Infusion of Off-the-Shelf Expanded Cord Blood Cells to Augment Cord Blood Transplant in Patients With Hematologic Malignancies

Nohla Therapeutics

Status and phase

Completed

Phase 2

Conditions

Childhood Chronic Myelogenous Leukemia

Refractory Anemia With Excess Blasts in Transformation

Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

de Novo Myelodysplastic Syndromes

Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)

Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)

Childhood Acute Myeloid Leukemia in Remission

Adult Acute Myeloid Leukemia in Remission

Previously Treated Myelodysplastic Syndromes

Relapsing Chronic Myelogenous Leukemia

Childhood Myelodysplastic Syndromes

Secondary Myelodysplastic Syndromes

Childhood Acute Lymphoblastic Leukemia in Remission

Accelerated Phase Chronic Myelogenous Leukemia

Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)

Refractory Anemia With Excess Blasts

Chronic Phase Chronic Myelogenous Leukemia

Refractory Anemia

Adult Acute Myeloid Leukemia With Del(5q)

Treatments

Drug: cyclosporine

Drug: fludarabine phosphate

Procedure: umbilical cord blood transplantation

Drug: mycophenolate mofetil

Drug: cyclophosphamide

Other: laboratory biomarker analysis

Radiation: total-body irradiation

Biological: ex vivo-expanded cord blood progenitor cell infusion

Study type

Interventional

Funder types

Other

Industry

NIH

Identifiers

NCT01175785

2378

RC2HL101844 (U.S. NIH Grant/Contract)

2378.00 (Other Identifier)

P30CA015704 (U.S. NIH Grant/Contract)

NCI-2010-01426 (Registry Identifier)

Details and patient eligibility

About

This phase II trial is studying the safety and potential efficacy of infusing non-human leukocyte antigen matched ex vivo expanded cord blood progenitors with one or two unmanipulated umbilical cord blood units for transplantation following conditioning with fludarabine phosphate, cyclophosphamide and total body irradiation, and immunosuppression with cyclosporine and mycophenolate mofetil for patients with hematologic malignancies. Chemotherapy, such as fludarabine phosphate and cyclophosphamide, and total-body irradiation given before an umbilical cord blood transplant stops the growth of leukemia cells and works to prevent the patient's immune system from rejecting the donor's stem cells. The healthy stem cells from the donor's umbilical cord blood help the patient's bone marrow make new red blood cells, white blood cells, and platelets. It may take several weeks for these new blood cells to grow. During that period of time, patients are at increased risk for bleeding and infection. Faster recovery of white blood cells may decrease the number and severity of infections. Studies have shown that counts recover more quickly when more cord blood cells are given with the transplant. We have developed a way of growing or "expanding" the number of cord blood cells in the lab so that there are more cells available for transplant. We are doing this study to find out whether or not giving these expanded cells along with one or two unexpanded cord blood units is safe and if use of expanded cells can decrease the time it takes for white blood cells to recover after transplant. We will study the time it takes for blood counts to recover, which of the two or three cord blood units makes up the patient's new blood system, and how quickly immune system cells return.

Full description

PRIMARY OBJECTIVES:

I. Examine the safety and toxicity when ex vivo expanded cord blood cells are infused as an off-the-shelf non-human leukocyte antigen (HLA) matched product with the goal of providing rapid but transient myelopoiesis in the setting of a single or double umbilical cord blood transplant.

II. Examine the in vivo persistence of the ex vivo expanded cord blood product. The kinetics and durability of hematopoietic reconstitution will be determined and the relative contribution to engraftment of the expanded cord blood product and the unmanipulated cord blood unit(s) in early and long-term engraftment will be determined by frequent determination of donor chimerisms in the peripheral blood.

SECONDARY OBJECTIVES

I. Estimate the incidence and severity of acute and chronic graft-versus-host-disease (GVHD) in patients receiving off-the-shelf ex vivo expanded and cryopreserved cord blood cells.

II. Estimate the incidence of transplant related mortality at day 100.

III. Estimate the incidence of malignant relapse and probabilities of overall and event-free survival at 1 and 2 years post transplant.

IV. Obtain preliminary data on the incidence of infections/viral reactivation from the start of conditioning to 100 days post transplant and then at 6 months, 1 year and 2 years post transplant as possible.

V. Obtain preliminary data on the phenotype and function of immune cells recovering in patients receiving expanded and unmanipulated cord blood grafts.

