Trial of Reduced Intensity Conditioning and Haploidentical BMT for 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.

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.

Inclusion Criteria:

- Patients must have an HLA-mismatched, related donor (3/6 to 5/6 i.e., 3 to 6 antigen
match). Patients who have inherited a recombinant HLA haplotype may receive marrow
from parent in whose gamete the recombination occurred.

- Sarcoma patients: Males and Females < 40 years of age. All other diagnosis: Males and
Females < 21 years of age

-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 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 who do not meet eligibility requirements/organ function requirements for
myeloablative conditioning; Patients with >5 identified lesions on the end of
induction MIBG scan

- Stage 4 rhabdomyosarcoma

- Metastatic Ewing Sarcoma

- Osteosarcoma with metastatic disease beyond the lungs and/or with lung 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 neuroepithelial tumors, neuronal and mixed neuronal-glial
tumors, tumors of the pineal region, embryonic tumors

- 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 4
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 70-100)

- 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 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

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

- 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

Exclusion Criteria:

- 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 or who are not practicing
adequate contraception

- Uncontrolled viral, bacterial, or fungal infections.