Clinical Trials /

Combination Chemotherapy, Total Body Irradiation, and Donor Blood Stem Cell Transplant in Treating Patients With Primary or Secondary Myelofibrosis

NCT03426969

Description:

This early phase I trial studies the side effects of combination chemotherapy, total body irradiation, and donor blood stem cell transplant in treating patients with primary or secondary myelofibrosis. Drugs used in chemotherapy, such as melphalan, fludarabine phosphate, cyclophosphamide, tacrolimus, mycophenolate mofetil, and filgrastim work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving combination chemotherapy and total body irradiation before a donor blood stem cell transplant helps to stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Related Conditions:
  • Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy, Total Body Irradiation, and Donor Blood Stem Cell Transplant in Treating Participants With Primary or Secondary Myelofibrosis
  • Official Title: A Pilot Study of Reduced Intensity HLA-Haploidentical Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide in Patients With Advanced Myelofibrosis

Clinical Trial IDs

  • ORG STUDY ID: 2017-0375
  • SECONDARY ID: NCI-2018-00910
  • SECONDARY ID: 2017-0375
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03426969

Conditions

  • Hematopoietic Cell Transplantation Recipient
  • Primary Myelofibrosis
  • Secondary Myelofibrosis

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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (combination chemotherapy, TBI, HCT)
FilgrastimFILGRASTIM, LICENSE HOLDER UNSPECIFIED, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, TevagrastimTreatment (combination chemotherapy, TBI, HCT)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (combination chemotherapy, TBI, HCT)
MelphalanAlanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine nitrogen mustard, Sarcoclorin, Sarkolysin, WR-19813Treatment (combination chemotherapy, TBI, HCT)
Mycophenolate MofetilCellcept, MMFTreatment (combination chemotherapy, TBI, HCT)
TacrolimusFK 506, Fujimycin, Hecoria, Prograf, ProtopicTreatment (combination chemotherapy, TBI, HCT)

Purpose

This early phase I trial studies the side effects of combination chemotherapy, total body irradiation, and donor blood stem cell transplant in treating participants with primary or secondary myelofibrosis. Drugs used in chemotherapy, such as melphalan, fludarabine phosphate, cyclophosphamide, tacrolimus, mycophenolate mofetil, and filgrastim work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving combination chemotherapy and total body irradiation before a donor blood stem cell transplant helps to stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of reduced-intensity (FM) haploidentical
      hematopoietic cell transplantation (Haplo-HCT) followed by post-transplant cyclophosphamide
      (PTCy) in patients with advanced myelofibrosis (MF), as assessed by the evaluation of
      toxicities, including type, frequency, severity, attribution, time course and duration.

      SECONDARY OBJECTIVES:

      I. To summarize and evaluate hematologic (neutrophil and platelet) recovery. II. To estimate
      graft failure-free survival (GFS) at 100-days post-transplant. III. To estimate overall
      survival (OS), progression-free survival (PFS) and cumulative incidence (CI) of
      relapse/progression, and non-relapse mortality (NRM) at 100-days, 1-year, and 2-year post
      transplant.

      IV. To estimate the cumulative incidence of acute graft-versus-host disease (GvHD), grade
      II-IV, at 100-days post-transplant (per Keystone Consensus modification of the Glucksberg
      criteria).

      V. To estimate the cumulative incidence of chronic GvHD at 1-year and 2-year post transplant
      (per National Institute of Health [NIH] Consensus Criteria).

      VI. To characterize the severity and extent of acute and chronic GvHD.

      OUTLINE:

      Participants receive melphalan intravenously (IV) over 30 minutes on days -5, fludarabine
      phosphate IV over 1 hour on days -5 to -2. Participants undergo total body irradiation (TBI)
      on day -1 and hematopoietic stem cell transplant (HCT) on day 0. Participants then receive
      cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning on day 5, participants receive
      tacrolimus IV continuously for approximately 2 weeks, then orally (PO) for 6 months followed
      by a taper, mycophenolate mofetil PO thrice daily (TID) until day 100, and filgrastim
      subcutaneously (SC) daily from day 7 until continued until absolute neutrophil count (ANC) >
      1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression
      or unexpected toxicity.

      After completion of study treatment, participants are followed up at 1, 3, 6, 9, 12 and 24
      months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (combination chemotherapy, TBI, HCT)ExperimentalParticipants receive melphalan IV over 30 minutes on days -5, fludarabine phosphate IV over 1 hour on days -5 to -2. Participants undergo TBI on day -1 and HCT on day 0. Participants then receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning on day 5, participants receive tacrolimus IV continuously for approximately 2 weeks, then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 100, and filgrastim SC daily from day 7 until continued until ANC > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
  • Cyclophosphamide
  • Filgrastim
  • Fludarabine Phosphate
  • Melphalan
  • Mycophenolate Mofetil
  • Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of primary or secondary myelofibrosis with transplant indication by Dynamic
             International Prognostic Scoring System (DIPSS)-plus (> intermediate -1)

          -  Age 18-70; patients >= age 50 must have an comorbidity score (hematopoietic cell
             transplant-comorbidity index [HCT-CI]) =< 4 (Sorror). The principal investigator is
             the final arbiter for comorbidity;

