Clinical trial NCT00366145: Efficacy and Safety of Adult Human Mesenchymal Stem Cells to Treat Steroid Refractory Acute Graft Versus Host Disease (GVHD)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Graft Versus Host Disease
Keywords: Acute GVHD
Steroid refractory GVHD
Severe steroid refractory acute GVHD
Steroid refractory
Steroid Refractory Acute Graft Versus Host Disease
Lead sponsor: Mesoblast, Ltd.
Sponsor class: INDUSTRY
First posted: 2006-08-21
Enrollment: 260
Sex: ALL
Minimum age (years): 6
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Participants achieving Complete Response of Greater Than or Equal to 28 Days Duration
timeFrame: up to 100 Days post first infusion
Secondary outcomes:
measure: Overall Survival at 180 days Post First Infusion
timeFrame: Day 180
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Tucson
country: United States
facility: Arizona Cancer Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: San Francisco
country: United States
facility: Univeristy of California San Francisco
state: California
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern Center for Clinical Research
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Illinois - Chicago
state: Illinois
city: Beech Grove
country: United States
facility: Indiana Blood and Bone Marrow Transplant Center
state: Indiana
city: Iowa City
country: United States
facility: Univeristy of Iowa Hospitals and Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Shreveport
country: United States
facility: Louisiana State University
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland/Greenbaum
state: Maryland
city: Boston
country: United States
facility: Tufts-New England Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos/Wayne State University
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Jackson
country: United States
facility: Univeristy of Mississippi Medical Center
state: Mississippi
city: Omaha
country: United States
facility: University of Nebraska
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University/New York Presbyterian Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Univeristy School of Medicine
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Western Pennsylvania Cancer Institute
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: Texas Cancer Center at Medical City
state: Texas
city: Dallas
country: United States
facility: Baylor University
state: Texas
city: Dallas
country: United States
facility: Univeristy of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Texas Research Center
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth/Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Madison
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Herston
country: Australia
facility: Royal Brisbane Hospital
state: Queensland
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Calgary
country: Canada
facility: Co-Medica Research Network
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia's Children's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba
state: Manitoba
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre- Westminster Campus
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Maisonneuve-Rosemont Hospital
state: Quebec
city: Quebec
country: Canada
facility: Hopital Enfant-Jesus
city: Quebec
country: Canada
facility: Hopital du Saint-Sacrement
city: Pesaro
country: Italy
facility: Universia degli Studi di Pesaro
state: PU
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo
city: Basel
country: Switzerland
facility: Kantonsspital Basel
city: London
country: United Kingdom
facility: Barts & London School of Medicine
state: England
city: Headington
country: United Kingdom
facility: John Radcliffe Hospital
state: Oxford
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
state: UK
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
state: UK
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
state: UK
Study officials:
affiliation: Mesoblast, Inc.
name: Christopher James, PA
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Le Blanc K, Pittenger M. Mesenchymal stem cells: progress toward promise. Cytotherapy. 2005;7(1):36-45. doi: 10.1080/14653240510018118.
citation: 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.