A Phase II Trial of Reduced Intensity Conditioning and Haploidentical BMT for High-risk Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01804634
Recruitment Status : Recruiting
First Posted : March 5, 2013
Last Update Posted : June 17, 2016
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Refractory and/or Relapsed Metastatic Solid Tumors Drug: Cyclophosphamide Drug: Fludarabine Radiation: low dose total body irradiation Drug: Melphalan Drug: Sirolimus Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Reduced Intensity Conditioning and Partially HLA-mismatched (HLA-haploidentical) Bone Marrow Transplantation for High-risk Solid Tumors
Study Start Date : February 2013
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : December 2018

Arm Intervention/treatment
Experimental: 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.
Drug: Cyclophosphamide
preparative regimen
Other Name: cytoxan
Drug: Fludarabine Radiation: low dose total body irradiation Drug: Melphalan Drug: Sirolimus

Primary Outcome Measures :
  1. Donor cell engraftment [ Time Frame: 14-60 Days ]
    To estimate the incidence of donor cell engraftment following reduced intensity conditioning, HLA-mismatched BMT for patients with high risk high-risk solid tumor malignancies.

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 1-2 years ]
    To estimate overall survival in patients receiving reduced intensity conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow.

  2. Relapse [ Time Frame: 1-2 years ]
    To estimate overall relapse, in patients receiving reduced intensity conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow.

  3. Non-Relapse Mortality [ Time Frame: 1-2 years ]
    To estimate overall non-relapse mortality in patients receiving reduced intensity conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow.

Other Outcome Measures:
  1. Document toxicities [ Time Frame: 30-180 days ]
    To document rates of acute and chronic GVHD, unexpected toxicities after RIC haploidentical BMT.

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Ages Eligible for Study:   up to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01804634

Contact: Heather Symons, MD, MHS 410-502-4997

United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231
Contact: Heather Symons, MD, MHS    410-502-4997   
Principal Investigator: Heather Symons, MD, MHS         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Principal Investigator: Heather Symons, MD, MHS Johns Hopkins University

Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Identifier: NCT01804634     History of Changes
Other Study ID Numbers: J12106
First Posted: March 5, 2013    Key Record Dates
Last Update Posted: June 17, 2016
Last Verified: June 2016

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
Solid Tumors
Ewing Sarcoma
Desmoplastic Round Cell Tumor
brain tumors

Additional relevant MeSH terms:
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents