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Donor Bone Marrow Transplant in Treating Patients with High-Risk Solid Tumors

Trial Status: Active

This phase II trial studies how well a donor bone marrow transplant works in treating patients with solid tumors that are likely to recur (come back) or spread. Giving low doses of chemotherapy and total body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells when they do not exactly match the patient's blood. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving sirolimus and mycophenolate mofetil before transplant may stop this from happening.

Inclusion Criteria

  • 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

Exclusion Criteria

  • 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

Florida

Saint Petersburg
Johns Hopkins All Children's Hospital
Status: ACTIVE
Contact: Benjamin Reed Oshrine
Phone: 727-767-4176

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Heather Jill Symons
Phone: 410-502-4997

PRIMARY OBJECTIVE:

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.

SECONDARY OBJECTIVES:

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.

EXPLORATORY OBJECTIVES:

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.

OUTLINE:

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

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Heather Jill Symons

  • Primary ID J12106
  • Secondary IDs NCI-2013-00702, CIR00008429, CIR00009228, NA_00076243
  • Clinicaltrials.gov ID NCT01804634