Reduced Intensity, Sequential Double Umbilical Cord Blood Transplantation Using Prostaglandin E2 (PGE2)

Condition(s) targeted: Hematologic Malignancies; Allogeneic Stem Cell Transplantation

Intervention: Fludarabine (Drug); Melphalan (Drug); Antithymocyte Globulin (Drug); Sirolimus (Drug); Tacrolimus (Drug); Ex-vivo 16, 16 dimethyl-prostaglandin E2 expansion (Other)

Phase: Phase 1

Status: Recruiting

Sponsored by: Fate Therapeutics

Official(s) and/or principal investigator(s):
Corey Cutler, MD, MPH, FRCP(C), Principal Investigator, Affiliation: Dana-Farber Cancer Institute

Overall contact:
Corey Cutler, MD, MPH, FRCP(C), Phone: 617-632-5946

The purpose of this research study is to determine the effects of 16, 16 Dimethyl-Prostaglandin E2 (dmPGE2) treatment on umbilical cord blood units to be used in transplantation. dmPGE2 treatment is being tested to see if it can improve the ability of umbilical cord blood stem cells to grow after transplantation. The growth of stem cells after transplantation is sometimes referred to as "engraftment". One of the major problems after umbilical cord transplantation is the time required for engraftment. After transplantation of two umbilical cord blood units, the average time to achieve engraftment is 21 days. In addition, up to 10% of patients who undergo umbilical cord blood transplantation never engraft, a potentially life-threatening condition. In laboratory studies, treatment of umbilical cord blood stem cells with dmPGE2 was shown to enhance engraftment.

Official title: A Phase I Study of Reduced Intensity, Sequential Double Umbilical Cord Blood Transplantation Using Ex-Vivo 16, 16 Dimethyl-Prostaglandin E2 Expanded Umbilical Cord Blood Units

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Determine the safety of ex-vivo 16, 16 dimethyl-prostaglandin E2-expanded umbilical cord blood units when used for transplantation in a reduced intensity, sequential umbilical cord blood transplantation model.

Secondary outcome:

Time to engraftment of umbilical cord blood units

Fractional chimerism of transplanted cord blood units

Rates of acute and chronic GVHD

30- and 100-day treatment related mortality

Measures of immune reconstitution and relapse-free and overall survival at 1 and 2 years after transplantation

Detailed description:

- On the day of admission to the hospital, two intravenous catheters will be placed in

the large veins in the participant's upper chest underneath the collarbone. The catheters will remain in place throughout the transplant.

- The chemotherapy portion of the treatment is called "Conditioning Therapy". The

chemotherapy is used to prepare the bone marrow space to receive the transplanted umbilical cord blood units. It consists of three intravenous medications; fludarabine, melphalan and antithymocyte globulin or thymoglobulin.

- Starting three days before transplant and every day for 6-9 months after the

transplant, participants will receive the immune suppressive drugs tacrolimus and sirolimus. These drugs are used to prevent Graft-Vs.-Host-Disease (GVHD), which might develop as the transplant engrafts.

- After the participant completes the "Conditioning Therapy", they will have their

transplant. The day of the transplant is referred to as Day 0. On the day of the transplant, each cord blood unit will be thawed and washed in the laboratory and be given through the central venous catheter. All participants receive 2 cord blood units 2-5 hours apart.

- As part of this research study some cord units will be treated in the laboratory with

dmPGE2 before it is given to the participant. 4 different dmPGE2 treatment groups will be tested. Group 1: will have the second cord blood unit treated; Group 2: will have their first cord blood unit treated and; Groups 3 and 4 will have both cord blood units treated. The four groups will be treated sequentially. If the treatment strategy in Group 1 is deemed to be safe, Group 2 will be treated. If there is evidence that the treated umbilical cord blood units from Groups 1 and 2 are engrafting, and that the treatment is safe, Group 3 will be tested. Group 4 will be treated if Group 3 is safe.

- Participants will also be treated with antibiotics to prevent and treat infection.

They may also receive transfusions of red blood cells and platelets. To help with engraftment, they will be given the drug G-CSF (Neupogen) starting five days after the transplant and until their white blood cells recover.

- After participants leave the hospital, they will be required to come back for

monitoring and routine care very frequently. This is standard after umbilical cord blood transplantation.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients with hematologic malignancies for whom allogeneic stem cell transplantation

is deemed clinically appropriate

- Patient must be ineligible for traditional myeloablative transplantation according to

treating physician

- Lack of 6/6 or 5/6 HLA-matched related, 8/8 HLA-matched unrelated donor, or unrelated

donor not available within a time frame necessary to perform a potentially curative stem cell transplant

- 18-65 years of age

- ECOG Performance Status 0-2

Exclusion Criteria:

- The following hematologic malignancies are excluded:

- Myelofibrosis unless there has been exposure to cytotoxic chemotherapy for the

treatment of progression to acute myeloid leukemia

- Chronic Myelogenous Leukemia, unless there has been exposure to cytotoxic

chemotherapy for the treatment of blast phase, 3) Aplastic anemia, in the absence of transformation to Myelodysplastic disorder

- Cardiac disease: symptomatic congestive heart failure or evidence of left ventricular

dysfunction as measured by gated radionucleotide ventriculogram or echocardiogram; active angina pectoris, or uncontrolled hypertension

- Pulmonary disease: symptomatic chronic obstructive lung disease, symptomatic

restrictive lung disease, or corrected DLCO of < 50% of predicted, corrected hemoglobin

- Renal disease: serum creatinine > 2. 0mg/dl

- Hepatic disease: serum bilirubin > 2. 0mg/dl (expect in the case of Gilbert's syndrome

or ongoing hemolytic anemia), SGOT or SGPT > 3 x upper limit of normal

- Neurologic disease: symptomatic leukoencephalopathy, active CNS malignancy or other

neuropsychiatric abnormalities believed to preclude transplantation

- HIV antibody

- Uncontrolled infection

- Pregnancy or breast feeding mother

- Inability to comply with the requirements for care after allogeneic stem cell

transplantation

Corey Cutler, MD, MPH, FRCP(C), Phone: 617-632-5946

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States; Recruiting
Corey Cutler, MD, MPH, FRCP(C), Principal Investigator

Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Not yet recruiting
Karen Ballen, MD, Principal Investigator

Starting date: April 2009
Last updated: February 2, 2010