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Umbilical Cord Derived Mesenchymal Stromal Cells For The Treatment of Severe Steroid-resistant Graft Versus Host Disease (PTC-UC-MSC)

Primary Purpose

Hematologic Malignancies

Status
Unknown status
Phase
Phase 1
Locations
Italy
Study Type
Interventional
Intervention
UMBILICAL CORD DERIVED MESENCHYMAL STROMAL CELLS (UC-MSC)
Sponsored by
A.O. Ospedale Papa Giovanni XXIII
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hematologic Malignancies

Eligibility Criteria

undefined - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients are required to meet the following inclusion criteria:

  1. Patients with steroid refractory grade III-IV classic acute graft versus host disease (GvHD)occurring within 100 days after transplant or induced by donor lymphocyte infusions (DLI) or T-cell add back. Steroid refractory graft versus host disease (GvHD)is defined according to Pidala and Anasetti10 as follows: a) progression of at least 1 overall grade within 3 days of optimal steroid treatment; b) failure to demonstrate any overall grade improvement over 5 to 7 days; c) incomplete response by 14 days of 2 mg/kg/day of steroid therapy.
  2. Patients with persistent, recurrent, or late acute graft versus host disease (GvHD) (features of acute graft versus host disease occurring beyond 100 days, often during withdrawal of immune suppression).
  3. Patients with an overlap syndrome in which diagnostic or distinctive features of chronic graft versus host disease (GvHD) and acute graft versus host disease (GvHD) appear together79.

Exclusion Criteria:

1. Inability to obtain written informed consent

Sites / Locations

  • A O Papa Giovanni XXIIIRecruiting
  • Ao S Croce E CarleRecruiting
  • AO Careggi
  • IRCCS G Gaslini
  • Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
  • Clinica Pediatrica San Gerardo
  • Azienda Ospedaliero-Universitaria Di Udine
  • Ospedale San BortoloRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Umbilical Cord Mesenchymal stromal cells (UC-MSC)

Arm Description

Pentostatin will be given by intravenous infusion at a dose of 1 mg/m2 for 3 consecutive days. Thereafter, three Umbilical Cord Mesenchymal stromal cells (UC-MSC) infusions will be given at weekly interval starting from day 5. We will follow a dose escalating programme with progressively increasing doses of cells until the maximally tolerated dose (MTD) is achieved. The dose escalating design will be characterised by the administration of 1x106 /kg UC-MSC per dose per three doses for the first three patients (total up to 3x106/kg). The second three patients will receive 2x106/kg UC-MSC per dose per three doses (total up to 6x106/kg). The third three patients will receive 3x106/kg UC-MSC per dose per three doses (total up to 9x106 cells/kg). Since three dosages of cells are programmed for each group of 3 patients, a minimum of 9 patients should be studied, unless unacceptable acute infusion related toxicity is observed.

Outcomes

Primary Outcome Measures

vital parameters
Following infusion of UC-MSC, the patient will be monitored for acute infusion-related toxicity. Any toxicity will be treated at the discretion of the attending physician. Infusional toxicity is defined as any alteration of the vital parameters of the patient if they have appeared acutely and may be directly correlated to the UC-MSC infusion

Secondary Outcome Measures

assessed of acute graft versus host disease (GvHD)
graft versus host disease will be assessed at day +7, +9, +12, +14, +16, +19, +21, +28, + 35, +42 e +49 and after 6 months and 1 year from the last UC-MSC infusion. Efficacy on acute graft versus host disease is defined as complete or partial resolution of acute GvHD evaluated according to conventional staging and grading score systems.The efficacy will be evaluated at day +30 after the third UC-MSC infusion or, if less, at day +30 after the last UC-MSC infusion.

Full Information

First Posted
November 4, 2013
Last Updated
January 17, 2019
Sponsor
A.O. Ospedale Papa Giovanni XXIII
Collaborators
Associazione Italiana per la Ricerca sul Cancro
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1. Study Identification

Unique Protocol Identification Number
NCT02032446
Brief Title
Umbilical Cord Derived Mesenchymal Stromal Cells For The Treatment of Severe Steroid-resistant Graft Versus Host Disease
Acronym
PTC-UC-MSC
Official Title
UMBILICAL CORD DERIVED MESENCHYMAL STROMAL CELLS (UC-MSC) FOR THE TREATMENT OF SEVERE (GRADE III-IV) STEROID-RESISTANT GRAFT VERSUS HOST DISEASE (GvHD): A PHASE I/II TRIAL
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Unknown status
Study Start Date
September 2013 (undefined)
Primary Completion Date
September 2016 (Actual)
Study Completion Date
September 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
A.O. Ospedale Papa Giovanni XXIII
Collaborators
Associazione Italiana per la Ricerca sul Cancro

