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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2013 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01804634
First received: March 1, 2013
Last updated: March 18, 2013
Last verified: March 2013
  Purpose

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

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • Donor cell engraftment [ Time Frame: 14-60 Days ] [ Designated as safety issue: Yes ]
    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:
  • Overall survival [ Time Frame: 1-2 years ] [ Designated as safety issue: Yes ]
    To estimate overall survival in patients receiving reduced intensity conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow.

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

  • Non-Relapse Mortality [ Time Frame: 1-2 years ] [ Designated as safety issue: Yes ]
    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:
  • Document toxicities [ Time Frame: 30-180 days ] [ Designated as safety issue: Yes ]
    To document rates of acute and chronic GVHD, unexpected toxicities after RIC haploidentical BMT.


Estimated Enrollment: 20
Study Start Date: February 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   up to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01804634

Contacts
Contact: Heather Symons, MD, MHS 410-502-4997 hsymons2@jhmi.edu

Locations
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    hsymons2@jhmi.edu   
Principal Investigator: Heather Symons, MD, MHS         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Investigators
Principal Investigator: Heather Symons, MD, MHS Johns Hopkins University
  More Information

No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01804634     History of Changes
Other Study ID Numbers: J12106
Study First Received: March 1, 2013
Last Updated: March 18, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
Solid Tumors
Neuroblastoma
Osteosarcoma
Ewing Sarcoma
Rhabdomyosarcoma
Hepatoblastoma
Melanoma
Desmoplastic Round Cell Tumor
brain tumors

Additional relevant MeSH terms:
Neoplasms
Cyclophosphamide
Melphalan
Sirolimus
Alkylating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014