Organ-Sparing Marrow-Targeted Irradiation Before Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

Sponsor
Ohio State University Comprehensive Cancer Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT02122081
Collaborator
(none)
45
1
1
89.2
0.5

Study Details

Study Description

Brief Summary

This pilot clinical trial aims to assess feasibility and tolerability of using an LINAC based "organ-sparing marrow-targeted irradiation" to condition patients with high-risk hematological malignancies who are otherwise ineligible to undergo myeloablative Total body irradiation (TBI)-based conditioning prior to allogeneic stem cell transplant. The target patient populations are those with ALL, AML, MDS who are either elderly (>50 years of age) but healthy, or younger patients with worse medical comorbidities (HCT-Specific Comorbidity Index Score (HCT-CI) > 4). The goal is to have the patients benefit from potentially more efficacious myeloablative radiation based conditioning approach without the side effects associated with TBI.

Detailed Description

PRIMARY OBJECTIVES:
  1. To assess feasibility and tolerability of OSMI based hematopoietic stem cell transplant (HSCT) as defined by transplant-related mortality (TRM) at day 30 as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days.
SECONDARY OBJECTIVES:
  1. Day 100 transplant-related mortality (TRM). II. Donor chimerism assessment at day 100 (to assess failure of engraftment rate).

  2. Incidence of acute graft-versus-host disease (aGVHD) by day 100. IV. Incidence of chronic GVHD at one year. V. Cumulative incidence of grade II organ toxicity through day 100.

  3. Rate and kinetics of hematopoietic recovery. VII. Incidence of graft failure (primary and secondary). VIII. Rate of infectious complications. IX. Cumulative incidence of relapse, overall survival, and progression-free survival at 1 year.

OUTLINE:

CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation twice daily (BID) on days -6 to -4 and receive cyclophosphamide intravenously (IV) over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV or orally (PO) beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.

TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.

After completion of study treatment, patients are followed up weekly for 12 weeks, at day 100, and then at 6 and 12 months.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
45 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Feasibility Study of Organ-Sparing Marrow-Targeted Irradiation (OSMI) to Condition Patients With High-Risk Hematologic Malignancies Prior to Allogeneic Hematopoietic Stem Cell Transplantation
Actual Study Start Date :
Jul 27, 2015
Anticipated Primary Completion Date :
Dec 31, 2022
Anticipated Study Completion Date :
Dec 31, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (OSMI, allogeneic transplant)

CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2. GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11. TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.

Radiation: radiation therapy
Undergo organ-sparing marrow irradiation BID on days -6 to -4
Other Names:
  • irradiation
  • radiotherapy
  • therapy, radiation
  • Drug: cyclophosphamide
    Given IV over 1-2 hours every 24 hours on days -3 to -2.
    Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
  • Biological: anti-thymocyte globulin
    Other Names:
  • ATG
  • ATGAM
  • lymphocyte immune globulin
  • Thymoglobulin
  • Drug: tacrolimus
    Given IV or PO
    Other Names:
  • FK 506
  • Prograf
  • Drug: methotrexate
    Given IV
    Other Names:
  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
  • Procedure: allogeneic bone marrow transplantation
    Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0
    Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
  • Procedure: allogeneic hematopoietic stem cell transplantation
    Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant

    Procedure: peripheral blood stem cell transplantation
    Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant
    Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
  • Other: laboratory biomarker analysis
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. TRM, defined as death occurring in a patient from causes other than disease relapse [At day 30 post-transplant]

      Proportions will be derived for incidence of TRM divided by all evaluable patients along with corresponding 95% binomial confidence intervals.

    2. Rate of grade II/III organ toxicity, defined by the Bearman Regimen-Related Toxicities Scale [Up to 30 days]

      Toxicities will be tabulated by grade for each cohort, by type of toxicity, as well as the maximum grade overall. Toxicity frequencies will be described for the day +30, day +100, and one year time intervals as well as cumulative over time. Proportions will be derived for incidence of grade II/III organ toxicity divided by all evaluable patients along with corresponding 95% binomial confidence intervals.

    Secondary Outcome Measures

    1. TRM [Day 100 post-transplant]

      Proportions will be derived for incidence of toxicity divided by all evaluable patients along with corresponding 95% binomial confidence intervals.

    2. Donor chimerism [Day 100]

      Donor chimerism is used to assess failure of engraftment rate.

    3. Incidence of aGVHD, graded according to Ohio State University Bone Marrow Transplant (OSU BMT) Program policy [Up to day 100]

      The first day of aGVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade.

    4. Incidence of chronic GVHD, scored according to the OSU BMT Program policy [At 1 year]

      The first day of chronic GVHD onset will be used to calculate cumulative incidence curves. Rates and severity of chronic GHVD will be calculated.

    5. Cumulative incidence of grade II organ toxicity [Up to day 100]

      Toxicity will be tabulated by grade for each cohort, by type of toxicity as well as the maximum grade overall.

    6. Incidence of hematopoietic recovery [Up to day 100]

      The rate and kinetics of hematopoietic recovery will be assessed. The kinetics of post-transplant recovery of both neutrophil and platelet engraftment will be assessed.

