Clinical Trials /

Total Marrow and Lymphoid Irradiation as Conditioning Regimen Before Hematopoietic Cell Transplantation in Patients With Myelodysplastic Syndrome or Acute Leukemia

NCT04262843

Description:

This phase II trial studies how well total marrow and lymphoid irradiation works as a conditioning regimen before hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute leukemia. Total body irradiation can lower the relapse rate but has some fatal side effects such as irreversible damage to normal internal organs and graft-versus-host disease (a complication after transplantation in which donor's immune cells recognize the host as foreign and attack the recipient's tissues). Total body irradiation is a form of radiotherapy that involves irradiating the patient's entire body in an attempt to suppress the immune system, prevent rejection of the transplanted bone marrow and/or stem cells and to wipe out any remaining cancer cells. Intensity-modulated radiation therapy (IMRT) is a more recently developed method of delivering radiation. Total marrow and lymphoid irradiation is a method of using IMRT to direct radiation to the bone marrow. Total marrow and lymphoid irradiation may allow a greater dose of radiation to be delivered to the bone marrow as a preparative regimen before hematopoietic cell transplant while causing less side effects to normal organs than standard total body irradiation.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Total Marrow and Lymphoid Irradiation as Conditioning Regimen Before Hematopoietic Cell Transplantation in Patients With Myelodysplastic Syndrome or Acute Leukemia
  • Official Title: Phase II Study of Evaluating the Efficacy of Total Marrow and Lymphoid Irradiation (TMLI) as the Conditioning Regimen for HLA-Haploidentical Hematopoietic Cell Transplantation in Patients With Myelodysplasia or Acute Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 19518
  • SECONDARY ID: NCI-2019-08984
  • SECONDARY ID: 19518
  • NCT ID: NCT04262843

Conditions

  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • High Risk Myelodysplastic Syndrome
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (fludarabine, TMLI, HCT, cyclophosphamide)
FludarabineFluradosaTreatment (fludarabine, TMLI, HCT, cyclophosphamide)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (fludarabine, TMLI, HCT, cyclophosphamide)
Granulocyte Colony-Stimulating FactorColony Stimulating Factor 3, Colony-Stimulating Factor (Granulocyte), Colony-Stimulating Factor 3, CSF3, G CSF, G-CSF, Granulocyte Colony Stimulating Factor, PluripoietinTreatment (fludarabine, TMLI, HCT, cyclophosphamide)
Mycophenolate MofetilCellcept, MMFTreatment (fludarabine, TMLI, HCT, cyclophosphamide)
TacrolimusFK 506, Fujimycin, Hecoria, Prograf, ProtopicTreatment (fludarabine, TMLI, HCT, cyclophosphamide)

Purpose

This phase II trial studies how well total marrow and lymphoid irradiation works as a conditioning regimen before hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute leukemia. Total body irradiation can lower the relapse rate but has some fatal side effects such as irreversible damage to normal internal organs and graft-versus-host disease (a complication after transplantation in which donor's immune cells recognize the host as foreign and attack the recipient's tissues). Total body irradiation is a form of radiotherapy that involves irradiating the patient's entire body in an attempt to suppress the immune system, prevent rejection of the transplanted bone marrow and/or stem cells and to wipe out any remaining cancer cells. Intensity-modulated radiation therapy (IMRT) is a more recently developed method of delivering radiation. Total marrow and lymphoid irradiation is a method of using IMRT to direct radiation to the bone marrow. Total marrow and lymphoid irradiation may allow a greater dose of radiation to be delivered to the bone marrow as a preparative regimen before hematopoietic cell transplant while causing less side effects to normal organs than standard total body irradiation.

Detailed Description

      PRIMARY OBJECTIVE:

      I. Evaluate the efficacy of the haploidentical hematopoietic cell transplantation (haploHCT)
      total marrow and lymphoid organ irradiation (TMLI), with high dose post-transplant
      cyclophosphamide (PTCy) as graft-versus host disease (GvHD) prophylaxis, as assessed by
      1-year graft versus (vs) host disease-free relapse-free survival (GRFS) rate in each arm (Arm
      A: patients with acute myeloid leukemia [AML] or myelodysplastic syndrome [MDS] and Arm B:
      Patients with acute lymphoblastic leukemia [ALL]).

