or breast-feeding.
11. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent > 5 years previously will be allowed. Cancer treated with curative intent ≤ 5 years previously will not be allowed unless approved by the Protocol Chairs and/or Protocol Officer.
12. Alemtuzumab or ATG within 2 weeks of enrollment.

Contacts and Locations

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Contacts

Contact: Alyssa Ramirez	301-251-1161	aramirez@emmes.com
Contact: Adam Mendizabal, PhD		amendizabal@emmes.com

  Show 28 Study Locations

Sponsors and Collaborators

Medical College of Wisconsin

National Heart, Lung, and Blood Institute (NHLBI)

National Cancer Institute (NCI)

Blood and Marrow Transplant Clinical Trials Network

National Marrow Donor Program

Investigators

Study Director:	Mary Horowitz, MD, MS	Center for International Blood and Marrow Transplant Research

More Information

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Additional Information:

Blood and Marrow Transplant Clinical Trials Network Website 

National Marrow Donor Program 

Responsible Party:	Medical College of Wisconsin
ClinicalTrials.gov Identifier:	NCT02918292 History of Changes
Other Study ID Numbers:	BMTCTN1502; 2U10HL069294-11 ( U.S. NIH Grant/Contract ); 5U24CA076518 ( U.S. NIH Grant/Contract )
First Posted:	September 28, 2016
Last Update Posted:	August 30, 2017
Last Verified:	August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
Supporting Materials:	Study Protocol; Informed Consent Form (ICF)
Time Frame:	Within 6 months of official study closure at participating sites.
Access Criteria:	Available to the public
URL:	https://biolincc.nhlbi.nih.gov/home/

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

Keywords provided by Medical College of Wisconsin:

Unrelated Cord Blood (UCB); Haploidentical Bone Marrow; Hematopoietic Stem Cell Transplant (HSCT); Severe Aplastic Anemia (SAA); Antithymocyte Globulin (ATG)

Additional relevant MeSH terms:

Anemia; Anemia, Aplastic; Hematologic Diseases; Bone Marrow Diseases; Cyclophosphamide; Tacrolimus; Fludarabine phosphate; Thymoglobulin; Antilymphocyte Serum; Fludarabine; Mycophenolic Acid; Vidarabine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs	Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Calcineurin Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antibiotics, Antitubercular; Antitubercular Agents