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A Multi-Center, Phase III, Randomized Trial of Reduced Intensity (RIC) Conditioning and Transplantation of Double Unrelated Umbilical Cord Blood (dUCB) Versus HLA-Haploidentical Related Bone Marrow (Haplo-BM) for Patients With Hematologic Malignancies (BMT CTN #1101)


Phase 3
18 Years
70 Years
Open (Enrolling)
Both
Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Burkitt's Lymphoma, Follicular Lymphoma, Hodgkin Lymphoma, Mantle Cell Lymphoma

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Trial Information

A Multi-Center, Phase III, Randomized Trial of Reduced Intensity (RIC) Conditioning and Transplantation of Double Unrelated Umbilical Cord Blood (dUCB) Versus HLA-Haploidentical Related Bone Marrow (Haplo-BM) for Patients With Hematologic Malignancies (BMT CTN #1101)


Reduced intensity conditioning (RIC) blood or marrow transplantation (BMT) has allowed older
and less clinically fit patients to receive potentially curative treatment with allogeneic
HCT for high risk or advanced hematological malignancies. Patients lacking an HLA-matched
sibling may receive a graft from a suitably HLA-matched unrelated donor. However, up to a
third of patients will not have an HLA-matched sibling or a suitably matched adult unrelated
donor (i.e., no more than a mismatch at a single locus). Even when a suitably matched
unrelated donor is identified, data from the National Marrow Donor Program (NMDP) indicate
that a median of four months is required to complete searches that result in
transplantation; thus, some number of patients succumb to their disease while awaiting
identification and evaluation of a suitably matched adult unrelated donor.

Single or dual center studies have shown that partially HLA-mismatched related bone marrow
(haplo-BM) and unrelated double umbilical cord blood (dUCB) are valuable sources of donor
cells for RIC HCT, thus extending this treatment modality to patients who lack other donors.
In order to study the reproducibility, and thus, the wider applicability of these two
alternative donor strategies, The Blood and Marrow Transplantation Clinical Trials Network
(BMT CTN) conducted two parallel multicenter prospective Phase II clinical trials. These
two studies evaluated the safety and efficacy of related haplo-BM (BMT CTN 0603) and dUCB
(BMT CTN 0604) transplantation after RIC. Both of these alternative donor approaches
produced early results similar to that reported with unrelated donor, and even HLA-matched
sibling, HCT. These data demonstrate not only the efficacy of both of these approaches, but
also that both can be safely exported from the single center setting. Both haplo-BM and
dUCB grafts can be obtained rapidly for greater than 90% of patients lacking an HLA-matched
donor. This study will test the hypothesis that progression free survival at two years
after RIC haplo-BM transplantation is similar to the progression free survival after RIC
dUCB transplantation.


Inclusion Criteria:



- Patients 18 to 70 years old

- Patients must have available both: a)One or more potential related mismatched donors
(biologic parent(s) or siblings (full or half) or children). Low resolution using
DNA based typing at HLA-A, -B, and -DRB1 for potential haploidentical donors is
required. b)At least two potential umbilical cord blood units identified. Each
unit must have a minimum of 1.5 x 10^7/kg pre-cryopreserved total nucleated cell
dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total
nucleated cell dose of each unit must be at least 2.0 x 10^7/kg. Units must be HLA
matched at a minimum of 4/6 to the recipient at HLA-A, HLA-B (at low resolution using
DNA based typing) and HLA-DRB1 (at high resolution using DNA based typing).
Confirmatory typing is not required for randomization.

- Patients must have received either: a)At least one cycle of a the following cytotoxic
chemotherapy regimen (or regimen of similar intensity) within 3 months of enrollment
(measured from the start date of chemotherapy)(1. multiagent chemotherapy, 2.
chemotherapy regimens like those that are given as induction or consolidation of
acute leukemia, 3. single drug alkylator agent. 4. single agent alemtuzumab or
brentuximab vedotin); or, b) Autologous HCT greater than 6 months and less than 2
years prior to enrollment.

- ALL in first complete remission (CR1) that is NOT considered favorable-risk as
defined by the presence of at least one of the following: Adverse cytogenetics such
as t(9;22), t(1;19), t(4;11), other MLL rearrangements; White blood cell counts of
greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL)at diagnosis;
Recipient age older than 30 years at diagnosis; Time to CR greater than 4 weeks

- AML in CR1 that is NOT considered as favorable-risk. Favorable risk is defined as
having one of the following: t(8.21) without CKIT mutation, inv(16) without CKIT
mutation or t(16;16), normal karyotype with mutated NPM1 and not FLT-IND, normal
karyotype with double mutated CEBPA, APL in first molecular remission at end of
consolidation

- Acute Leukemias in 2nd or subsequent CR

- Biphenotypic/Undifferentiated/Prolymphocyctic Leukemias in first or subsequent CR,
adult T-cell leukemia/lymphoma in first or subsequent CR

- Burkitt's lymphoma: second or subsequent CR

- Lymphoma fulfilling the following criteria: a) Chemotherapy-sensitive (complete or
partial response; lymphomas that have failed at least 1 prior regimen of multi-agent
chemotherapy and are INELIGIBLE for an autologous transplant; b) Marginal zone B-cell
lymphoma or follicular lymphoma that has progressed after at least at least two prior
therapies (excluding single agent Rituxan).