      SECONDARY OBJECTIVES:

      I. Estimate overall survival (OS), cumulative incidences of relapse/disease progression, and
      non-relapse mortality (NRM) in each arm at 100 days, and 1 year post-transplant.

      II. Estimate rate of relapse and non-relapse mortality (NRM) at 1 year post-transplant.

      III. Estimate rates of acute and chronic GvHD, infections, complete remission and neutrophil
      recovery.

      IV. Describe and characterize cytokine release syndrome (CRS) post-haploidentical HCT with
      TMLI as conditioning regimen and PTCy as GvHD prophylaxis as assessed by incidence, frequency
      and severity.

      V. Further evaluate the safety of this regimen by assessing:

      Va. Adverse events: type, frequency, severity, attribution, time course, duration.

      Vb. Complications: including acute/chronic GVHD, infection and delayed engraftment.

      EXPLORATORY OBJECTIVES:

      I. Characterize minimal residual disease from bone marrow aspirates and investigate the
      possible association between TMLI-based regimen and patient's disease status.

      II. Describe the kinetics of immune cell recovery. III. Describe the kinetics of serum
      pro-inflammatory cytokines and GvHD biomarkers.

      IV. Longitudinal and spatial assessment of TMLI effect on bone marrow environment.

      V. Cellular and molecular assessment of TMLI effect on bone marrow environment and TMLI
      effect on the engraftment and disease relapse.

      OUTLINE:

      CONDITIONING: Patients receive fludarabine intravenously (IV) once daily (QD) on days -7 to
      -5, and undergo TMLI twice daily (BID) on days -4 to 0 in the absence of disease progression
      or unacceptable toxicity.

      TRANSPLANT: Patients undergo hematopoietic cell transplantation on day 0.

      GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV QD on days 3-4 in the absence of
      disease progression or unacceptable toxicity. Beginning on day 5, patients also receive
      granulocyte colony stimulating factor and tacrolimus/mycophenolate mofetil per institutional
      standard.

      After completion of study treatment, patients are followed up twice weekly for the first 100
      days post-transplant, twice monthly until 6 months post-transplant, monthly until patient
      discontinues immunosuppressive therapy, and then yearly for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (fludarabine, TMLI, HCT, cyclophosphamide)ExperimentalCONDITIONING: Patients receive fludarabine IV QD on days -7 to -5, and undergo TMLI BID on days -4 to 0 in the absence of disease progression or unacceptable toxicity. TRANSPLANT: Patients undergo hematopoietic cell transplantation on day 0. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV QD on days 3-4 in the absence of disease progression or unacceptable toxicity. Beginning on day 5, patients also receive granulocyte colony stimulating factor and tacrolimus/mycophenolate mofetil per institutional standard.
  • Cyclophosphamide
  • Fludarabine
  • Fludarabine Phosphate
  • Granulocyte Colony-Stimulating Factor
  • Mycophenolate Mofetil
  • Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Documented informed consent of the participant and/or legally authorized
             representative

          -  Karnofsky performance status >= 70

          -  Histologically confirmed diagnosis of one the following:

               -  Patients with acute myelogenous leukemia

                    -  In first complete remission (CR1) with intermediate or poor risk
                       cytogenetics according to National Comprehensive Cancer Network (NCCN)
                       guidelines for acute myeloid leukemia (AML) or European LeukemiaNet (ELN)
                       2017

                    -  In second complete remission (CR2) or third complete remission (CR3)

                    -  Patients with chemosensitive active disease

               -  Patients with acute lymphocytic leukemia

                    -  In CR1 with poor risk cytogenetics:

               -  For adults according to NCCN guidelines for acute lymphoblastic leukemia (ALL):
                  Patients older than 40 year of age; with high white blood cell count (WBC) at
                  diagnosis (>= 30,000 for B lineage or >= 50,000 for T lineage), or with high risk
                  cytogenetics including: hypoploidy (< 44 chromosomes); t(v;11q23): MLL
                  rearranged; t(9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal
                  abnormalities)