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
MESENCHYMAL STROMAL CELLS (MSC) have shown promising albeit not always consistent therapeutic effects in the treatment of severe steroid-resistant acute Graf versus Host Disease. Remarkably, in all reported clinical studies the toxicity of Mesenchymal stromal cells administration has been found consistently negligible. The investigators believe that Umbilical Cord (UC) derived Mesenchymal stromal cells may represent a stronger immunosuppressive tool for such clinical emergency and no data suggest any change in the safety profile of these cells. For this reason, and in the best interest of the patient, the investigators plan to test the safety and activity of Umbilical Cord Mesenchymal stromal cells when given sequentially to another partially effective treatment of steroid resistant acute graf versus host disease such as Pentostatin.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hematologic Malignancies

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
47 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Umbilical Cord Mesenchymal stromal cells (UC-MSC)
Arm Type
Experimental
Arm Description
Pentostatin will be given by intravenous infusion at a dose of 1 mg/m2 for 3 consecutive days. Thereafter, three Umbilical Cord Mesenchymal stromal cells (UC-MSC) infusions will be given at weekly interval starting from day 5. We will follow a dose escalating programme with progressively increasing doses of cells until the maximally tolerated dose (MTD) is achieved. The dose escalating design will be characterised by the administration of 1x106 /kg UC-MSC per dose per three doses for the first three patients (total up to 3x106/kg). The second three patients will receive 2x106/kg UC-MSC per dose per three doses (total up to 6x106/kg). The third three patients will receive 3x106/kg UC-MSC per dose per three doses (total up to 9x106 cells/kg). Since three dosages of cells are programmed for each group of 3 patients, a minimum of 9 patients should be studied, unless unacceptable acute infusion related toxicity is observed.
Intervention Type
Biological
Intervention Name(s)
UMBILICAL CORD DERIVED MESENCHYMAL STROMAL CELLS (UC-MSC)
Intervention Description
pentostatin, dose 1 mg/m2 § MSC doses: 3 patients → 3 infusions of 1x106 cells /kg 3 patients → 3 infusions of 2x106 cells /kg 3 patients → 3 infusions of 3x106 cells /kg
Primary Outcome Measure Information:
Title
vital parameters
Description
Following infusion of UC-MSC, the patient will be monitored for acute infusion-related toxicity. Any toxicity will be treated at the discretion of the attending physician. Infusional toxicity is defined as any alteration of the vital parameters of the patient if they have appeared acutely and may be directly correlated to the UC-MSC infusion
Time Frame
one year
Secondary Outcome Measure Information:
Title
assessed of acute graft versus host disease (GvHD)
Description
graft versus host disease will be assessed at day +7, +9, +12, +14, +16, +19, +21, +28, + 35, +42 e +49 and after 6 months and 1 year from the last UC-MSC infusion. Efficacy on acute graft versus host disease is defined as complete or partial resolution of acute GvHD evaluated according to conventional staging and grading score systems.The efficacy will be evaluated at day +30 after the third UC-MSC infusion or, if less, at day +30 after the last UC-MSC infusion.
Time Frame
one year

10. Eligibility

Sex
All
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients are required to meet the following inclusion criteria: Patients with steroid refractory grade III-IV classic acute graft versus host disease (GvHD)occurring within 100 days after transplant or induced by donor lymphocyte infusions (DLI) or T-cell add back. Steroid refractory graft versus host disease (GvHD)is defined according to Pidala and Anasetti10 as follows: a) progression of at least 1 overall grade within 3 days of optimal steroid treatment; b) failure to demonstrate any overall grade improvement over 5 to 7 days; c) incomplete response by 14 days of 2 mg/kg/day of steroid therapy. Patients with persistent, recurrent, or late acute graft versus host disease (GvHD) (features of acute graft versus host disease occurring beyond 100 days, often during withdrawal of immune suppression). Patients with an overlap syndrome in which diagnostic or distinctive features of chronic graft versus host disease (GvHD) and acute graft versus host disease (GvHD) appear together79. Exclusion Criteria: 1. Inability to obtain written informed consent
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
ALESSANDRO RAMBALDI, MD
Phone
035.2673681
Ext
0039
Email
arambaldi@asst-pg23.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alessandro Rambaldi, MD
Organizational Affiliation
A.O. Ospedale Papa Giovanni XXIII
Official's Role
Principal Investigator
Facility Information:
Facility Name
A O Papa Giovanni XXIII
City
Bergamo
ZIP/Postal Code
24127
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maria Luisa Ferrari, Study coordinator
Phone
035.2673681
Ext
0039
Email
mlferrari@asst-pg23.it
First Name & Middle Initial & Last Name & Degree
Alessandra Algarotti, MD
First Name & Middle Initial & Last Name & Degree
Caterina Micò, MD
First Name & Middle Initial & Last Name & Degree
Anna Grassi, MD
Facility Name
Ao S Croce E Carle
City
Cuneo
ZIP/Postal Code
12100
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
NICOLA MORANDINI, MD
Phone
+3901716424478
Email
MORANDININ@GMAIL.COM
Facility Name
AO Careggi
City
Firenze
ZIP/Postal Code
50134
Country
Italy
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Riccardo Saccardi, MD
Phone
0557947672
Email
riccardo.saccardi@aou.unifi.it
Facility Name
IRCCS G Gaslini
City
Genova
ZIP/Postal Code
16147
Country
Italy
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Edoardo Lanino, MD
Phone
01056362405
Email
edoardolanino@gaslini.org
Facility Name
Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
City
Milano
ZIP/Postal Code
20122
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
Clinica Pediatrica San Gerardo
City
Monza
ZIP/Postal Code
20900
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
Azienda Ospedaliero-Universitaria Di Udine
City
Udine
ZIP/Postal Code
33100
Country
Italy
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
RENATO FANIN, MD
Phone
+39.0432559662
Email
RENATO.FANIN@UNIUD.IT
Facility Name
Ospedale San Bortolo
City
Vicenza
ZIP/Postal Code
36100
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
ROBERTO RAIMONDI, MD
Phone
+39.0444753518
Email
RAIMONDI@HEMATO.VEN.IT

