Trial Information

A Pilot Study to Assess the Feasibility of Unrelated Umbilical Cord Blood Transplantation With Coinfusion of Third-party Mesenchymal Stem Cells After Myeloablative or Nonmyeloablative Conditioning in Patients With Hematological Malignancies

PROTOCOL SYNOPSIS

Title of the study A pilot study to assess the feasibility of unrelated umbilical cord blood
transplantation with coinfusion of third-party mesenchymal stem cells after myeloablative or
nonmyeloablative conditioning in patients with hematological malignancies.

Design of the study This is a multicenter single arm, phase I-II pilot study.

Primary objective The primary objective of this study is to determine the feasibility of UCB
HSCT with co-infusion of third party mesenchymal stem cells as assessed by the
treatment-related mortality at d100 after transplant.

Secondary objectives

- Chimerism at multiple time points

- Hematopoietic recovery (neutrophil and platelet engraftment)

- Immune recovery

- Incidence of acute and chronic graft-versus-host disease (GVHD)

- Infectious complications

- Disease free survival

- Relapse incidence

- Overall survival

Graft criteria

- No peripheral blood or marrow donor available at the 9/10 compatibility level using
high resolution typing techniques

- Adequate cord blood transplant available:

a)Single cord blood

- Minimal 4/6 match (DR1-high, A-low, B-low)

- Minimal 2 (6/6), 2.5 (5/6) or 3 (4/6) x 10exp7 nucleated cells per kg in the graft
b)Double cord blood

- At least 4/6 common antigens shared by recipient and the 2 cord blood transplants

- Minimal 3x 10exp7 nucleated cells per kg in the combined graft

Patient inclusion criteria

- Age 15-60 yrs

- Allogeneic stem cell transplantation is the preferred treatment option:

a)High risk acute myeloid leukemia (AML) in first complete remission (CR)

- Preceding myelodysplastic syndrome

- High risk karyotypes (e.g. monosomy 5 or 7, complex)

- FLT3 alteration

- > 2 cycles to obtain CR

- Erythroblastic or megakaryocytic leukemia b)High risk acute lymphoblastic leukemia
(ALL) in first CR

- High risk karyotypes (e.g. t[9;22], t[4;11], t[1;19], complex)

- MLL rearrangements c)Acute leukemia in second or third remission d)High risk
myelodysplastic syndrome: IPSS Intermediate-2 or high risk e)Advanced
lymphoproliferative disorders

- Diffuse large B-cel non-Hodgkin lymphoma (NHL) or mantle cell NHL or B-prolymphocytic
leukemia

- Sensitive relapse after autologous HSCTx

- T-prolymphocytic leukemia

- Chronic lymphocytic leukemia

- Refractory to fludarabine

- Adverse karyotypes (del p17) f)Chronic myeloid leukemia

- Refractory or intolerant to second-line tyrosine kinase inhibitors g)Multiple myeloma

- Advanced disease (selected cases)

- Informed consent given

Patient exclusion criteria

- Previous allogeneic transplant

- Progressive malignant disease

- Significant organ damage as a contraindication to allotransplantation

- Creatinine clearance < 60 ml/min

- AST/ALT > 3x normal value and/or serum bilirubin >3 mg/dL

- Cardiac failure (LVEF < 50%)

- Clinical relevant pulmonary disease: DLCO < 50% normal

- Significant psychiatric or neurological disorder

- Uncontrolled viral, fungal or bacterial infection

- Pregnancy

- HIV positive

Study procedure Patients will receive either myeloablative or reduced intensity
conditioning. One or 2 cord blood transplants will be transplanted, followed by infusion of
a third-party mesenchymal stem cell transplant

Adverse event reporting BHS transplant committee will establish a protocol review committee
which will organize a central monitoring of the study. Within the context of allogeneic
HSCTx many severe events are likely to occur.

Statistics and stopping rules The trial will be stopped at any time that there is reasonable
evidence that the true rate of day +100 nonrelapse mortality exceeds 0.40. It is the
intention to include an initial 20 patients.