    7. Incidence of graft failure [Up to 1 year post-transplant]

      Primary graft failure (defined by the lack of neutrophil engraftment by 28 days) and secondary graft failure (defined by initial neutrophil engraftment followed by subsequent decline in neutrophil counts < 500/uL unresponsive to growth factor therapy) will be assessed on days 30 and 100 and at 1 year post-transplant.

    8. Rate of infectious complications [Up to 12 months]

      The number of infections and the number of patients experiencing infections will be tabulated by type of infection, severity, and time period after transplant. The cumulative incidence of severe, life-threatening, or fatal infections will be tabulated.

    9. Incidence of relapse [Time from start of conditioning to relapse, assessed at 1 year]

    10. Overall survival [Time from start of conditioning to death, loss to follow up, or end of study, whichever comes first, assessed at 1 year]

    11. Progression-free survival [Time from start of conditioning to relapse, progression, death, initiation of non-protocol therapy, loss to follow up or end of study, whichever comes first, assessed at 1 year]

      Patients are considered a failure of this endpoint if they die or suffer from disease relapse or progression.

    12. Immune reconstitution [Up to 12 months post transplant]

      Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19, and CD56 positive lymphocytes will be done throw flow cytometric analysis at baseline, 100 days, and 12 months post transplantation.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients with a diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndromes (MDS) with fewer than 10% myeloblasts or lymphoblasts in the bone marrow and no blasts in the peripheral blood on morphologic analysis performed within 30 days of start of the conditioning regimen; if remission bone marrow is available beyond 30 days a new bone marrow evaluation is required to assess remission status

    • The diagnosis of AML, ALL, or MDS will be based on World Health Organization (WHO) criteria

    • Pre-transplant bone marrow sample must be evaluable for assessment of remission status (i.e. aspirate smear containing particles and/or evaluable bone marrow core biopsy)

    • Patients with leukemia infiltration in the central nervous system (CNS) are eligible if cerebrospinal fluid (CSF) cytospin is negative for myeloblasts or lymphoblasts at time of enrollment

    • If the patient has an intra-abdominal chloroma on presentation, and has a partial response or complete response to treatment (size reduction of chloroma and marrow blast < 10%), the patient is eligible; however the chloroma must be included as part of the treatment target

    • For patients receiving treatment of their AML, MDS or ALL prior to transplantation:

    • Interval between the start of a cycle of conventional cytotoxic chemotherapy and the start of conditioning regimen must be at least 30 days

    • Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and the start of conditioning regimen must be at least 10 days

    • Hematopoietic Cell Transplantation-Specific Comorbidity Index score (HCT-CI) =< 4 for patients in Cohort 1 and > 4 for Cohort 2

    • Patient must be able to lie still in full body cast for 45 minutes

    • Must have a suitable donor defined as a sibling matched at 5/6 or 6/6 antigens (human leukocyte antigen [HLA]-A, B, and DRB1) or an unrelated volunteer matched at 7/8 or 8/8 HLA alleles (HLA-A, B, C, and DRB1)

    • Signed informed consent

    • DONOR: "High resolution" typing at HLA-A, B, C and DRB1 alleles

    • Single antigen mismatch for siblings and single allele mismatch for volunteer unrelated donors is acceptable

    • Donors must be >= 17 years of age

    Exclusion Criteria:
    • Circulating peripheral blood myeloblasts or lymphoblasts on morphologic analysis from time of last treatment to time of enrollment

    • Prior allograft or prior autograft

    • Active CNS disease as identified by positive CSF cytospin at time of enrollment

    • Karnofsky performance score < 70

    • Symptomatic uncontrolled coronary artery disease or ejection fraction < 40%

    • Total bilirubin >= 2 x the upper limit of normal

    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >= 3 x the upper limit of normal

    • Diffusion capacity of the lung for carbon monoxide (DLCO) < 40%

    • Forced expiratory volume in one second (FEV1) < 50% (corrected for hemoglobin)

    • Receiving supplementary continuous oxygen

    • Creatinine clearance < 50 mL/min/1.73m^2

    • Patients with active uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms)

    • Patients seropositive for the human immunodeficiency virus (HIV)

    • Females who are pregnant or breastfeeding

    • Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment

    • Patients who had prior radiation to more than 20% bone marrow containing areas or to any areas exceeding 2000 cGy

    • DONOR:

    • Donors will be excluded if they are an identical twin of the recipient

    • Females who are pregnant (positive serum beta human chorionic gonadotropin beta [β HCG]) or uninterruptible breastfeeding

    • HIV seropositive

    • Donors receiving experimental therapy or investigational agents unless approved by the protocol chair

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center Columbus Ohio United States 43210

    Sponsors and Collaborators

    • Ohio State University Comprehensive Cancer Center

    Investigators

    • Principal Investigator: Meng Welliver, MD, Ohio State University Comprehensive Cancer Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Meng Welliver, Principal Investigator, Ohio State University Comprehensive Cancer Center
    ClinicalTrials.gov Identifier:
    NCT02122081
    Other Study ID Numbers:
    • OSU-13219
    • NCI-2014-00763
    First Posted:
    Apr 24, 2014
    Last Update Posted:
    Feb 14, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    Yes
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Feb 14, 2022