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
interim analysis
Citations:
PubMed Identifier
18468541
Citation
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O; Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008 May 10;371(9624):1579-86. doi: 10.1016/S0140-6736(08)60690-X.
Results Reference
result
PubMed Identifier
21417678
Citation
Capelli C, Gotti E, Morigi M, Rota C, Weng L, Dazzi F, Spinelli O, Cazzaniga G, Trezzi R, Gianatti A, Rambaldi A, Golay J, Introna M. Minimally manipulated whole human umbilical cord is a rich source of clinical-grade human mesenchymal stromal cells expanded in human platelet lysate. Cytotherapy. 2011 Aug;13(7):786-801. doi: 10.3109/14653249.2011.563294. Epub 2011 Mar 18.
Results Reference
result
PubMed Identifier
20350611
Citation
Lucchini G, Introna M, Dander E, Rovelli A, Balduzzi A, Bonanomi S, Salvade A, Capelli C, Belotti D, Gaipa G, Perseghin P, Vinci P, Lanino E, Chiusolo P, Orofino MG, Marktel S, Golay J, Rambaldi A, Biondi A, D'Amico G, Biagi E. Platelet-lysate-expanded mesenchymal stromal cells as a salvage therapy for severe resistant graft-versus-host disease in a pediatric population. Biol Blood Marrow Transplant. 2010 Sep;16(9):1293-301. doi: 10.1016/j.bbmt.2010.03.017. Epub 2010 Mar 27.
Results Reference
result
PubMed Identifier
16732175
Citation
Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z, Omazic B, Aschan J, Barkholt L, Le Blanc K. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation. 2006 May 27;81(10):1390-7. doi: 10.1097/01.tp.0000214462.63943.14.
Results Reference
result
PubMed Identifier
18820709
Citation
von Bonin M, Stolzel F, Goedecke A, Richter K, Wuschek N, Holig K, Platzbecker U, Illmer T, Schaich M, Schetelig J, Kiani A, Ordemann R, Ehninger G, Schmitz M, Bornhauser M. Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium. Bone Marrow Transplant. 2009 Feb;43(3):245-51. doi: 10.1038/bmt.2008.316. Epub 2008 Sep 29.
Results Reference
result
PubMed Identifier
21393326
Citation
Perez-Simon JA, Lopez-Villar O, Andreu EJ, Rifon J, Muntion S, Diez Campelo M, Sanchez-Guijo FM, Martinez C, Valcarcel D, Canizo CD. Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial. Haematologica. 2011 Jul;96(7):1072-6. doi: 10.3324/haematol.2010.038356. Epub 2011 Mar 10.
Results Reference
result
PubMed Identifier
18703664
Citation
Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, VanderWerff I, Troyer D, McIntosh KR. Immune properties of human umbilical cord Wharton's jelly-derived cells. Stem Cells. 2008 Nov;26(11):2865-74. doi: 10.1634/stemcells.2007-1028. Epub 2008 Aug 14.
Results Reference
result
Links:
URL
http://www.agenziafarmaco.gov.it
Description
Agenzia Italiana del Farmaco (AIFA)

Learn more about this trial

Umbilical Cord Derived Mesenchymal Stromal Cells For The Treatment of Severe Steroid-resistant Graft Versus Host Disease

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