Clinical trial NCT02181478: Intra-Osseous Co-Transplant of UCB and hMSC
Official title: Intra-osseous Co-transplant of Cord Blood and Mesenchymal Stromal Cells: A Feasibility Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Acute Lymphoblastic Leukemia
Acute Myelogenous Leukemia
Myelodysplastic Syndromes
Myelofibrosis
Relapsed Non-Hodgkin Lymphoma
Refractory Non-Hodgkin Lymphoma
Hodgkin Lymphoma
Refractory Hodgkin Lymphoma
Relapsed Chronic Lymphocytic Leukemia
Refractory Chronic Lymphocytic Leukemia
Lymphoid Malignancies
Chronic Myelogenous Leukemia
Keywords: Total Body Irradiation
Human Mesenchymal Stromal Cells
hMSC
Cyclophosphamide
Fludarabine
Dimethyl Sulfoxide
DMSO
Cyclosporine
Mycophenolate Mofetil
MMF
Granulocyte- Colony Stimulating Factor
G-CSF
GVHD
Cancer
feasibility
Lead sponsor: Case Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2014-07-04
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This clinical trial studies intra-osseous donor umbilical cord blood and mesenchymal stromal cell co-transplant in treating patients with hematologic malignancies. Giving low doses of chemotherapy and total-body irradiation before a co-transplant of donor umbilical cord blood and mesenchymal stromal cells into the bone (intra-osseous) helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil at the time of transplant may stop this from happening.

Detailed description: PRIMARY OBJECTIVES:

I. To estimate the feasibility of combining intra-osseous umbilical cord blood (UCB) hematopoietic stem cells and human mesenchymal stromal cells (hMSC) following reduced intensity conditioning (RIC).

SECONDARY OBJECTIVES:

I. To estimate the time to engraftment of intra-osseous (IO) UCB transplant combined with hMSC following RIC.

II. To estimate the safety profile of IO UBC transplant combined with hMSC.

OUTLINE:

REDUCED INTENSITY CONDITIONING: Patients receive cyclophosphamide intravenously (IV) over 2 hours on day -6 and fludarabine phosphate IV on days -6 to -2 and undergo total body irradiation (TBI) on day -1.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive cyclosporine orally (PO) or IV over 2 hours every 12 hours on beginning on days -5 to 100 with taper beginning on day 100 and mycophenolate mofetil IV or PO twice daily (BID) on days -5 to 100.

TRANSPLANT: Patients undergo intra-osseous UCB and hMSC co-transplant on day 0.

After completion of study treatment, patients are followed up at days 28 and 100, and then at 6, 9, and 12 months.

Eligibility criteria: Inclusion Criteria:

* Patients must have one of the following malignancies:

  * Acute myelogenous leukemia (AML): high-risk AML including:

    * Antecedent hematological disease (e.g., myelodysplasia \[MDS\])
    * Treatment-related leukemia
    * Complete remission (first complete remission \[CR1\]) with poor-risk cytogenetics or molecular markers (e.g. fms-related tyrosine kinase 3 \[Flt 3\] mutation, 11q23, del 5, del 7, complex cytogenetics)
    * Second complete remission (CR2) or third complete remission (CR3)
    * Induction failure or first relapse with either

      * ≤ 10% blasts in the marrow and/or
      * ≤ 5% blasts in the peripheral blood
  * Acute lymphoblastic leukemia (ALL)

    * High-risk CR1 including:
    * Poor-risk cytogenetics (e.g., Philadelphia chromosome t(9;22)or 11q23 rearrangements)
    * Presence of minimal disease by flow cytometry after 2 or more cycles of chemotherapy
    * No complete remission (CR) within 4 weeks of initial treatment
    * Induction failure
    * CR2 or CR3 with either:

      * ≤ 10% blasts in the marrow and/or
      * ≤ 5% blasts in the peripheral blood
  * Myelodysplastic syndromes (MDS), Intermediate-1 (INT-1), intermediate-2 (INT-2) or high Revised International Prognostic Scoring System (IPSS-R) score that has failed at least 1 first line therapy
  * Myelofibrosis (MF):

