Expanded Cord Blood in Patients in Need of an Allogeneic Stem Cell Transplant

A Phase I-II Open-label Study of UM171 Expanded Cord Blood in a Fed-batch Culture System (UFCB-001) in Patients Who Need an Allogeneic Hematopoietic Stem Cell Transplant But Lack a Suitable Donor

Allogeneic hematopoietic stem cell transplantation is a life-saving procedure in patients with blood cancers, but only 25% of transplant candidates have a sibling donor. A matched unrelated donor can be found for 60% of patients but this number is lower for non-Caucasians. Cord blood (CB), another source of stem cells, has major advantages over unrelated donors including immediate availability, better permissiveness in immune mismatches between donor and transplant recipient, better availability for non-Caucasians, and less graft versus host disease, a complication frequently seen after transplant which negatively affects quality of life. Unfortunately, the use of CB is still limited in adults because of the small number of stem cells. UM171, a molecule with hematopoietic stem cell expansion properties, has been shown to increase cord blood stem cells 13 fold. In this trial, Investigators will use UM171 treated CB in patients who need a transplant but lack an acceptable donor.This protocol seeks to test the safety of CB cells expanded with UM171, and to determine the kinetics of engraftment as well as the minimal cord blood unit cell dose that when expanded achieves prompt engraftment.

Investigators are proposing a phase I-II, Canadian multi-center, open-label study of UM171 ex vivo expanded CB transplant in 25 patients who need an allogeneic hematopoietic stem cell transplantation (HSCT) but lack a Human Leucocyte Antigen (HLA) matched donor.

Investigators key primary and secondary objectives include:

1. To establish the feasibility of expanding cord blood units for allogeneic cord blood transplantation.
2. To establish the safety and identify unexpected toxicities associated with the transplantation of cord blood cells expanded with UM171/fed-batch culture system.
3. To measure kinetics of neutrophil and platelet recovery.
4. To determine minimal cord blood unit cell dose (Total Nucleated Cell (TNC)/CD34+ cells) that when expanded achieves prompt engraftment as a single cord transplant.

Methodology:

Patients with a hematologic malignancy and an indication for allogeneic HSCT who lack a matched unrelated donor will receive a myeloablative or submyeloablative conditioning regimen followed by infusion of UM171 expanded CB graft. Accrual is expected to last 18 months and patients will be followed for 3 years.

Expected benefits:

Investigators expect that expansion with UM171/fed-batch will be safe and lead to both rapid and sustained engraftment. This will likely decrease the high early morbidity/mortality of CB HSCT and improve access to transplant, especially ethnic minorities. In addition, if low cell dose is solved, patients will benefit from CB's lower risk of chronic (graft versus host disease) GVHD, a major cause of morbidity.

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Inclusion

1. 3-64 years old (Pediatric patients will become eligible only after 5 adult patients have been enrolled in the study and received the UM171 expanded product).

2. Weight ≥ 12kg

3. Underlying hematologic malignancy excluding primary myelofibrosis requiring an unrelated donor allogeneic HSC transplant (as defined by the transplant center) but patient lacks an 8/8 HLA identical donor or disease requires an urgent transplant and cannot wait the required time to identify an unrelated donor.

4. Availability of at least 3 cord bloods with HLA match ≥ 4/6 and ≥4/8 and meeting the following requirements:

   • CB to be expanded: CD34+ cell count 1.0-4.9 x 10E5/kg for cohort 1, 0.5-4.9 x 10E5/kg for cohort 2, and 0.25-4.9 x 10E5/kg for cohort 3; nucleated cell count ≥ 2.0 x 10E7/kg for cohort 1, ≥ 1.5 x 10E7/kg for cohort 2, and ≥ 1.25 x 10E7/kg for cohort 3.
   • Non expanded cord: TNC count ≥ 2.0 x 10E7/kg with CD34 min of 1 x 10E5/kg or minimum of 1.5 x 10E7 TNC/kg with 1.8 x 10E5 CD34+ cells/kg.
   • Back up cord: TNC count ≥ 1.5 x 10E7/kg with CD34 min of 1 x 10E5/kg

5. Left ventricular ejection fraction > 40%.

6. Karnofsky score ≥ 70%

7. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and diffusing capacity corrected for hemoglobin (DLCOc) ≥ 50% of predicted

8. Bilirubin < 2 x upper limit of normal (ULN) unless felt to be related to Gilbert's disease or hemolysis; AST (aspartate aminotransferase) and ALT (alanine aminotransférase) ≤ 2.5 x ULN; alkaline phosphatase ≤ 5 x ULN.

9. Measured or estimated creatinine clearance ≥ 60 ml/min/1.73m2.

Exclusion

1. Myeloablative transplant within 24 months.
2. Uncontrolled infection.
3. Presence of a malignancy other than the one for which the UCB transplant is being performed and the expected survival related to the malignancy is estimated to be less than 75% at 5 years.
4. HIV positivity.
5. Hepatitis B or C infection with measurable viral load.
6. Liver cirrhosis.
7. Availability of a cord with ≥ 5 x 105/kg CD34+ cells.
8. Pregnancy, breastfeeding or unwillingness to use appropriate contraception.
9. Participation in a trial with an investigational agent within 30 days prior to entry in the study.
10. Patient unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, follow-up, and tests.
11. Any abnormal condition or laboratory result that is considered by the principal investigator capable of altering patient condition or study outcome.