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A Phase II Trial of Reduced Intensity Conditioning and HLA-matched or partially HLA-mismatched (HLA-haploidentical) Related Donor Bone Marrow Transplantation for High-Risk Solid Tumors
Johns Hopkins Kimmel Cancer Center in Baltimore
Allogeneic hematopoietic stem cell transplantation (HSCT) may be associated with a clinically significant "graft-versus-tumor" (GVT) effect, even against disease that is unresponsive to chemotherapy and radiation therapy. Graft-vs.-tumor (GVT) effects have been described after allogeneic HCT for neuroblastoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, melanoma and hepatoblastoma.Our goal is to maximize a T cell and NK cell mediated graft versus tumor effect in poor prognosis solid tumor patients using haploidentical donors, T cell replete bone marrow, and a unique post-transplant immunosuppression regimen containing post transplantation Cy and an mTOR inhibitor. This therapy will be widely applicable because almost all patients have a half-matched donor available (parent or sibling). We hope to demonstrate the safety and feasibility of this therapy in anticipation of combining this platform with additional post-transplantation therapy such as cryoablation, Donor Lymphocyte Infusion (DLI), stem cell directed therapy, immunologic checkpoint inhibitors, and/or metabolic inhibitors.
Patients must have an HLA-mismatched, related donor.Sarcoma patients, both males and females must be less than 40 years of age. For all other solid tumors, both malesand females, must be less than 21 years of age.Patients must have a confirmed diagnosis and be classified as high risk, as defined by having an expected survival of less than 10%. ï¿½?? Examples include:- Neuroblastoma or ganglioneuroblastoma- Failure to achieve at least a partial remission after induction therapywith COG ANBL0532 or standard chemotherapy- Refractory to induction chemotherapy with COG ANBL0532 or standardchemotherapy- Stage 4 rhabdomyosarcoma- Metastatic Ewing Sarcoma- Osteosarcoma with metastatic disease beyond the lungs and/or withlung metastases not amenable to resection- Hepatoblastoma not amenable to resection- Metastatic Melanoma- Desmoplastic small round cell tumor- Brain tumors such as astrocytic tumors, oligodendroglial tumors,ependymal tumors, choroid plexus tumors, other neuroepithelialtumors, neuronal and mixed neuronal-glial tumors, tumors of thepineal region, embryonic tumors- Any other solid tumor and soft tissue sarcoma with an estimated less than 10% chance of survival will be considered on a case by case basis.
Reducued Intesity Conditioning:Given our promising results with low rates of GVHD and TRM using non-myeloablative haploidentical BMT in hematologic malignancies, we will use this backbone for very high risk solid tumors in order to maximize a graft versus tumor effect with allogeneic T cells and NK cells for patients with poor prognosis. We will modify our current regimen to include a reduced intensity dose of melphalan as an additional chemotherapeutic agent in the preparative regimen, as melphalan has commonly been incorporated into the myeloablative preparative regimens for solid tumors because of its tolerable side effect profile and anti-tumor efficacy.84 Sirolimus will be given post- transplant because of the potential for its additional anti-tumor benefit.
05/26/2017 05:03 AM