Reduced Intensity Haploidentical BMT for High Risk Solid Tumors
Reduced Intensity Haploidentical BMT for High Risk Solid Tumors
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.
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).

 Melphalan: Recommended to be administered as an IV infusion over 30-60 minutes, depending on
 volume, on D-2. The dose will be 100mg/m2. Other institutional infusion standards are
 acceptable and will not be a protocol deviation.

 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.

 Day of rest: A day of rest, i.e. after preparative regimen completion and prior to bone
 marrow infusion, is not routinely scheduled. Up to one day of rest in-between TBI and the
 infusion of bone marrow may be added in this window based on logistical considerations or
 clinically as indicated

 Bone marrow transplantation

 Bone Marrow will be harvested and infused on day 0. Institutional guidelines for the infusion
 of bone marrow (i.e. major or minor ABO incompatible bone marrow, etc.) will be followed. The
 marrow infusion will be done by designated members of the BMT team. The bone marrow graft
 will not be manipulated to deplete T cells. The donor will be harvested with a target yield
 of 4 x 108 nucleated cells/kg recipient IBW. The lowest acceptable yield is 1.5 x 108
 nucleated cells/kg. The CD 34+, CD4+, CD8+, and CD3+ cell count in the marrow will be
 quantified by flow cytometry.

 Post-transplantation Cyclophosphamide

 Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow
 infusion) and on D+4 post-transplant. Cyclophosphamide will be given as an IV infusion over
 1- 2 hours (depending on volume). Dosing of cyclophosphamide is based on ideal body weight
 for subjects whose ideal body weights less than or equal to their actual body weight. On
 occasion, a subject's actual body weight may be less than his/her ideal body weight, in which
 case cyclophosphamide will be dosed using the subject's actual body weight.

 Patients will be instructed to increase fluids overnight before cyclophosphamide
 administration. Hydration with normal saline at 3 cc/kg/hr iv will be started 8 hr prior to
 cyclophosphamide, then the rate will be reduced to 2 cc/kg/hr for 1 hr pre-cyclophosphamide
 and continued for at least 8 hr post-cyclophosphamide or administered per institutional
 standards. Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours
 post-cyclophosphamide or administered per institutional standards. Mesna dose will be based
 on the cyclophosphamide dose being given. The total daily dose of mesna is equal to 80% of
 the total daily dose of cyclophosphamide.

 Patients will be instructed to increase fluids overnight before cyclophosphamide
 administration. Hydration will be administered per institutional standards. Protocol
 recommendation of normal saline at 3 cc/kg/hr iv will be started 8 hr prior to
 cyclophosphamide, then the rate will be reduced to 2 cc/kg/hr for 1 hr pre-cyclophosphamide
 and continued for at least 8 hr post-cyclophosphamide. Mesna will be administered per
 institutional standards. Mesna dose will be based on the cyclophosphamide dose being given.
 The total daily dose of mesna is equal to 80% of the total daily dose of cyclophosphamide.

 It is crucial that no immunosuppressive agents are given until 24 hours after the completion
 of the post-transplant Cy. This includes steroids as anti-emetics.

 GVHD prophylaxis

 Tacrolimus On day +5, patients will begin prophylaxis with Tacrolimus (PO or IV as per
 institutional standards for starting this prophylaxis).Tacrolimus begins on Day 5, at least
 24 hours after completion of posttransplantation Cy. The tacrolimus starting dose will be
 given per institutional standards for adult or pediatric patients. The recommended, but not
 required, The starting dose of tacrolimus is 0.015mg/kg IBW/dose IV over 4 hours every 12
 hours. , or per institutional standard. Serum trough levels of tacrolimus should be measured
 around D+7 and the dose should be adjusted based on this level to maintain a level of 5-15
 ng/ml. Tacrolimus should be converted to oral dosing when patient has a stable, therapeutic
 level and is able to tolerate food or other oral medications. For pediatric patients, the
 oral dosing is approximately two to four times the IV dosing. It is recommended that serum
 trough levels should be checked at steady state after any dose modification and when
 switching from IV to oral to ensure therapeutic trough concentrations. Serum trough
 concentrations should be checked at a minimum weekly thereafter and the dose adjusted
 accordingly to maintain a level of 5-15 ng/ml. Tacrolimus will be discontinued after the last
 dose on Day 90, or may be continued if active GVHD is present. This should be discussed with
 the PI. Tacrolimus may also be discontinued early if patients have progressive disease or
 relapse. If tacrolimus is stopped earlier or later than day 90 +/- 7 days , this should be
 discussed with the PI This should also be discussed with the PI.

 Mycophenolic acid mofetil (MMF) MMF 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). MMF
 prophylaxis will be discontinued after the last dose on D35.

 Infection prophylaxis and therapy All infection prophylaxis and therapy will be administered
 and discontinued as per institutional requirements. The following are recommendations only.

 i) During pre-transplant evaluation patients will be screened for respiratory syncytial
 virus, influenza A, B and parainfluenza viruses if symptomatic. Assays of these viruses must
 be negative for symptomatic patients to be admitted for transplant. Strong consideration
 should be given to institution of ribavirin therapy if positive for adenovirus or nalidixic
 acid if positive for BK virus.

 ii) Oral hygiene will be maintained according to institutional standards.

 iii) Prophylactic anti-microbial therapy will be started during the preparative regimen, per
 institutional guidelines.

 iv) Empiric therapy with broad-spectrum antibiotics will be instituted for the first
 neutropenic fever (specific agents as per current practice).

 Growth factor support

 Patients will receive G-CSF (Filgrastim®) 5µg/kg/d SC or IV starting at Day 5 and continuing
 until the ANC>1000/mm3 x 3days or two consecutive measurements over a three day period. For
 use in the case of fungal infections or subsequent neutropenia (ANC<500/mm3), G-CSF should be
 continued until the WBC>10,000-15,000.

 Transfusion support Platelet and packed red cell transfusions will be given per current
 institutional recommendations.

 Anti-ovulatory treatment Menstruating females will are recommended to should be be started on
 an anti-ovulatory agent, such as Lupron prior to the initiation of the preparative regimen.
 The treatment administered will be at the discretion of the treating physician.

 Post-BMT evaluation Patients will be followed during (i) the initial post-BMT period (ii)
 after discharge to the referring physician as per standard practice.
Presence of a suitable related HLA-haploidentical bone marrow donor.a. The donor and
 recipient must be identical at 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.

 1 year-50 years

 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 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/1.73m2.

 -  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:

 1. Medically and psychologically fit and willing to donate

 2. Killer Immunoglobulin Receptor (KIR) Haplotype B Donor

 3. Red blood-cell compatibility (in order of preference)

 1. RBC cross-match compatible

 2. Minor ABO incompatibility

 3. Major ABO incompatibility

 4. For CMV seronegative recipients, a CMV seronegative donor. For CMV seropositive
 recipients, a CMV seropositive donor is preferred.

 5. 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:

 1. If the patient is male, choose a male donor

 2. Choose the youngest preferred donor

 3. If the patient and family express a strong preference for a particular donor, use that
 one.