               -  For pediatrics t(9;22), iAMP21loss of 13q, and abnormal 17p

                    -  In CR2 or CR3

                    -  Patients with chemosensitive active disease

               -  Myelodysplastic syndrome in high-intermediate (int-2) and high risk categories by
                  International Prognostic Scoring System (IPSS) or revised (R)-IPSS

          -  Total bilirubin =< 2 X upper limit of normal (ULN) (unless has Gilbert's disease) (to
             be performed within 28 days prior to day 1 of protocol therapy unless otherwise
             stated)

          -  Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault
             formula (to be performed within 28 days prior to day 1 of protocol therapy unless
             otherwise stated)

          -  Ejection fraction measured by echocardiogram or multigated acquisition scan (MUGA) >=
             50% (to be performed within 28 days prior to day 1 of protocol therapy unless
             otherwise stated)

               -  Note: To be performed within 28 days prior to day 1 of protocol therapy

          -  If able to perform pulmonary function tests: forced expiratory volume in 1 second
             (FEV1), forced vital capacity (FVC) and carbon monoxide diffusing capability test
             (DLCO) (diffusion capacity) >= 50% of predicted (corrected for hemoglobin). If unable
             to perform pulmonary function tests: oxygen (O2) saturation > 92% on room air

               -  Note: To be performed within 28 days prior to day 1 of protocol therapy

          -  Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo,
             hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative),
             and syphilis (rapid plasma reagin [RPR]) (to be performed within 28 days prior to day
             1 of protocol therapy unless otherwise stated)

               -  If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed

          -  Meets other institutional and federal requirements for infectious disease titer
             requirements

               -  Note: Infectious disease testing to be performed within 28 days prior to Day 1 of
                  protocol therapy

          -  Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

               -  If the urine test is positive or cannot be confirmed as negative, a serum
                  pregnancy test will be required

          -  Agreement by females and males of childbearing potential* to use an effective method
             of birth control or abstain from heterosexual activity for the course of the study
             through at least 6 months after the last dose of protocol therapy

               -  Childbearing potential defined as not being surgically sterilized (men and women)
                  or have not been free from menses for > 1 year (women only)

          -  The recipient must have a related donor genotypically human leukocyte antigen (HLA)-A,
             B,C and DRB1 loci haploidentical to the recipient

          -  No HLA matched sibling or matched unrelated donor is available

          -  Patients should be off all previous intensive therapy, chemotherapy or radiotherapy
             for 3 weeks prior to commencing therapy on this study

               -  (NOTE: Low dose chemotherapy or maintenance chemotherapy given within 7 days of
                  planned study enrollment is permitted. These include: Hydroxyurea,
                  6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine
                  kinase inhibitors [TKIs]. FLT-3 inhibitors such as sorafenib, crenolanib,
                  midostaurin can also be given up to 3 days before conditioning regimen.)

          -  DONOR: The donor must be examined and have specific tests performed according to
             existing institutional guidelines to evaluate his/her candidacy as a donor including
             the following:

          -  DONOR: Age =< 60 years of age

          -  DONOR: For younger donors, no more than 20 mL bone marrow may be harvested per kg of
             donor body weight

          -  DONOR: Medical history and physical examination confirm good health status as defined
             by institutional standards

          -  DONOR: Seronegative for HIV Ag, HIV 1+2 Ab, HTLV I/II Ab, hepatitis B surface antigen
             (HBsAg), hepatitis B core antibody (HBcAb) (IgM and IgG), HCV Ab, RPR for syphilis
             within 30 days of apheresis collection

          -  DONOR: Genotypically haploidentical as determined by HLA typing, preferably a
             nonmaternal HLA haploidentical relative due to data of high incidence of graft failure
             with use of maternal HLA haploidentical cells. Eligible donors include biological
             parents, siblings or half siblings, or children

          -  DONOR: Female donors of child-bearing potential must have a negative serum or urine
             beta-human chorionic gonadotropin (HCG) test within seven days of mobilization

          -  DONOR: The donor must have been informed of the investigational nature of this study
             and have signed a consent form in accordance with Federal Guidelines and the
             guidelines of the participating institution

          -  DONOR: Selection of a haploidentical donor will require absence of pre-existing
             donor-directed anti-HLA antibodies in the recipient

        Exclusion Criteria:

          -  Patients should not have any uncontrolled illness including ongoing or active
             bacterial, viral or fungal infection

          -  Patient may not be receiving any other investigational agents or concurrent
             biological, intensive chemotherapy or radiation therapy for the previous three weeks
             from conditioning

               -  (NOTE: Low dose chemotherapy or maintenance chemotherapy given within 7 days of
                  planned study enrollment is permitted. These include: Hydroxyurea,
                  6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine
                  kinase inhibitors [TKIs]. FLT-3 inhibitors such as sorafenib, crenolanib,
                  midostaurin can also be given up to 3 days before conditioning regimen.)

