Mesenchymal Stromal Cells (MSCs) for the Treatment of Graft Versus Host Disease (GVHD) (MSC-GvHD)

Mesenchymal Stromal Cells (MSC) for the Treatment of Severe (Grade II-IV) Steroid-resistant Graft Versus Host Disease (GVHD): a Phase I Trial

This is a bicentric, prospective, non randomized study. Pediatric and adult patients will be treated.

Rationale: MSC have shown promising effects by reversal of severe therapy-resistant acute GvHD. As a common therapeutic line of action is not shared for steroid resistant GVHD, it is important to establish the toxicity and the feasibility of preparation and infusion of third party MSCs for acute steroid resistant GVHD and acute phases of chronic steroid resistant GVHD.

A total of 10 patients (pediatric and adults) need to be enrolled in the study. Patients who present clinical signs of either acute or chronic steroid resistant GVHD will receive by intravenous infusion at least two fixed doses of mesenchymal stem cells with 5 to 7 days of interval one from the other, derived from HLA unrelated donor different from the HSC donor (third party donor) regardless of the rate of HLA mismatch.

Primary objectives are to establish the feasibility and the toxicity of preparation and infusions of third party MSCs for the treatment of steroid resistant acute and acute phases of chronic grade II-IV GVHD.

Secondary objectives are:

1. To document the efficacy of MSC infusion in steroid resistant acute and acute phases of chronic GVHD grade II-IV.
2. To document the rate of GVHD recurrence in MSCs infused patients.
3. To document relapse of hematological malignancies post MSC infusions in patients undergoing MSCs treatment for steroid refractory GvHD.
4. To document the overall survival of MSC infused patients for steroid refractory GvHD.

Study Overview

• Status: Unknown
• Conditions: Graft vs Host Disease
• Intervention / Treatment: Genetic: Mesenchymal stromal cells

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ettore Biagi, MD; Phone Number: 2232 +39 039 233; Email: e.biagi@hsgerardo.org

Study Locations

• Italy
  • BG
    • Bergamo, BG, Italy, 24128
      • Recruiting
      • U.O. Ematologia - Ospedali Riuniti di Bergamo
      • Contact: Alessandro Rambaldi, MD; Email: arambaldi@ospedaliriuniti.bergamo.it
  • MB
    • Monza, MB, Italy, 20052
      • Recruiting
      • Clinica Pediatrica CTMO - Azienda Ospedaliera San Gerardo
      • Contact: Ettore Biagi, MD; Email: e.biagi@hsgerardo.org
      • Principal Investigator: Ettore Biagi, MD
    • Monza, MB, Italy, 20052
      • Recruiting
      • U.O. Ematologia CTMO - Azienda Ospedaliera San Gerardo
      • Contact: Matteo Parma, MD; Email: m.parma@hsgerardo.org
      • Principal Investigator: Matteo Parma, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Informed consent.
2. Patients are required to meet the following inclusion criteria:

Any patient that has undergone allogeneic stem cell transplantation with steroid refractory grades II-IV acute GvHD either occurring post transplant, or induced by donor lymphocyte infusions (DLI) or T-cell add back, or chronic steroid refractory GVHD in acute phase. Patients may be receiving local best treatment for steroid refractory GVHD. A positive biopsy for GvHD is not required if clinical signs and symptoms are characteristic for GvHD and other etiologies are excluded. See 6.4 for acute GvHD grading.

1. Steroids have been given, for instance methylprednisolone 2 mg/kg/day, for at least 72h in case of progressive acute GvHD, 5 days in case of stable acute GVHD (grade II to IV) or chronic GvHD in active phase, according to the local policy.
2. Despite this treatment, the patient has unresponsive GvHD after 5 days, or progressive acute GvHD after 72 hours. If single organ acute GvHD grade II from gut or liver, either progression from single organ or addition of one or two more organs. As an example, if the patient has grade II acute GvHD of the skin, GvHD is more intense and more widespread, or GvHD also includes liver and/or gut.
3. Patients with steroid refractory GvHD fulfilling the requirements mentioned in a) - b) may be treated with second line therapy according to the clinical guidelines at each center prior to enrolment in this study.
4. Patients under treatment with best available local treatment for steroid resistant GVHD will not interrupt the ongoing treatment unless clinically required for safety reasons.

Exclusion Criteria:

1. Inability to obtain informed consent.
2. Patients with documented uncontrolled EBV, CMV or fungal infection.
3. Patients in poor clinical conditions with life expectancy of less than 30 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Mesenchymal Stromal Cells (MSC); Intravenous injections for a dose of 1 ± 0.5 x 106 MSC/kg recipient body weight	Genetic: Mesenchymal stromal cells; Mesenchymal stromal cells (MSC) intravenous infusion at least two fixed doses of mesenchymal stem cells (1 ± 0.5 x 106/kg recipient body weight for each injection) with 5 to 7 days of interval one from the other, derived from HLA unrelated donor different from the HSC donor (third party donor).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Any toxic effect reported during MSCs infusion or in the subsequent 10 days by clinical monitoring	During MSCs infusion or in the subsequent 10 days
Feasibility as the possibility of producing adequate lots of patient dedicated MSCs for any patients presenting with steroid resistant GVHD	three years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with GvHD resolution	Complete resolution of GvHD: Control of all signs and symptoms attributed to acute GvHD; Partial resolution of GvHD: Control of some signs and symptoms attributed to acute GvHD with an improvement of overall grade; Refractory GvHD: No change in signs or symptoms of GvHD within 10 days of MSC infusion.; Worsening GvHD: Any progress of GvHD signs and symptoms that increase overall grade. a and b will be defined as response. c and d will be defined as no response.	One month
Determination of recurrence of GvHD		After 1 month from MSCs infusion
Relapse of haematological disease		Every three months
Survival		Every three months

Collaborators and Investigators

• Sponsor: Ettore Biagi, MD
• Investigators: Principal Investigator: Ettore Biagi, MD, San Gerardo Hospital

Publications and helpful links

General Publications

• Introna M, Lucchini G, Dander E, Galimberti S, Rovelli A, Balduzzi A, Longoni D, Pavan F, Masciocchi F, Algarotti A, Mico C, Grassi A, Deola S, Cavattoni I, Gaipa G, Belotti D, Perseghin P, Parma M, Pogliani E, Golay J, Pedrini O, Capelli C, Cortelazzo S, D'Amico G, Biondi A, Rambaldi A, Biagi E. Treatment of graft versus host disease with mesenchymal stromal cells: a phase I study on 40 adult and pediatric patients. Biol Blood Marrow Transplant. 2014 Mar;20(3):375-81. doi: 10.1016/j.bbmt.2013.11.033. Epub 2013 Dec 7.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (ANTICIPATED): May 1, 2013
• Study Completion (ANTICIPATED): September 1, 2013

Study Registration Dates

• First Submitted: May 5, 2010
• First Submitted That Met QC Criteria: January 7, 2013
• First Posted (ESTIMATE): January 9, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): January 9, 2013
• Last Update Submitted That Met QC Criteria: January 7, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: PTC-MSC; 2008-007869-23 (EUDRACT_NUMBER)