Additional Patient Inclusion Criteria for Conditioning:

- Patients with Adequate Physical Function as Measured by: a. Cardiac: Left ventricular
ejection fraction at rest must be greater than or equal to 40%, or shortening
fraction less than 25%; b. Hepatic: Bilirubin less than or equal to 2.5 mg/dL,
except for patients with Gilbert's syndrome or hemolysis. ALT, AST, and Alkaline
Phosphatase less than 5 x ULN; c. Renal: Serum creatinine within normal range, or if
serum creatinine outside normal range, then renal function (measured or estimated
creatinine clearance or GFR)greater than 40 mL/min/1.73m^; d. Pulmonary: DLCO
(corrected for hemoglobin), FEV1, and FVC greater than 50% predicted; e. Performance
status: Karnofsky score greater than or equal to 70%.

- Additional Patient Inclusion Criteria for Patients Assigned to Haploidentical BM Arm:
Patients must be HLA typed at high resolution using DNA based typing at the following
HLA-loci: HLA-A, -B, -C and DRB1 and have available a related haploidentical BM donor
with 2, 3, or 4 HLA-mismatches. A unidirectional mismatch in either the graft versus
host or host versus graft direction is considered a mismatch. The donor and
recipient must be HLA identical for at least one antigen (using high resolution DNA
based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1.
Fulfillment of this criterion shall be considered sufficient evidence that the donor
and recipient share one HLA haplotype, and typing of additional family members is not
required.

- Additional Patient Inclusion Criteria for Patients Assigned to Double Umbilical Cord
Blood Arm: Patients must have available two UCB units fulfilling the following
criteria: a. Each unit must have a minimum of 1.5 x 10^7/kg pre-cryopreserved total
nucleated cell dose. For non-red blood cell depleted units, the minimum
pre-cryopreserved total nucleated cell dose of each unit must be at least 2.0 x
10^7/kg; and, b. Units must be HLA matched at a minimum of 4/6 to the recipient at
HLA-A, HLA-B (at low resolution using DNA based typing) and HLA-DRB1 (at high
resolution using DNA based typing.

Exclusion Criteria:

- Patients with suitably matched related or unrelated donor.

- Autologous hematopoietic stem cell transplant less than 6 months prior to enrollment.

- Pregnancy or breast-feeding.

- Evidence of HIV infection or known HIV positive serology.

- Current uncontrolled bacterial, viral or fungal infection (currently taking
medication with evidence of progression of clinical symptoms or radiologic findings).

- Prior allogeneic HCT.

- Patients with history of primary idiopathic myelofibrosis or any severe marrow
fibrosis.

- Planned use of prophylactic donor lymphocyte infusion (DLI) therapy.

- Anti-donor HLA antibodies.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression free survival

Outcome Description:

The primary endpoint is PFS at 2-years from the date of randomization. PFS is defined as the time interval from date of randomization and time to relapse/progression, to death or to last follow-up.

Outcome Time Frame:

two years from the date of randomization

Safety Issue:

No

Principal Investigator

Mary Horowitz, MD, MS

Investigator Role:

Study Director

Investigator Affiliation:

Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin

Authority:

United States: Federal Government

Study ID:

715

NCT ID:

NCT01597778

Start Date:

June 2012

Completion Date:

June 2019

Related Keywords:

  • Acute Lymphocytic Leukemia
  • Acute Myelogenous Leukemia
  • Burkitt's Lymphoma
  • Follicular Lymphoma
  • Hodgkin Lymphoma
  • Mantle Cell Lymphoma
  • Haplo identical transplant
  • Cord blood transplant
  • Reduced intensity conditioning regimen
  • Lymphoma
  • Leukemia
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Mantle-Cell

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205
Cleveland Clinic FoundationCleveland, Ohio  44195
Fred Hutchinson Cancer Research CenterSeattle, Washington  98109
University of Pennsylvania Cancer CenterPhiladelphia, Pennsylvania  19104
Medical University of South CarolinaCharleston, South Carolina  29425-0721
University Hospitals of ClevelandCleveland, Ohio  44106
University of Rochester Medical CenterRochester, New York  14642
City of Hope National Medical CenterLos Angeles, California  91010
Duke University Medical CenterDurham, North Carolina  27710
Emory UniversityAtlanta, Georgia  30322
Virginia Commonwealth UniversityRichmond, Virginia  
Stanford Hospital and ClinicsStanford, California  94305
University of Kansas HospitalKansas City, Kansas  66160
West Virginia UniversityMorgantown, West Virginia  26506
Stony Brook University Medical CenterStony Brook, New York  11794
BMT Program at Northside HospitalAtlanta, Georgia  30342
University of North Carolina Hospital at Chapel HillChapel Hill, North Carolina  27599
Dana Farber Cancer Institute, Brigham & Women's HospitalBoston, Massachusetts  02115
Univeristy of MinnesotaMinneapolis, Minnesota  55455
University of Florida College of Medicine/ShandsGainesville, Florida  32610-0277
Univesity of Texas, MD Anderson CRCHouston, Texas  77030