          -  Herbal medications dependency

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to study agent

          -  No intercurrent illness or other malignancy (other than non-melanoma skin cancer)

          -  Active infection requiring antibiotics

          -  Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection

          -  Females only: Pregnant or breastfeeding

          -  Any other condition that would, in the investigator's judgment, contraindicate the
             patient's participation in the clinical study due to safety concerns with clinical
             study procedures

          -  Patients who had a prior autologous or allogeneic transplant

          -  Patients who had prior radiation therapy of more than 20% of bone marrow containing
             areas or to any area exceeding 2000 cGy

          -  Patients with HLA-matched or partially matched (7/8 or 8/8) related or fully matched
             unrelated donor available to donate

          -  Patients who have received more than 3 prior regimens, where the regimen intent was to
             induce remission

          -  Patients with treatment history including anti-CD33 monoclonal antibody therapy (e.g.,
             SGN-CD33 or Mylotarg)

          -  Prospective participants who, in the opinion of the investigator, may not be able to
             comply with all study procedures (including compliance issues related to
             feasibility/logistics)

          -  DONOR: Evidence of active infection

          -  DONOR: Medical or physical reason which makes the donor unlikely to tolerate or
             cooperate with growth factor therapy and leukapheresis

          -  DONOR: Factors which place the donor at increased risk for complications from
             leukapheresis or granulocyte colony-stimulating factor (G-CSF) therapy

          -  DONOR: HIV positive
      
Maximum Eligible Age:60 Years
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to day 100
Safety Issue:
Description:Evaluated using the Bearman scale and National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:Time from start of protocol therapy to death from any cause, or last follow-up, whichever comes first, assessed up to 2 years post-transplant
Safety Issue:
Description:
Measure:Relapse-free survival
Time Frame:Time from the start of protocol therapy to the date of death, disease relapse, or last follow-up, whichever comes first, assessed up to 2 years post-transplant.]
Safety Issue:
Description:
Measure:Time to relapse/progression
Time Frame:Time from the start of protocol therapy to death, disease relapse or progression, or last follow-up, whichever comes first, assessed up to 2 years post-transplant
Safety Issue:
Description:
Measure:Non-relapse mortality
Time Frame:Time from start of therapy until non-disease related death, or last follow-up, whichever comes first, assessed up to 2 years post-transplant
Safety Issue:
Description:
Measure:Incidence of adverse events that meet grade 3, 4, or 5 per CTCAE version 5.0
Time Frame:From day -9 to day -1, from day 0 to day 30, and day 31 to day 100 post-transplant
Safety Issue:
Description:
Measure:Incidence of acute GvHD of grades 2-4 and 3-4
Time Frame:From date of stem cell infusion to documented/biopsy proven acute GVHD onset date (within the first 100 days post-transplant)
Safety Issue:
Description:
Measure:Incidence of chronic GvHD
Time Frame:From approximately 80-100 days post-transplant to the documented/biopsy proven chronic GvHD onset date
Safety Issue:
Description:
Measure:Incidence of infection
Time Frame:From day 0 to day 100 post-transplant
Safety Issue:
Description:
Measure:Complete remission proportion
Time Frame:At day 30
Safety Issue:
Description:
Measure:Rate of neutrophil recovery
Time Frame:Up to 2 years
Safety Issue:
Description:Measured from stem cell infusion to the first to three consecutive days with neutrophil count greater than 0.5 x 10^9/l.
Measure:Incidence of cytokine release syndrome
Time Frame:Up to 2 years
Safety Issue:
Description:Defined and graded per American Society for Transplantation and Cellular Therapy (ASTCT) criteria.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

February 7, 2020