A Phase II Trial of Reduced Intensity Conditioning and Partially HLA-mismatched (HLA-haploidentical) Related Donor Bone Marrow Transplantation for High-risk Solid Tumors
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 3
- 主要终点
- Safety of Shortened duration of tacrolimus as assessed by number of participants with NRM and Grade III-IV acute GVHD at Day 120
研究概览
简要总结
The purpose of this study is to see if giving reduced intensity chemotherapy, haploidentical bone marrow, post-transplant cyclophosphamide and shortened duration tacrolimus is safe and feasible for patients with very high-risk solid tumors.
详细描述
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.
The investigators' 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 shortened duration tacrolimus. This therapy will be widely applicable because almost all patients have a half-matched donor available (parent or sibling). The investigators hope to demonstrate the safety and feasibility of this therapy in anticipation of combining this platform with additional post-transplantation relapse/progression prevention therapy such as an immune checkpoint inhibitor.
TREATMENT PLAN Indwelling central venous catheter Placement of a double lumen central venous catheter will be required for administration of IV medications and transfusion of blood products.
Pre-treatment Evaluation All patients will require documentation of a detailed history and physical examination and standard evaluation of cardiac, pulmonary, liver and renal function. All patients will undergo disease evaluation as specified in Table 1, utilizing whichever modalities following the guidelines in 6.1.3 (i). Pre-BMT blood will be drawn per section section 5.12 for correlative labs.
Preparative regimen Fludarabine: administered as an IV infusion over 30 minutes on D-7 to D-3. The dose will be 30 mg/m2/dose (adjusted for renal function).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 50 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Neuroblastoma or ganglioneuroblastoma
- •Failure to achieve at least a PR after induction therapy with COG ANBL0532 or standard chemotherapy
- •Refractory to induction chemotherapy with COG ANBL0532 or standard chemotherapy
- •Patients with high risk disease as defined in Appendix 1 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 as defined in Appendix 1 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) MIBG scan
- •Stage 4 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
- •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.
- •Patients with adequate organ function as measured by
- •Cardiac: Left ventricular ejection fraction at rest must be ≥ 35%, or shortening fraction > 25%.
- •Hepatic: Bilirubin ≤ 3.0 mg/dL; and ALT, AST, and Alkaline Phosphatase < 5 x ULN.
- •Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or GFR) > 40 mL/min/1.73m
- •Pulmonary: FEV1, FVC, DLCO (diffusion capacity) > 50% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then 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
- •Criteria for recipient ineligibility Patients will not be excluded on the basis of sex, racial or ethnic background.
- •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 (HCG+) or who are not practicing adequate contraception
- •Uncontrolled viral, bacterial, or fungal infections.
- •Criteria for donor eligibility Age >0.5 years
- •Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT).
- •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 PI and one of the immunogenetics directors.
- •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)
- •RBC cross-match compatible
- •Minor ABO incompatibility
- •Major ABO incompatibility
- •For 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.
- •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.
排除标准
- 未提供
研究组 & 干预措施
Reduced intensity conditioning
Fludarabine IV infusion over 30 minutes on D-7 to D-3. The dose will be 30 mg/m2/dose (adjusted for renal function). Melphalan: IV infusion over 30-60 minutes, depending on volume, on D-2. The dose will be 100mg/m2.Total body irradiation: 200 cGy AP/PA with 4MV or 6MV photons at 8 12 cGy/min at the point of prescription (average separation of measurements at mediastinum, abdomen, and hips) will be administered in a single fraction on day -1. Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on Day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 3 hours every 12 hours. Mycophenolic acid mofetil (MMF) F will be given at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Cyclophosphamide (Drug)
Reduced intensity conditioning
Fludarabine IV infusion over 30 minutes on D-7 to D-3. The dose will be 30 mg/m2/dose (adjusted for renal function). Melphalan: IV infusion over 30-60 minutes, depending on volume, on D-2. The dose will be 100mg/m2.Total body irradiation: 200 cGy AP/PA with 4MV or 6MV photons at 8 12 cGy/min at the point of prescription (average separation of measurements at mediastinum, abdomen, and hips) will be administered in a single fraction on day -1. Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on Day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 3 hours every 12 hours. Mycophenolic acid mofetil (MMF) F will be given at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Fludarabine (Drug)
Reduced intensity conditioning
Fludarabine IV infusion over 30 minutes on D-7 to D-3. The dose will be 30 mg/m2/dose (adjusted for renal function). Melphalan: IV infusion over 30-60 minutes, depending on volume, on D-2. The dose will be 100mg/m2.Total body irradiation: 200 cGy AP/PA with 4MV or 6MV photons at 8 12 cGy/min at the point of prescription (average separation of measurements at mediastinum, abdomen, and hips) will be administered in a single fraction on day -1. Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on Day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 3 hours every 12 hours. Mycophenolic acid mofetil (MMF) F will be given at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: low dose total body irradiation (Radiation)
Reduced intensity conditioning
Fludarabine IV infusion over 30 minutes on D-7 to D-3. The dose will be 30 mg/m2/dose (adjusted for renal function). Melphalan: IV infusion over 30-60 minutes, depending on volume, on D-2. The dose will be 100mg/m2.Total body irradiation: 200 cGy AP/PA with 4MV or 6MV photons at 8 12 cGy/min at the point of prescription (average separation of measurements at mediastinum, abdomen, and hips) will be administered in a single fraction on day -1. Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on Day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 3 hours every 12 hours. Mycophenolic acid mofetil (MMF) F will be given at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Melphalan (Drug)
Reduced intensity conditioning
Fludarabine IV infusion over 30 minutes on D-7 to D-3. The dose will be 30 mg/m2/dose (adjusted for renal function). Melphalan: IV infusion over 30-60 minutes, depending on volume, on D-2. The dose will be 100mg/m2.Total body irradiation: 200 cGy AP/PA with 4MV or 6MV photons at 8 12 cGy/min at the point of prescription (average separation of measurements at mediastinum, abdomen, and hips) will be administered in a single fraction on day -1. Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on Day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 3 hours every 12 hours. Mycophenolic acid mofetil (MMF) F will be given at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).
干预措施: Tacrolimus (Drug)
结局指标
主要结局
Safety of Shortened duration of tacrolimus as assessed by number of participants with NRM and Grade III-IV acute GVHD at Day 120
时间窗: up to 120 Days
Safety of shortened duration immunosuppression assessed by the number of participants with non-relapse mortality (NRM) and grade III-IV acute graft versus host disease (Przepiorka criteria stages the degree of organ involvement in the skin, liver and gastrointestinal (GI) tract, based on severity, with Stage 1+ being least sever and Stage 4+ being most severe. Grading of acute GVHD is as follows: Grade I (skin involvement stages 1+ to 2+, with no liver or GI involvement), Grade II (skin involvement stages 1+ to 3+, liver 1+, GI tract 1+), Grade III (skin involvement stages 2+ to 3+, liver 1+, GI tract 2+ to 4+), Grade IV (skin involvement stages 4+, liver 4+))
次要结局
- Relapse(up to 2 years)
- progression-free survival at 6 months(6 months)
- Overall survival at 6 months(6 months)
- Overall survival at 1 year(1 year)
- Non-Relapse Mortality(up to 2 years)
- Event-free survival at 6 months(6 months)
- progression-free survival at 1 year(1 year)
- acute GVHD(30-180)
- Event-free survival at 1 year(1 year)
- chronic GVHD(75days -1year)