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

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

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.

Study Overview

• Status: Completed
• Conditions: Graft Versus Host Disease
• Intervention / Treatment: Biological: Prochymal®; Drug: Standard of Care for GVHD; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane Hospital
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6100
      • Royal Perth Hospital
• Canada
  • Quebec, Canada, G1J 1Z4
    • Hôpital Enfant-Jésus
  • Quebec, Canada, G1S4L8
    • Hôpital du Saint-Sacrement
  • Alberta
    • Calgary, Alberta, Canada, T1Y6J4
      • Co-Medica Research Network
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H3V4
      • British Columbia's Children's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E0V9
      • Cancer Care Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H2Y9
      • Queen Elizabeth II Health Sciences Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N3Z5
      • Hamilton Health Sciences Centre
    • London, Ontario, Canada, N6A4G5
      • London Health Sciences Centre- Westminster Campus
    • Ottawa, Ontario, Canada, K1H8L6
      • Ottawa Hospital
    • Toronto, Ontario, Canada, M5G 1X8
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M5G1X8
      • Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Maisonneuve-Rosemont Hospital
• Italy
  • Pavia, Italy, 27100
    • IRCCS Policlinico San Matteo
  • PU
    • Pesaro, PU, Italy, 61100
      • Universia degli Studi di Pesaro
• Switzerland
  • Basel, Switzerland, 4031
    • Kantonsspital Basel
• United Kingdom
  • England
    • London, England, United Kingdom, EC1M 6BQ
      • Barts & London School of Medicine
  • Oxford
    • Headington, Oxford, United Kingdom, OX3 0Du
      • John Radcliffe Hospital
  • UK
    • Bristol, UK, United Kingdom, BS2 8BJ
      • Bristol Royal Hospital for Children
    • Glasgow, UK, United Kingdom, G4 OSF
      • Glasgow Royal Infirmary
    • Leeds, UK, United Kingdom, LS1 3EX
      • Leeds General Infirmary
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Arizona Cancer Center
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • San Francisco, California, United States, 94143
      • Univeristy of California San Francisco
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale New Haven Hospital
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois - Chicago
    • Chicago, Illinois, United States, 60611
      • Northwestern Center for Clinical Research
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • Indiana Blood and Bone Marrow Transplant Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Univeristy of Iowa Hospitals and Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Louisiana
    • Shreveport, Louisiana, United States, 71130
      • Louisiana State University
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Greenbaum
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02111
      • Tufts-New England Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos/Wayne State University
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • Univeristy of Mississippi Medical Center
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10032
      • Columbia University/New York Presbyterian Hospital
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Univeristy School of Medicine
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15224
      • Western Pennsylvania Cancer Institute
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75230
      • Texas Cancer Center at Medical City
    • Dallas, Texas, United States, 75246
      • Baylor University
    • Dallas, Texas, United States, 75390
      • Univeristy of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Md Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Texas Research Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth/Massey Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109-1024
      • Fred Hutchinson Cancer Research Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Madison
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Mesoblast, Inc.

Publications and helpful links

General Publications

• Camilleri ET, Gustafson MP, Dudakovic A, Riester SM, Garces CG, Paradise CR, Takai H, Karperien M, Cool S, Sampen HJ, Larson AN, Qu W, Smith J, Dietz AB, van Wijnen AJ. Identification and validation of multiple cell surface markers of clinical-grade adipose-derived mesenchymal stromal cells as novel release criteria for good manufacturing practice-compliant production. Stem Cell Res Ther. 2016 Aug 11;7(1):107. doi: 10.1186/s13287-016-0370-8.
• Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004 May 1;363(9419):1439-41. doi: 10.1016/S0140-6736(04)16104-7.
• Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002 Jan;30(1):42-8. doi: 10.1016/s0301-472x(01)00769-x.
• Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol. 2000 Aug;28(8):875-84. doi: 10.1016/s0301-472x(00)00482-3.
• Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, Shpall EJ, McCarthy P, Atkinson K, Cooper BW, Gerson SL, Laughlin MJ, Loberiza FR Jr, Moseley AB, Bacigalupo A. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant. 2005 May;11(5):389-98. doi: 10.1016/j.bbmt.2005.02.001.
• Le Blanc K, Pittenger M. Mesenchymal stem cells: progress toward promise. Cytotherapy. 2005;7(1):36-45. doi: 10.1080/14653240510018118.

Helpful Links

• Description Click here for more information about this study: A Phase III Study to Evaluate the Efficacy and Safety of Prochymal® (Ex vivo Cultured Adult Human Mesenchymal Stem Cells) Infusion for the Treatment of Steroid-Refractory Acute GVHD

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2006
• Primary Completion (Actual): December 26, 2008
• Study Completion (Actual): May 28, 2009

Study Registration Dates

• First Submitted: August 17, 2006
• First Submitted That Met QC Criteria: August 18, 2006
• First Posted (Estimate): August 21, 2006

Study Record Updates

• Last Update Posted (Actual): February 10, 2022
• Last Update Submitted That Met QC Criteria: February 9, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Acute GVHD; Steroid refractory GVHD; Severe steroid refractory acute GVHD; Steroid refractory; Steroid Refractory Acute Graft Versus Host Disease
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Anti-Infective Agents; Antiviral Agents; Anti-Inflammatory Agents; Remestemcel-l
• Other Study ID Numbers: 280

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No