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Reduced Intensity Haploidentical BMT for High Risk Solid Tumors

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ClinicalTrials.gov Identifier: NCT01804634
Recruitment Status : Recruiting
First Posted : March 5, 2013
Last Update Posted : April 30, 2019
Sponsor:
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 shortened duration tacrolimus is safe and feasible for patients with very high-risk solid 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: Tacrolimus Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 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) Related Donor Bone Marrow Transplantation for High-risk Solid Tumors
Actual Study Start Date : March 27, 2013
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: Reduced intensity conditioning
Fludarabine IV infusion over 30 minutes on D-7 to D-3. The dose will be 30 mg/m2/dose (adjusted for renal function). Melphalan: IV infusion over 30-60 minutes, depending on volume, on D-2. The dose will be 100mg/m2.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. Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on Day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours. Mycophenolic acid mofetil (MMF) F 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).
Drug: Cyclophosphamide
preparative regimen
Other Name: cytoxan

Drug: Fludarabine
Other Name: Flu

Radiation: low dose total body irradiation
Other Name: TBI

Drug: Melphalan
Other Name: Mel

Drug: Tacrolimus
Other Name: tacro




Primary Outcome Measures :
  1. Safety of Shortened duration of tacrolimus as assessed by number of participants with NRM and Grade III-IV acute GVHD [ Time Frame: up to 120 Days ]
    Safety of shortened duration immunosuppression assessed by the number of participants with non-relapse mortality (NRM) and grade III-IV acute graft versus host disease (Przepiorka criteria stages the degree of organ involvement in the skin, liver and gastrointestinal (GI) tract, based on severity, with Stage 1+ being least sever and Stage 4+ being most severe. Grading of acute GVHD is as follows: Grade I (skin involvement stages 1+ to 2+, with no liver or GI involvement), Grade II (skin involvement stages 1+ to 3+, liver 1+, GI tract 1+), Grade III (skin involvement stages 2+ to 3+, liver 1+, GI tract 2+ to 4+), Grade IV (skin involvement stages 4+, liver 4+))


Secondary Outcome Measures :
  1. Overall survival at 6 months [ Time Frame: 6 months ]
    Overall survival in patients receiving reduced intensity conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow.

  2. Overall survival at 1 year [ Time Frame: 1 year ]
    Overall survival in patients receiving reduced intensity conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow.

  3. Relapse [ Time Frame: up to 2 years ]
    Cumulative incidence by competing risks analysis of relapse in patients receiving reduced intensity conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow.

  4. Non-Relapse Mortality [ Time Frame: up to 2 years ]
    Time from start of intervention to death without relapse in patients receiving reduced intensity conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow.

  5. Event-free survival at 6 months [ Time Frame: 6 months ]
    Number of months from start of intervention until first adverse event as defined as relapse/disease progression or death by CTCAE v5.0 in participants receiving reduced intensity conditioning haploBMT

  6. Event-free survival at 1 year [ Time Frame: 1 year ]
    Number of months from start of intervention until first adverse event as defined as relapse/disease progression or death by CTCAE v5.0 in participants receiving reduced intensity conditioning haploBMT

  7. progression-free survival at 6 months [ Time Frame: 6 months ]
    Number of months alive without progression in patients receiving reduced intensity conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow.

  8. progression-free survival at 1 year [ Time Frame: 1 year ]
    Number of months alive without progression (as defined by RECIST, Any new lesion or increase of a measurable lesion by >25%; previous negative marrow positive for tumor. ** MIBG scan must be negative for patient to be classified as having a complete response. New site of disease documented by MIBG scan qualifies patient as having progressive disease.) in patients receiving reduced intensity conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow.

  9. engraftment [ Time Frame: day 60 ]
    % of patients achieving donor bone marrow chimerism >/= 95% at Day 60

  10. acute GVHD [ Time Frame: 30-180 ]
    To determine the cumulative incidence by competing risks analysis of acute GVHD as defined by Przepiorka criteria stages the degree of organ involvement in the skin, liver and gastrointestinal (GI) tract, based on severity, with Stage 1+ being least sever and Stage 4+ being most severe. Grading of acute GVHD is as follows: Grade I (skin involvement stages 1+ to 2+, with no liver or GI involvement), Grade II (skin involvement stages 1+ to 3+, liver 1+, GI tract 1+), Grade III (skin involvement stages 2+ to 3+, liver 1+, GI tract 2+ to 4+), Grade IV (skin involvement stages 4+, liver 4+)

  11. chronic GVHD [ Time Frame: 75days -1year ]
    To determine the cumulative incidence by competing risks analysis of chronic GVHD as defined by the NIH Consensus criteria


Other Outcome Measures:
  1. Document toxicities [ Time Frame: 30-180 days ]
    To document any unexpected toxicities after RIC haploidentical BMT.

  2. To compare the tumor microenvironment, circulating tumor cells, and expression of MHC antigens as well as tumor specific antigens pre- and post BMT [ Time Frame: 30days-180 days ]
    To compare the tumor microenvironment, circulating tumor cells, and expression of MHC antigens as well as tumor specific antigens pre- and post BMT

  3. To document the incidence of significant viral, bacterial and fungal infections [ Time Frame: 0-180 days ]
    To document the incidence of significant viral, bacterial and fungal infections as defined by the NCI's Common Terminology Criteria for Adverse Events (CTCAE) as well as the fungal criteria (proven and probable)



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Ages Eligible for Study:   1 Year to 50 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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 ClinicalTrials.gov identifier (NCT number): NCT01804634


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

Locations
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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 at Johns Hopkins
Investigators
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Principal Investigator: Heather Symons, MD, MHS Johns Hopkins University

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT01804634     History of Changes
Other Study ID Numbers: J12106
NA_00076243 ( Other Identifier: JHM IRB )
First Posted: March 5, 2013    Key Record Dates
Last Update Posted: April 30, 2019
Last Verified: April 2019
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
Solid Tumors
Neuroblastoma
Osteosarcoma
Ewing Sarcoma
Rhabdomyosarcoma
Hepatoblastoma
Desmoplastic Round Cell Tumor
Additional relevant MeSH terms:
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Neoplasms
Cyclophosphamide
Melphalan
Fludarabine
Fludarabine phosphate
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Calcineurin Inhibitors
Enzyme Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites