Clinical Trials /

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

NCT03118492

Description:

This pilot clinical trial studies the side effects of combination chemotherapy, total body irradiation, and donor blood stem cell transplant in treating patients with secondary myelofibrosis. Drugs used in chemotherapy 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:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy, Total Body Irradiation, and Donor Blood Stem Cell Transplant in Treating Patients With 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: 16420
  • SECONDARY ID: NCI-2017-00613
  • SECONDARY ID: 16420
  • NCT ID: NCT03118492

Conditions

  • 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)
FludarabineFluradosaTreatment (combination chemotherapy, TBI, HCT)
Glycosylated Recombinant Human G-CSF AVI-014AVI-014Treatment (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 pilot clinical trial studies the side effects of combination chemotherapy, total body irradiation, and donor blood stem cell transplant in treating patients with secondary myelofibrosis. Drugs used in chemotherapy 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 Institutes of Health [NIH] Consensus Criteria).

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

      TERTIARY OBJECTIVES:

      I. To conduct correlative studies and describe inflammatory cytokine levels and GVHD
      biomarker levels in plasma and T cell differentiation/functions in patients enrolled onto the
      trial.

      OUTLINE:

      Patients receive melphalan intravenously (IV) over 30 minutes on day -5, fludarabine IV over
      30-60 minutes on days -5 to -2. Patients undergo total body irradiation (TBI) on day -1 and
      hematopoietic cell transplantation (HCT) on day 0. Patients receive cyclophosphamide IV over
      1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then orally (PO)
      for 6 months followed by a taper, mycophenolate mofetil PO thrice daily (TID) until day 35,
      and glycosylated recombinant human G-CSF AVI-014 (G-CSF) IV daily until absolute neutrophil
      count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease
      progression or unexpected toxicity.

      After completion of study treatment, patients are followed for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (combination chemotherapy, TBI, HCT)ExperimentalPatients receive melphalan IV over 30 minutes on day -5, fludarabine IV over 30-60 minutes on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 35, and G-CSF IV daily until absolute neutrophil count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.
  • Cyclophosphamide
  • Fludarabine
  • Glycosylated Recombinant Human G-CSF AVI-014
  • Melphalan
  • Mycophenolate Mofetil
  • Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

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

          -  Patients >= age 50 must have a comorbidity score (hematopoietic cell
             transplant-comorbidity index [HCT-CI]) < 4 (Sorror)

          -  Patients can be in chronic phase (CP) with bone marrow (BM) blast count =< 15% as long
             as no evidence of disease acceleration per principal investigator (PI) and treating
             physician's opinion or after progression to acute myeloid leukemia (AML) and achieved
             =< 5% BM blasts (morphologic complete remission [CR] prior to transplant)

          -  Lack of an 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)/bilirubin =< 5 X upper
             limit of normal (ULN)

          -  Measured creatinine clearance > 60 mls/min

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

          -  Corrected carbon monoxide diffusing capability (DLCOc) >= 50%

          -  No active infections

          -  Prior treatment with JAK2 inhibitor therapy is not excluded; a JAK2 inhibitor will
             need to be stopped 1-2 days prior to starting conditioning regimen

          -  DONOR: Documented informed consent per local, state and federal guidelines

          -  DONOR: Genotypically haploidentical as determined by HLA typing

               -  Preferably a non-maternal 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, children,
                  or cousins in rare instances

          -  DONOR: Absence of pre-existing donor-specific anti-HLA antibodies (DSA) in the
             recipient; Patients with pre-existing DSA could undergo desensitization per City of
             Hope (COH) standard operating procedures [SOP] and should have DS < 2000 prior to
             conditioning at discretion of principal investigator (PI)

          -  DONOR: Infectious disease screening performed within 30 days prior to stem cell
             mobilization per federal guidelines and is:

               -  Seronegative for HIV 1+2 antibody (Ab) and/or HIV polymerase chain reaction
                  (PCR), human T-cell leukemia virus (HTLV) I/II Ab, hepatitis B virus surface
                  antigen (HBsAg), hepatitis B virus surface antibody (HBcAb), hepatitis C virus
                  (HCV) Ab

               -  Negative rapid plasma reagin (RPR) for syphilis

          -  DONOR: Women of childbearing potential (WOCBP): Urine pregnancy testing performed
             within 7 days prior to stem cell mobilization

          -  DONOR: Is approved and completed evaluation prior to recipient initiation of the
             preparative regimen per institutional guidelines

        Exclusion Criteria:

          -  Evidence of severe portal hypertension with evidence of decompensation either with
             bleeding varices, large volume ascites, or hepatic encephalopathy

          -  In a bone marrow biopsy 4 weeks prior to start of conditioning on study:

               -  > 15% bone marrow blasts at transplant if no history of AML and per PI and
                  treating physician's opinion of disease acceleration

               -  > 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 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

          -  DONOR: Has undergone solid organ, stem cell, bone marrow or blood transplantation

          -  DONOR: Receiving any investigational agents, or concurrent biological, chemotherapy,
             immunosuppression or radiation therapy

          -  DONOR: Active infection

          -  DONOR: Thrombocytopenia < 150,000 cells /mm^3 at baseline evaluation

          -  DONOR: Sero-positive for HIV-1 & 2 antibody, HTLV-I & II antibody, hepatitis B virus
             (HBV) and HCV

          -  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 G-CSF therapy

          -  DONOR: WOCBP: Pregnant or =< 6 months breastfeeding
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events assessed by Bearman Toxicity Scale and NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Time Frame:Up to 100 days post-HCT
Safety Issue:
Description:Observed toxicities will be 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:Cumulative incidence of acute GvHD assessed by Keystone Consensus criteria
Time Frame:Up to day 100 post-HCT
Safety Issue:
Description:Time to the first day of acute GvHD onset (of any grade) will be used to estimate the cumulative incidence.
Measure:Cumulative incidence of chronic GvHD assessed by NIH Consensus Criteria
Time Frame:Up to 2 years post-HCT
Safety Issue:
Description:Time to the first day of chronic GvHD onset (of any grade) will be used to estimate the cumulative incidence.
Measure:Cumulative incidence of relapse/progression
Time Frame:Up to 2 years
Safety Issue:
Description:The cumulative incidence of relapse/progression will be estimated using the method described by Gooley et al. (1999).
Measure:Graft failure-free survival
Time Frame:Time from start of protocol treatment/infusion of stem cell product to graft-failure, death (from any cause), or last contact, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be calculated using Kaplan-Meier product-limit method, 95% confidence intervals will be calculated.
Measure:Neutrophil recovery
Time Frame:Up to 2 years
Safety Issue:
Description:Defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of >= 500/uL after conditioning.
Measure:Non-relapse mortality
Time Frame:Up to 2 years
Safety Issue:
Description:The cumulative incidence of NRM will be estimated using the method described by Gooley et al. (1999).
Measure:Overall survival
Time Frame:Time from start of protocol treatment/infusion of stem cell product to death (from any cause), or last contact, whichever occurs first, assessed up to 36 months
Safety Issue:
Description:Will be calculated using Kaplan-Meier product-limit method, 95% confidence intervals will be calculated.
Measure:Platelet recovery
Time Frame:Up to 2 years
Safety Issue:
Description:Defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count >= 20,000/uL and did not receive a platelet transfusion in the previous 7 days.
Measure:Progression-free survival
Time Frame:Time from start of protocol treatment/infusion of stem cell product to, relapse, progression, death (from any cause), or last contact, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be calculated using Kaplan-Meier product-limit method, 95% confidence intervals will be calculated.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

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