A Phase II Trial of Reduced Intensity Conditioning and Haploidentical BMT for High-risk Solid Tumors
Refractory and/or Relapsed Metastatic Solid Tumors
Conditions: Keywords
Solid Tumors, Neuroblastoma, Osteosarcoma, Ewing Sarcoma, Rhabdomyosarcoma, Hepatoblastoma, Melanoma, Desmoplastic Round Cell Tumor, brain tumors
Study Type
Study Phase
Phase 2
Study Design
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Name: Cyclophosphamide Type: Drug
Name: Fludarabine Type: Drug
Name: low dose total body irradiation Type: Radiation
Name: Melphalan Type: Drug
Name: Sirolimus Type: Drug
Overall Status
The purpose of this study is to see if giving reduced intensity chemotherapy, haploidentical bone marrow, post-transplant cyclophosphamide and sirolimus is safe and feasible for patients with very high-risk solids tumors.
Detailed Description
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.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: 40 Years
Minimum Age: N/A
Gender: Both
Criteria: 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.
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
Status: Recruiting
Contact: Heather Symons, MD, MHS - 410-502-4997 - hsymons2@jhmi.edu
Start Date
February 2013
Completion Date
December 2016
Sidney Kimmel Comprehensive Cancer Center
Sidney Kimmel Comprehensive Cancer Center
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page