A Prospective Study of Remestemcel-L, Ex-vivo Cultured Adult Human Mesenchymal Stromal Cells, for the Treatment of Pediatric Participants Who Have Failed to Respond to Steroid Treatment for Acute Graft-Versus-Host Disease (aGVHD)
Condition: Grade B aGVHD; Grade C aGVHD; Grade D aGVHD
Intervention: remestemcel-L
Intervention description: Participants were treated with IV remestemcel-L at a dose of 2 x 10^6 MSC/kg (actual body weight at screening) twice per week for each of 4 consecutive weeks. Infusions were administered at least 3 days apart and no more than 5 days apart for any infusion.
Intervention MeSH terms: Remestemcel-l
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 55.0
Sex: All
Minimum age: 2 Months
Maximum age: 17 Years
Healthy volunteers: No
Keywords: GVHD

Summary:

      The study plans to treat at least 60 pediatric participants, male and female, between the
      ages of 2 months and 17 years inclusive with aGVHD following allogeneic hematopoietic stem
      cell transplant (HSCT) that has failed to respond to treatment with systemic corticosteroid
      therapy. Participants may have Grades C and D aGVHD involving the skin, liver and/or
      gastrointestinal (GI) tract or Grade B aGVHD involving the liver and/or GI tract, with or
      without concomitant skin disease.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Participant is diagnosed with Grade B-D acute GVHD requiring corticosteroid systemic
             therapy. The participant may have Grade C or D aGVHD involving the skin, liver, and/or
             GI tract or may have Grade B aGVHD involving the liver and/or GI tract, with or
             without concomitant skin disease. Acute GVHD is defined as the presence of skin rash
             and/or persistent nausea, vomiting, and/or diarrhea and/or cholestasis presenting in a
             context in which aGVHD is likely to occur and where other etiologies such as drug
             rash, enteric infection, or hepatotoxic syndromes are unlikely or have been ruled out.

          2. Participant has failed to respond to steroid treatment, with failure to respond
             defined as any Grade B-D [International Bone Marrow Transplant Registry (IBMTR)
             grading] aGVHD that shows progression within 3 days, or no improvement within 7 days
             of consecutive treatment with 2 mg/kg/day methylprednisolone or equivalent.

          3. Participant must be able to be treated with remestemcel-L within 4 days of signing of
             informed consent.

          4. Participants who have had persistent GI GVHD manifested by diarrhea with stool volume
             < 500 mL/kg/day (for participants >50 kg) or <30 mL/kg/day (for participants ≤50 kg).
             See GVHD Organ Severity Criteria (Table 2) for values in mL/m^2. In the absence of
             nausea or vomiting, participants could have been considered to have Grade B GVHD if:

               1. other causes of diarrhea had been ruled out (eg, Clostridium difficile,
                  adenovirus or cytomegalovirus [CMV] infection, or oral magnesium administration),
                  and if

               2. the low stool volume reflected the effects of fasting, narcotics, or
                  antidiarrheal medications.

          5. Participant must have adequate renal function as defined by a calculated creatinine
             clearance of >30 mL/min per 1.73 m^2. For participants 1 to 18 years of age,
             creatinine clearance is calculated using the Bedside Schwartz equation:

             Glomerular filtration rate (GFR, in mL/min per 1.73 m^2) = (0.413 * height [cm])/serum
             creatinine (mg/dL)

             For participants younger than 1 year of age, renal function is determined using the
             Schwartz equation adjusted for this age group:

             Creatinine clearance (mL/min per 1.73 m^2= (height [cm] x 0.45)/ (serum creatinine
             [mg/dL]).

          6. Participant has a minimum Karnofsky/Lansky Performance Level of at least 30 at the
             time of study entry.

          7. Participant (or legal representative where appropriate) must be capable of providing
             written informed consent.

          8. Female participants of childbearing potential (≥10 years of age) are required to use a
             medically accepted method of contraception and to agree to continue use of this method
             for the duration of the study and for the follow-up time period. Acceptable methods of
             contraception include abstinence, barrier method with spermicide, intrauterine device
             (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in
             conjunction with a barrier method.

          9. Male participants with partners of childbearing potential must agree to use adequate
             contraception (barrier method or abstinence) during the study, including the follow-up
             time period.

         10. The participant must be willing and able to comply with study requirements, remain at
             the clinic, and return to the clinic for the follow-up evaluation during the study
             period, as specified in this protocol.

        Exclusion Criteria:

          1. Participant has Grade B aGvHD with skin-only involvement.

          2. Participant has received any second line therapy to treat aGVHD prior to screening.

          3. Participant has received systemic agents other than steroids and prophylactic agents
             for primary treatment of aGVHD.

          4. Participant shows evidence of diffuse alveolar hemorrhage or other active pulmonary
             disease, which is likely to require more than 2L of oxygen via face mask, or an
             estimated fractional inspired oxygen concentration (FiO2) of 28% via other delivery
             methods in order to sustain an O2 saturation of 92%.

          5. 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 but not limited to uncontrolled infection, heart failure, or
             pulmonary hypertension.

          6. Participant has received any stem cell agents (other than hematopoietic graft) during
             study participation or within 30 days prior to study entry. Previous use of irradiated
             granulocytes within 30 days is permitted.

          7. Participant has received an HSCT transplant for a solid tumor disease.

          8. Participant has had prior treatment with mesenchymal stem cells (MSCs), including
             remestemcel-L.

          9. Participant shows evidence of severe (required treatment) hepatic veno-occlusive
             disease (VOD) or sinusoidal obstruction at screening.

         10. Participant had positive laboratory test results indicating infection with the human
             immunodeficiency virus (HIV) at any time and/or active hepatitis B or C virus
             infection within 3 months prior to screening.

         11. Participant shows evidence of encephalopathy, as defined by a change in mental status
             since the onset of aGVHD.

         12. Participant is a female who is pregnant, lactating, or is planning a pregnancy during
             study participation, or in the follow-up period.

         13. Participant currently being treated for a solid tumor malignancy.

         14. Participant has participated in any interventional clinical trial for an aGVHD
             therapeutic agent. However, in exceptional cases, experimental agents may have been
             administered to enrolled participants at the Investigator's discretion.

         15. Participant has participated or is currently participating in any autologous and
             allogeneic stem cell or gene therapy study for the treatment of aGVHD. Participants
             participating in investigative protocols aimed at modification of the transplant graft
             (such as T-cell depletion) or aimed at modification of the conditioning regimen are
             allowed in the study.

         16. Participant has a known hypersensitivity to dimethyl sulfoxide (DMSO) or to murine,
             porcine, or bovine proteins.