A Prospective Study of Remestemcel-L, Ex-vivo Cultured Adult Human Mesenchymal Stromal Cells, for the Treatment of Pediatric Patients Who Have Failed to Respond to Steroid Treatment for Acute GVHD
- Children’s Medical Center (Dallas, Plano, Southlake)
Victor Aquino, M.D.
The study plans to treat at least 60 pediatric subjects, male and female, between the ages of 2 months and 17 years inclusive with acute Graft versus Host Disease (aGVHD) following allogeneic hematopoietic stem cell transplant (HSCT) that has failed to respond to treatment with systemic corticosteroid therapy. Subjects 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.
Remestemcel-L will be evaluated in pediatric subjects with acute Graft versus Host Disease (aGVHD) following allogeneic hematopoietic stem cell transplant (HSCT) that has failed to respond to treatment with systemic corticosteroid therapy.
1. Patient was diagnosed with Grade B-D acute GVHD requiring corticosteroid systemic therapy. The subject may have Grade C or D aGVHD involving the skin, liver, and/or gastrointestinal (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. Patient has failed to respond to steroid treatment, with failure to respond defined as any Grade B-D (IBMTR grading) acute GVHD that shows progression within 3 days, or no improvement within 7 consecutive days, of treatment with 2 mg/kg/day methylprednisolone or equivalent.
3. Patient must be able to be treated with remestemcel-L within 4 days of study entry.
4. Patients who have had persistent GI GVHD manifested by diarrhea with stool volume < 500 mL/day in the absence of nausea or vomiting may be deemed as having Grade B GVHD if other causes of diarrhea have been ruled out (e.g., C. difficile or cytomegalovirus (CMV) infection, oral magnesium administration) and if the low stool volume reflects the effects of fasting or administration of narcotics or antidiarrheal medications.
5. Patient must have adequate renal function as defined by a calculated creatinine clearance of >30 mL/min per 1.73 m determined using the Schwartz equation:
Creatinine clearance (ml/min per1.73 m= (height [cm] x k)/ (serum creatinine [mg/dL]) where k is a standard proportionality constant based on patient's gestational age, chronologic age and gender.
6. Patient has a minimum Karnofsky/Lansky Performance Level of at least 30 at the time of study entry.
7. Patient (or legal representative where appropriate) must be capable of providing written informed consent.
8. Female patients of childbearing potential (not surgically sterile) must use a medically accepted method of contraception and must 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 patients 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 patient must be willing and able to comply with study requirements, remain at the clinic, and be willing and able to return to the clinic for the follow-up evaluation as specified in this protocol during the study period.
1. Patient has Grade B aGvHD with skin-only involvement.
2. Patient has received any second line therapy to treat aGVHD prior to screening.
3. Patient has received systemic agents other than steroids and prophylactic agents for primary treatment of acute GVHD.
4. Patient 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 FiO(2) of 28% via other delivery methods in order to sustain an O(2) saturation of 92%.
5. Patient has any underlying or current medical or psychiatric condition that, in the opinion of the Investigator, would interfere with the evaluation of the subject including but not limited to uncontrolled infection, heart failure, pulmonary hypertension, etc.
6. Patient has received any stem cell agents (other than hematopoietic graft) during study participation or within 30 days prior to study entry.
7. Patient has a known allergy to bovine or porcine products.
8. Patient has received an HSCT transplant for a solid tumor disease.
9. Patient has had prior treatment with mesenchymal stem cells (MSCs), including remestemcel-L.
10. Patient shows evidence of severe hepatic veno-occlusive disease (VOD) or sinusoidal obstruction.
11. Patient shows evidence of encephalopathy as defined by a change in mental status since the onset of aGVHD.
12. Patient is a female who is pregnant, lactating, or is planning a pregnancy during study participation, or in the follow-up period.
13. Patient has had an active solid tumor malignancy within the last 5 years from screening, except for cervical carcinoma in situ localized prostate cancer or nonmelanoma skin cancer that has been definitively treated.
14. Patient has participated in any interventional clinical trial for an aGVHD therapeutic agent or for an immunomodulatory drug, within the past 30 days or within 5 half-lives of the investigational medicinal product (IMP), whichever is the greater.
15. Patient has participated or is currently participating in any bone marrow derived autologous and allogeneic stem cell or gene therapy study.
16. Patient has a known hypersensitivity to dimethyl sulfoxide (DMSO) or murine or bovine proteins.