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

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Brief Title

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

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

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:

      I. 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:

      I. Day 100 transplant-related mortality (TRM). II. Donor chimerism assessment at day 100 (to
      assess failure of engraftment rate).

      III. 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.
      VI. 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 Type

Interventional


Primary Outcome

TRM, defined as death occurring in a patient from causes other than disease relapse

Secondary Outcome

 TRM

Condition

Adult Acute Lymphoblastic Leukemia in Remission

Intervention

radiation therapy

Study Arms / Comparison Groups

 Treatment (OSMI, allogeneic transplant)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Radiation

Estimated Enrollment

45

Start Date

June 4, 2015

Completion Date

December 31, 2019

Primary Completion Date

December 31, 2019

Eligibility Criteria

        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
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Meng Welliver, MD, 1-800-293-5066, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02122081

Organization ID

OSU-13219

Secondary IDs

NCI-2014-00763

Responsible Party

Principal Investigator

Study Sponsor

Ohio State University Comprehensive Cancer Center


Study Sponsor

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


Verification Date

March 2019