    * Intermediate-2 or high risk by Dynamic International Prognostic Scoring System (DIPSS)-plus
    * Monosomal karyotype
    * Presence of inv(3)/i(17q) abnormalities
    * Other unfavorable karyotype OR leukocytes ≥40 X 10\^9/L AND
    * Circulating blasts ≤ 9%
  * Relapsed or refractory lymphoid malignancies (including non-Hodgkin lymphoma, Hodgkin lymphoma and chronic lymphocytic leukemia) meeting the following criteria:

    * Disease status: stable disease, partial remission or 2nd and 3rd complete remission
  * Chronic myelogenous leukemia (CML) in second chronic phase after accelerated or blast crisis; blast crisis defined as:

    * Blast count ≥ 20% in the peripheral blood or bone marrow
    * Large foci of blasts on bone marrow
    * Presence of extra-medullary blastic infiltrate (myeloid sarcoma or chloroma)
  * Recipients of prior autologous or allogeneic transplant are eligible, as long as at least 3 months have passed since the transplant, and the patient fulfills other eligibility criteria
  * Eastern Cooperative Oncology Group (ECOG) performance status ≤2
  * Candidates for reduced intensity conditioning regimens
  * Patients who do not have HLA-matched (defined as matched in HLA A, B, C, and DRB1) related or unrelated donors, those who elect to undergo UCB even if they have a MRD or MUD, or patients who require a UCB either for emergency indications such as primary graft failure.
  * Cord Blood Units available through NMDP with the following minimal criteria:

    * HLA Match: 4/6 or better match (HLA A, B, DRB1)
    * Cell dose: Minimum of 2.0x107TNC/kg pre thaw
  * Concurrent therapy for extramedullary leukemia or central nervous system (CNS) lymphoma: concurrent therapy or prophylaxis for testicular leukemia, CNS leukemia, and CNS lymphoma including standard intrathecal chemotherapy and/or radiation therapy will be allowed as clinically indicated; such treatment may continue until the planned course is completed; subjects must be in CNS remission at the time of protocol enrollment if there is a history of CNS involvement
  * Subjects must have a back-up umbilical cord on the registry in addition to the umbilical cord being used in this study
  * Subjects must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Patients with inadequate Organ Function as defined by:

  * Creatinine clearance \< 30 ml/min
  * Bilirubin ≥ 2 x institutional upper limit of normal
  * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) ≥ 2 x institutional upper limit of normal
  * Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≥ 2 x institutional upper limit of normal
  * Corrected diffusing capacity of the lung for carbon monoxide (DLCOcorr) \< 40% normal
* Left ventricular ejection fraction \< 35%
* Patients with uncontrolled inter-current illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Pregnant or breastfeeding women are excluded from this study

Primary outcomes:
measure: Number of patients with BM cellularity failure: Measure of feasibility
timeFrame: 42 days after transplant
measure: Number of patients with ANC failure without evidence of disease: Measure of feasibility
timeFrame: 42 days after transplant
measure: Number of patients with hematopoietic recovery without evidence of donor umbilical cord blood engraftment: Measure of feasibility
timeFrame: 42 days after transplant
measure: Number of patients with hematopoietic recovery without evidence of donor umbilical cord blood engraftment: Measure of feasibility
timeFrame: 100 days after transplant
Secondary outcomes:
measure: Incidence of toxicities assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
timeFrame: Up to 12 months
measure: Rate of neutrophil recovery
timeFrame: Up to 12 months
measure: Rate of platelet recovery
timeFrame: Up to 12 months
measure: Median time of neutrophil recovery
timeFrame: Up to 12 months
measure: Median time of platelet recovery
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Case Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Case Comprehensive Cancer Center
name: Leland Metheny, MD
role: PRINCIPAL_INVESTIGATOR
References: