15-007, A Phase 3, Randomized, Adaptive Study Comparing the Efficacy and Safety of Defibrotide vs Best Supportive Care in the Prevention of Hepatic Veno-Occlusive Disease in Adult and Pediatric Patients Undergoing Hematopoietic Stem Cell Transplant
Study ID: STU 092016-093
This is a Phase 3, randomized, adaptive study comparing the efficacy and safety of defibrotide vs best supportive care (BSC) in the prevention of hepatic veno-occlusive disease (VoD) in adult and pediatric patients undergoing hematopoietic stem cell transplant (HSCT) who are at high risk or very high risk of developing VoD, as diagnosed using the modified Seattle criteria. after informed consent or assent has been obtained from patients, or parent/legal guardians or representatives, as applicable, screening procedures will be performed within 14 days of the scheduled start of the patient's HSCT conditioning regimen. eligible participants will be randomly assigned to receive defibrotide prophylaxis 25 mg/kg/day in addition to BSC ([Quote]DP arm[Quote]) or BSC without defibrotide prophylaxis ([Quote]BSC arm[Quote]) in a 1:1 ratio. Randomization will be stratified according to risk of developing VoD (high-risk or very high-risk), age ([Greater Than] 16 years or [LessThanorequalTo] 16 years), and country using an interactive web response system (iWRS).
1. Patient must be above the age of 1 month as of the start date of study treatment. 2. Patient must be scheduled to undergo allogeneic (adults or pediatric patients) or autologous hematopoietic stem cell transplant (HSCT) (pediatric patients only) and be at high risk or very high risk of developing hepatic veno-occlusive disease (VOD). A. High-risk patients must meet both of the following criteria (i and ii): i. Patient must be scheduled to receive myeloablative conditioning, defined as either of the following: a. At least 2 alkylating agents (e.g., cyclophosphamide, busulfan, melphalan); the investigator must document in the medical chart that the conditioning regimen is considered to be myeloablative or b. Total body irradiation (TBI) (single dose of >=5 Gy, or >=8 Gy fractionated dose) and at least 1 alkylating agent, and ii. Patient must meet at least 1 of the following criteria (a or b): a. Has at least 1 hepatic-related risk factor, as defined by the European Society for Blood and Marrow Transplantation (EBMT) position statement during screening as follows: * Transaminase level > 2.5 times the upper limit of normal (ULN) during screening or within 14 days prior to screening on a non-screening test if the test was performed as part of patient[Single Quote]s routine standard of care * Serum total bilirubin level > 1.5 times the ULN during screening or within 14 days prior to screening on a non-screening test if the test was performed as part of patient[Single Quote]s routine standard of care * Prior history of cirrhosis (with biopsy evidence) * Prior history of hepatic fibrosis (by histology or other diagnostic scoring system per institutional guidelines) * Prior history of viral hepatitis within 1 year before the start of study treatment, as indicated by a positive test for any of the following: Hepatitis A virus (HAV) immunoglobulin M (IgM) (anti-HAV IgM); Hepatitis B virus (HBV) core immunoglobulin G (IgG) or IgM (anti-HBc IgG or anti-HBc IgM); HBV surface antigen (HBsAg); HBV DNA by polymerase chain reaction (PCR) or nucleic acid amplification testing (NAAT); Hepatitis C virus (HCV) antibody (anti-HCV) and HCV RNA by polymerase chain reaction (PCR) or NAAT * Any prior hepatic irradiation, including abdominal irradiation covering the hepatic area * Documented diagnosis of iron overload (serum ferritin > 2000 ng/mL or liver iron content >=5.0 mg/gdw as estimated by magnetic resonance imaging T2* within 3 months prior to screening; or b. Has advanced-stage neuroblastoma requiring myeloablative conditioning. Note: if the patient is scheduled to receive a tandem transplant, then enrollment may only occur following the first transplant and prior to second transplant. B. Very high-risk patients must meet 1 of the following criteria: i. Osteopetrosis and undergoing myeloablative conditioning ii. Primary hemophagocytic lymphohistiocytosis (HLH), Griscelli II Chediak-Higashi syndrome, Hermansky-Pudiak II, X-linked lymphoproliferative disorders, X-linked severe combined immunodeficiency, X-linked hypogammaglobulinemia, or familial HLH 1-5 and undergoing myeloablative conditioning iii. Prior treatment with an ozogamicin-containing monoclonal antibody using the minimum dose and schedule, according to the patient prescribing information; examples include the following: * Gemtuzumab ozogamicin, at least 9 mg/m2 total dose * Inotuzumab ozogamicin, at least 1.5 mg/mg2 over 28 days iv. Class III, high-risk thalassemia (i.e., patients who are >= 7 years old and have a liver size >= 5 cm at the time of screening 3. Female patients (and female partners of male patients) of childbearing potential who are sexually active must agree to use a highly effective method of contraception with their partners during exposure to defibrotide and for 1 week after the last dose of defibrotide. Highly effective methods of contraception that may be used by the patient or partner include abstinence (when this is in line with the preferred and usual lifestyle of the patient [periodic abstinence, e.g., calendar, post-ovulation, symptothermal methods, and withdrawal are not acceptable methods]), combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (i.e., birth control pills, patches, vaginal ring), progestogen-only hormonal contraception associated with inhibition of ovulation (i.e., progestin implant or injection), intrauterine device (IUD), intrauterine hormone-releasing system ( IUS), surgical sterilization, and vasectomy (> 6 months before Study Day 1). Post-menopausal women (i.e., women with > 2 years of amenorrhea) do not need to use contraception. 4. Adult patients must be able to understand and sign a written informed consent. For minor patients, the parent/legal guardian or representative must be able to understand and sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- Tiffany R Simms-Waldrip