VI. Examination of possible immunologic factors leading to emergence of a dominant unit.

OUTLINE:

MYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients undergo total-body irradiation (TBI) twice daily on days -4 to -1.

TRANSPLANTATION: Patients undergo unmanipulated single- or double-unit umbilical cord blood transplantation on day 0 and receive ex vivo-expanded cord blood progenitor cells IV over 4 hours following the last unmanipulated cord blood infusion.

GVHD PROPHYLAXIS: Patients initially receive cyclosporine (CSP) IV over 1 hour beginning on day -3. CSP may be given orally (PO) when the patient can tolerate oral medications and has a normal gastrointestinal transit time. CSP is given until day 100, and may taper on day 101 if there is no graft versus host disease. Patients also receive mycophenolate mofetil (MMF) IV every 8 hours on days 0 to 7 and then may receive MMF PO beginning day 8 to 30. MMF is continued for a minimum of 30 days or until 7 days after blood counts recover whichever is later. If there is no evidence of acute GVHD and donor cluster of differentiation (CD)3 engraftment is at least 50% from one donor MMF may be tapered.

Enrollment

15 patients

Sex

All

Ages

6 months to 45 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Acute myeloid leukemia:
- High risk complete response (CR)1 as evidenced by preceding myelodysplastic syndromes (MDS), high risk cytogenetics (for example, monosomy 5 or 7, or as defined by referring institution treatment protocol), >= 2 cycles to obtain CR, erythroblastic or megakaryocytic leukemia; >= CR2
- All patients must be in CR as defined by hematologic recovery and < 5% blasts by morphology within the bone marrow and a cellularity of >= 15%
- Patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the Principal Investigator, Colleen Delaney prior to enrollment
Acute lymphoblastic leukemia:
- High risk CR1 [for example, but not limited to: t(9;22), t(1;19), t(4;11) or other mixed lineage leukemia (MLL) rearrangements, hypodiploid]
- Greater than 1 cycle to obtain CR
- >= CR2
- All patients must be in CR as defined by hematologic recovery and < 5% blasts by morphology within the bone marrow and a cellularity of >= 15%
- Patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the Principal Investigator, Colleen Delaney prior to enrollment
Chronic myelogenous leukemia excluding refractory blast crisis; to be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate
Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate 2 (Int-2) or high risk (i.e., refractory anemia with excess myeloblasts [RAEB], refractory anemia with excess blasts in transformation [RAEB-T]) or refractory anemia with severe pancytopenia or high risk cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology
Karnofsky (>= 16 years old) >= 70%
Lansky (< 16 years old) >= 50%
Calculated creatinine clearance must be > 60 mL and serum creatinine =< 2 mg/dL (adults)
Calculated creatinine clearance must be > 60 mL/min (children < 18 years old)
Total serum bilirubin must be < 3 mg/dl
Transaminases must be < 3 x the upper limit of normal
Diffusion capacity of the lung for carbon monoxide (DLCO) corrected > 50% normal
For pediatric patients unable to perform pulmonary function tests, oxygen (O2) saturation > 92% on room air
Left ventricular ejection fraction > 45% OR shortening fraction > 26%
Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

Uncontrolled viral or bacterial infection at the time of study enrollment
Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval
History of human immunodeficiency virus (HIV) infection
Pregnant or breastfeeding
If =< 18 years old, prior myeloablative transplant within the last 6 months
If > 18 years old prior myeloablative allotransplant or autologous transplant
Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

15 participants in 1 patient group

Treatment (chemo, radiation, transplant, GVHD prophylaxis)

Experimental group

Description:

Patients receive fludarabine phosphate IV over 1 hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients undergo TBI twice daily on days -4 to -1. Patients undergo unmanipulated single- or double-unit umbilical cord blood transplantation on day 0 and receive ex vivo-expanded cord blood progenitor cells IV over 4 hours following the last unmanipulated cord blood infusion. Patients initially receive CSP IV over 1 hour beginning on day -3. CSP may be given PO when the patient can tolerate oral medications and has a normal gastrointestinal transit time. CSP is given until day 100, and may taper on day 101 if there is no graft versus host disease. Patients also receive MMF IV every 8 hours on days 0 to 7 and then may receive MMF PO beginning day 8 to 30. MMF is continued for a minimum of 30 days or until 7 days after blood counts recover whichever is later. If there is no evidence of acute GVHD and donor CD3 engraftment is at least 50% from one donor MMF may be tapered.

Treatment: