Donor Bone Marrow Transplant in Treating Patients with High-Risk Solid Tumors
- Presence of a suitable related human leukocyte antigen (HLA)-haploidentical marrow donor; the donor and recipient must be identical at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1; a minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype
- Patients must have a confirmed histopathologic diagnosis and be classified as high risk defined by having an expected survival of < 10%; examples include: * Neuroblastoma or ganglioneuroblastoma ** Failure to achieve at least a partial response (PR) after induction therapy with Children’s Oncology Group (COG) ANBL0532 or standard chemotherapy ** Refractory to induction chemotherapy with COG ANBL0532 or standard chemotherapy ** Patients with high risk disease whose autologous peripheral blood stem cell product is contaminated with neuroblastoma or who do not have an autologous product available ** Patients with high risk disease who do not meet eligibility requirements/organ function requirements for myeloablative conditioning; patients with >= 5 identified lesions on the end of induction (COG ANBL0532 or standard chemotherapy) meta-iodobenzylguanidine (MIBG) scan * Stage 4 alveolar rhabdomyosarcoma * Metastatic Ewing sarcoma * Osteosarcoma with metastatic disease beyond the lungs and/or with lung metastases not amenable to resection * Desmoplastic small round cell tumor * Fibrolamellar hepatocellular carcinoma (i.e. metastatic or relapsed) * Any other solid tumor and soft tissue sarcoma with an estimated < 10% chance of survival will be considered on a case by case basis at the departmental tumor board and/or sarcoma meeting
- Previous therapy: * It is expected that patients will have received upfront standard of care therapy for their respected disease * Patients who relapse after either single or tandem autologous BMT are eligible (> 6 months must have elapsed from start of last BMT) * Patients must be recovered from the acute toxicities of any prior chemo/radio/immunotherapy or BMT
- Patients do not need to have measurable disease at time of enrollment; patients with measurable disease must have stable disease by RECIST criteria on two scans at least 6 weeks apart
- Left ventricular ejection fraction at rest must be >= 35%, or shortening fraction > 25%
- Bilirubin =< 3.0 mg/dL
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 5 x upper limit of normal (ULN)
- Alkaline phosphatase < 5 x ULN
- Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or glomerular filtration rate [GFR]) > 40 mL/min/1.73m^2
- Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO) > 50% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then oxygen (O2) saturation > 92% on room air
- Good performance status (Karnofsky/Lansky 60-100)
- Patients (parents/guardians for those < 18) and donors must be able to sign consent forms
- Patients must be willing to participate in all stages of treatment
- DONOR: Age >= 0.5 years
- DONOR: Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT)
- DONOR: Lack of recipient anti-donor HLA antibody; Note: in some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry; this will be decided on a case-by-case basis by the principal investigator (PI) and one of the immunogenetics directors
- DONOR: In the event that two or more eligible donors are identified, the following order of priority will be used to determine the preferred donor: * Medically and psychologically fit and willing to donate * Killer immunoglobulin receptor (KIR) haplotype B donor * Red blood-cell compatibility (in order of preference) ** Red blood cell (RBC) cross-match compatible ** Minor ABO incompatibility ** Major ABO incompatibility * For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative donor; for CMV seropositive recipients, a CMV seropositive donor is preferred * When possible, HLA-mismatched donors will be prioritized over HLA-matched to maximize an allogeneic benefit
- DONOR: If more than one preferred donor is identified from the above list and there is no medical reason to prefer one of them, then the following guidelines are recommended: * If the patient is male, choose a male donor * Choose the youngest preferred donor * If the patient and family express a strong preference for a particular donor, use that one
- Patients will not be excluded on the basis of sex, racial or ethnic background
- Human immunodeficiency virus (HIV)-positive
- Donor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available
- Positive leukocytotoxic crossmatch
- Women of childbearing potential who currently are pregnant (beta-human chorionic gonadotropin [HCG]+) or who are not practicing adequate contraception
- Uncontrolled viral, bacterial, or fungal infections
I. Estimate the safety of shortened duration immunosuppression through the combined incidence of non-relapse mortality (NRM) and grade III-IV acute graft versus host disease at day 120.
I. To estimate the incidence of graft versus host disease (GVHD): acute (a) GVHD grade (gr) 2-4, 3-4, and chronic (c) GVHD.
II. To estimate overall survival (OS), relapse event-free survival (EFS), and progression-free survival (PFS) at 6 months and 1 year.
III. To estimate non-relapse mortality (NRM) and relapse.
IV. To estimate the incidence of graft rejection.
I. To estimate disease response after bone marrow transplant (BMT).
II. To assess additional hematologic and non-hematologic toxicities of reduced intensity conditioning haploidentical BMT.
III. To assess the relationship between NK cell alloreactivity on outcome.
IV. To assess the relationship between specific patient-donor human leukocyte antigen (HLA) mismatches on outcome (relapse, OS, progression free survival [PFS], engraftment, and GVHD).
V. To compare fludeoxyglucose F-18 (FDG) positron emission tomography (PET)-based qualitative and quantitative tumor response assessment with standard computed tomography (CT) based Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
VI. To assess response rates to post-transplant therapies given for relapse/progression.
VII. To compare the tumor microenvironment, circulating tumor cells, and expression of MHC antigens as well as tumor specific antigens pre- and post BMT.
PREPARATIVE REGIMEN: Patients receive fludarabine intravenously (IV) over 30 minutes on days -7 to -3 and melphalan IV over 30 minutes on day -2. Patients also undergo total body irradiation (TBI) on day -1.
TRANSPLANT: Patients undergo allogeneic bone marrow transplant on day 0.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3 to 4 and tacrolimus orally (PO) or IV over 3 or 4 hours every 12 hours on days 5-90 in the absence of GVHD. Patients also receive mycophenolate mofetil PO every 8 hours or thrice daily (TID) on days 0-35.
After completion of study treatment, patients are followed up at 6 months, 1 year, and then annually thereafter.
Trial Phase Phase II
Trial Type Treatment
Johns Hopkins University / Sidney Kimmel Cancer Center
Heather Jill Symons
- Primary ID J12106
- Secondary IDs NCI-2013-00702, CIR00008429, CIR00009228, NA_00076243
- Clinicaltrials.gov ID NCT01804634