Safety Study of Multipotent Progenitor Cells for Immunomodulation Therapy After Liver Transplantation

Phase 1

Terminated

Brief Summary: MultiStem ® is a new biological product, manufactured from human stem cells obtained from adult bone marrow. Factors expressed by MultiStem cells are believed to regulate immune system function and augment tissue repair.

Standard of care pharmacological immunosuppression after liver transplantation can achieve reasonable survival of liver grafts and patients. The side effects of this treatment, however, are clinically significant and diminish the overall success of organ transplantation as a curative therapy. It is therefore the objective of this study to implement cellular immunomodulation therapy with MultiStem as an adjunct to standard pharmacological immunosuppression with the ultimate goal of significantly reducing drug-based immunosuppression.

As this is the first study with MultiStem in this subject population it has been designed as a safety and feasibility trial. However, first evidence of a potential benefit for this patient population will be explored cautiously.

Recruitment & Eligibility

Inclusion Criteria

Patients ≥18 years of age undergoing allogeneic liver transplantation
Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Written informed consent prior to any study procedures

Exclusion Criteria

Known allergies to bovine or porcine products or any other ingredients of the product
Patients older than 65 years of age
Patients listed in a high-urgency status that would not allow proper preparation of the study interventions
Patients receiving a secondary liver graft (Re-Transplantation)
Double organ transplant recipients
Pre-existing renal failure that requires or has required hemodialysis within the last year
Pulmonary function: FEV1, FVC, DLCO ≤50% predicted
Cardiac function: left ventricular ejection fraction ≤50%
HIV seropositive, varicella virus active infection or any other clinically relevant infection
History of any malignancy (including lymphoproliferative disease and hepatocellular carcinoma) except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence
Unstable myocardium (evolving myocardial infarction), cardiogenic shock
Females of childbearing potential (hormonal status and gynecological consultation required)
Patients with portal vein thrombosis
Patients with a history of pulmonary embolism

Arm && Interventions

Group	Intervention	Description
MultiStem	MultiStem	Dose escalation Cohort 1 Drug: MultiStem, Dose 1 of MultiStem; Route and time: Two infusions; First: intra portal at liver transplantation (day 1), second: intra venous (day 3) Cohort 2 Drug: MultiStem, Dose 2 of MultiStem; Route and time: Two infusions; First: intra portal at liver transplantation (day 1), second: intra venous (day 3) Cohort 3 Drug: MultiStem, Dose 3 of MultiStem; Route and time: Two infusions; First: intra portal at liver transplantation (day 1), second: intra venous (day 3) Cohort 4 Drug: MultiStem, Dose 4 of MultiStem; Route and time: Two infusions; First: intra portal at liver transplantation (day 1), second: intra venous (day 3)

Primary Outcome Measures

Name	Time	Method
Infusional and Acute Toxicity, Using Toxicity Scoring Mechanism	up to day 30 (+10)	* For the description of intraportal toxicity a doppler ultrasound examination will be performed to assess various parameters that describe velocity of flow and flow pattern. * For pulmonary toxicity the assessment begins with an arterial blood gas. If this reveals pathological findings, a chest X-ray is required for clinical reasons independent of the study enrolment. In addition, clinical data describing the need for postoperative re-intubation will be recorded and the patient is assessed for the occurrence of a pulmonary embolism according to clinical guidelines. * For systemic toxicity, the occurrence of anaphylactic shock due to standard clinical guidelines is recorded.

Secondary Outcome Measures

Name	Time	Method
Time to First Biopsy-proven Acute Rejection	up to day 90 (+/-30)	Per protocol biopsies will be performed on days 1, 4, 10. Additional biopsies will be taken whenever clinically necessary.
Evidence Confirming That MultiStem Does Not Promote Malignant Transformation or Tumor Growth	up to day 365 (+/-30)	Four additional outpatient visits are planned to further evaluate the study patients (including screening for malignancies).
Evaluation of Data From Routine Examinations Following Last Study Visit for Evidence of Long Term Safety From MultiStem Administration	up to six years	The results of routine examinations, which are necessary for all transplant patients, will be used once a year and analyzed retrospectively.