Efficacy and Safety of Adult Human Mesenchymal Stem Cells to Treat Steroid Refractory Acute Graft Versus Host Disease (GVHD)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and gather additional safety information for Prochymal® in participants who have failed to respond to steroid treatment of Grades B-D acute GVHD.

Detailed Description
-----------------
Approximately 6300 patients receive allogeneic hematopoietic stem cell transplants in the United States each year (International Bone Marrow Transplant Registry [IBMTR], 2003). Nearly 50% (approximately 3,150) of these patients develop acute GVHD (Goker et al). A fraction of these patients (approximately 870) will progress to the severe stages of the disease, Grades III-IV. It is estimated that nearly 82% of those patients with severe acute GVHD will be steroid refractory (Przepiorka et al., 1995) and of these, only 50% of steroid-refractory patients will respond to secondary and tertiary treatments (Greinix et al., 2000). Thus, roughly 350 patients each year face tremendous odds against survival. In addition, most patients who initially responded to secondary and tertiary treatments have a high risk of dying within the first year (Remberger et al., 2001; Anasetti et al., 1994). Development of new therapeutic agents and strategies to rescue patients with steroid refractory, acute GVHD would provide a significant benefit in an area of unmet medical need. Participants will receive standard of care in addition to adult mesenchymal stem cells or placebo.

Official Title
-----------------
A Phase III, Randomized, Double Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Prochymal® (Ex-vivo Cultured Adult Human Mesenchymal Stem Cells) Infusion for the Treatment of Patients Who Have Failed to Respond to Steroid Treatment for Acute GVHD

Conditions
-----------------
Graft Versus Host Disease

Intervention / Treatment
-----------------
* Biological: Prochymal®
* Drug: Placebo
* Drug: Standard of Care for GVHD


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant must be 6 months to 70 years of age, inclusive. Participants who have failed to respond to steroid treatment. Failure to respond to steroid treatment is defined as any grade B-D (IBMTR) grading of acute GVHD that shows: No improvement after 3 days and a duration of no greater than 2 weeks while receiving treatment with methylprednisolone (greater than or equal to 1 mg/kg/day) or equivalent. Participant must be treated within 4 days of randomization. In urgent situations 2nd line therapy may be started 24 hours prior to randomization, and Prochymal® must be initiated within the following 3 days. Participants who have received an increase in their steroid dose treatment prior to randomization will be eligible for enrollment. An increase in steroid dose will not be considered as second line therapy. Participant must have adequate renal function as defined by: Calculated Creatinine Clearance of >30 milliliters per minute (mL/min) using the Cockcroft-Gault equation. For pediatric participants: Schwartz equation: (Participant population: infants over 1 week old through adolescence (<18 years old). Participants who are women of childbearing potential must be non-pregnant, not breast-feeding, and use adequate contraception. Male participants must use adequate contraception. Participant must have a minimum Karnofsky Performance Level of at least 30 at the time of study entry. Participant (or legal representative where appropriate) must be capable of providing written informed consent. Exclusion Criteria: Participant has started treatment with second line therapy >24 hours prior to randomization. Participant has received agents other than steroids for primary treatment of acute GVHD. Participant is participating in the CTN Protocol 0302. Participant has any underlying or current medical or psychiatric condition that, in the opinion of the Investigator, would interfere with the evaluation of the participant including uncontrolled infection, heart failure, pulmonary hypertension, etc. Participant may not receive any other investigational agents (not approved by the FDA) concurrently during study participation or within 30 days of randomization. Participant has a known allergy to bovine or porcine products. Participant has received a transplant for a solid tumor disease.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prochymal®<br>Participants who receive standard of care plus treatment with ex vivo cultured adult human mesenchymal stem cells. | Biological: Prochymal®<br>* 2 infusions of 2 million cells/kg per week for 4 weeks<br>* Other names: Mesenchymal Stem Cells;Drug: Standard of Care for GVHD<br>* Institutionally defined standard of care (e.g., maintenance of steroid treatment and the addition of a second-line therapy)<br>|
| Placebo Comparator: Placebo<br>Participants who receive standard of care and do not receive treatment with ex vivo cultured adult human mesenchymal stem cells. | Drug: Placebo<br>* 2 infusions per week for 4 weeks<br>* Other names: excipients without adult human mesenchymal stem cells;Drug: Standard of Care for GVHD<br>* Institutionally defined standard of care (e.g., maintenance of steroid treatment and the addition of a second-line therapy)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants achieving Complete Response of Greater Than or Equal to 28 Days Duration | A complete response was defined as complete resolution of all clinical signs of Graft versus host disease (GVHD)- that had to be maintained for at least 28 consecutive days (durable complete response [DCR]) within 100 days post first infusion. | up to 100 Days post first infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival at 180 days Post First Infusion | Percentage of participants who survived at 180 days post first infusion. | Day 180 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute GVHD, Steroid refractory GVHD, Severe steroid refractory acute GVHD, Steroid refractory, Steroid Refractory Acute Graft Versus Host Disease