          -  Patients can be in chronic phase (CP) with bone marrow (BM) blast count =< 10% or
             after progression to acute myeloid leukemia (AML) and achieved =< 5% BM blasts
             (morphologic complete remission [CR] prior to transplant);

          -  Lack of a human leukocyte antigen (HLA) matched donor or need to proceed fast to
             transplantation when a patient does not have an immediately available matched
             unrelated donor (typed by high-resolution in the registry);

          -  Performance status >= 70% (Karnofsky); patients > 50 years should have adequate
             cognitive function; any concerns regarding cognitive function should be addressed by a
             geriatrician/neurologist;

          -  Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 5X upper limit of
             normal (UNL);

          -  Bilirubin =< 5X UNL;

          -  Creatinine clearance > 50mls/min (calculated with Cockcroft-Gault formula);

          -  Left ventricular ejection fraction (LVEF) >= 50%;

          -  Corrected diffusion capacity of the lung for carbon monoxide (DLCOc) >= 50%;

          -  Prior treatment with JAK2 inhibitor therapy is not excluded. Patients on a JAK2
             inhibitor may continue through conditioning until day -3 then tapered at the
             discretion of the investigator.

        Exclusion Criteria:

          -  Evidence of portal hypertension with varices, ascites, or hepatic encephalopathy;

          -  > 10% bone marrow blasts at transplant if no history of AML and > 5% if had previous
             progression to AML;

          -  Human immunodeficiency virus (HIV) positive; active hepatitis B or C;

          -  Patients with active infections. The principal investigator (PI) is the final arbiter
             of the eligibility;

          -  Liver cirrhosis;

          -  Prior central nervous system (CNS) involvement by tumor cells;

          -  Severe pulmonary hypertension (PHT) (on echo or right side cardiac catheterization);

          -  History of another primary malignancy that has not been in remission for at least 3
             years (the following are exempt from the 3-year limit: non-melanoma skin cancer, fully
             excised melanoma in situ [stage 0], curatively treated localized prostate cancer, and
             cervical or breast carcinoma in situ on biopsy or a squamous intraepithelial lesion on
             Papanicolaou [PAP] smear);

          -  Positive beta human chorionic gonadotropin (HCG) test in a woman with child bearing
             potential defined as not post-menopausal for 12 months or no previous surgical
             sterilization;

          -  Noncompliance - inability or unwillingness to comply with medical recommendations
             regarding therapy or follow-up, including smoking tobacco. Smoking cessation is a
             standard teaching practice prior to admission for all patients undergoing stem cell
             transplant. Any patient who refuses to stop smoking prior to transplant will not be
             eligible for this study.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to day +100 post-hematopoietic cell transplantation (HCT)
Safety Issue:
Description:Observed toxicities will be tabulated and summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study regimen and reversibility or outcome.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:Up to 24 months
Safety Issue:
Description:Estimated will be calculated using the Kaplan-Meier product-limit method. Distributions will be compared using the log-rank test. Cox proportional hazards regression will be used to assess the association between survival endpoints and clinical and disease covariates of interest.
Measure:Progression-free survival
Time Frame:Up to 24 months
Safety Issue:
Description:Estimated will be calculated using the Kaplan-Meier product-limit method. Distributions will be compared using the log-rank test. Cox proportional hazards regression will be used to assess the association between survival endpoints and clinical and disease covariates of interest.
Measure:Graft failure-free survival
Time Frame:Up to 24 months
Safety Issue:
Description:Estimates will be calculated using the Kaplan-Meier product-limit method. Distributions will be compared using the log-rank test. Cox proportional hazards regression will be used to assess the association between survival endpoints and clinical and disease covariates of interest.
Measure:Time to neutrophil recovery
Time Frame:Up to 24 months
Safety Issue:
Description:Will be estimated using the Kaplan-Meier product-limit method. Distributions will be compared using the log-rank test. Cox proportional hazards regression will be used to assess the association between survival endpoints and clinical and disease covariates of interest.
Measure:Time to platelet recovery
Time Frame:Up to 24 months
Safety Issue:
Description:Will be estimated using the Kaplan-Meier product-limit method. Distributions will be compared using the log-rank test. Cox proportional hazards regression will be used to assess the association between survival endpoints and clinical and disease covariates of interest.
Measure:Non-relapse mortality (NRM)
Time Frame:Up to 24 months
Safety Issue:
Description:The cumulative incidence of relapse/progression with a competing risk of NRM will be estimated in a competing risks framework. Analyses to assess the association between the cumulative incidence of the above parameters and clinical and disease covariates of interest will be performed using the method of Fine and Gray.
Measure:Acute graft versus host disease (GvHD)
Time Frame:Up to 24 months
Safety Issue:
Description:Will be estimated in a competing risks framework with competing risks of relapse and NRM. Analyses to assess the association between the cumulative incidence of the above parameters and clinical and disease covariates of interest will be performed using the method of Fine and Gray.
Measure:Chronic GvHD
Time Frame:Up to 24 months
Safety Issue:
Description:Will be estimated in a competing risks framework with competing risks of relapse and NRM. Analyses to assess the association between the cumulative incidence of the above parameters and clinical and disease covariates of interest will be performed using the method of Fine and Gray.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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