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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03426969
Recruitment Status : Recruiting
First Posted : February 8, 2018
Last Update Posted : January 2, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE February 2, 2018
First Posted Date  ICMJE February 8, 2018
Last Update Posted Date January 2, 2020
Actual Study Start Date  ICMJE January 31, 2018
Estimated Primary Completion Date November 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 15, 2019)
Incidence of adverse events [ Time Frame: Up to day +100 post-hematopoietic cell transplantation (HCT) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 2, 2018)
Toxicities of HLA-Haploidentical SCT+ Post SCT Cy for Advanced Myelofibrosis scored using the NCI Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 4.03. [ Time Frame: Toxicities recorded from the start of protocol treatment through day +100 post-HCT. ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 15, 2019)
  • Overall survival [ Time Frame: Up to 24 months ]
    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.
  • Progression-free survival [ Time Frame: Up to 24 months ]
    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.
  • Graft failure-free survival [ Time Frame: Up to 24 months ]
    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.
  • Time to neutrophil recovery [ Time Frame: Up to 24 months ]
    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.
  • Time to platelet recovery [ Time Frame: Up to 24 months ]
    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.
  • Non-relapse mortality (NRM) [ Time Frame: Up to 24 months ]
    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.
  • Acute graft versus host disease (GvHD) [ Time Frame: Up to 24 months ]
    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.
  • Chronic GvHD [ Time Frame: Up to 24 months ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2018)
  • Time to neutrophil recovery defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of ≥500/ýL after conditioning. [ Time Frame: Daily up to 4 weeks after transplant ]
  • Time to platelet recovery [ Time Frame: Daily up to 4 weeks after transplant ]
    Time to platelet recovery defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count ≥20,000/ýL AND did not receive a platelet transfusion in the previous 7 days.
  • Graft Failure-Free Survival (GFS) [ Time Frame: After transplant up to 2 years ]
    GFS defined as time from start of protocol treatment/infusion of stem cell product to graft-failure, death (from any cause), or last contact, whichever occurs first.
  • Overall Survival (OS) [ Time Frame: After transplant up to 2 years ]
    OS defined as time from start of protocol treatment/infusion of stem cell product to death (from any cause), or last contact, whichever occurs first.
  • Progression Free Survival (PFS) [ Time Frame: After transplant up to 2 years ]
    PFS defined as time from start of protocol treatment/infusion of stem cell product to, relapse, progression, death (from any cause), or last contact, whichever occurs first.
  • Cumulative Incidence of Relapse/Progression (CIR) [ Time Frame: After transplant up to 2 years ]
    The event is relapse/progression. CIR described post-start of protocol treatment and post-HCT. Death without relapse/progression is considered a competing risk.
  • Non-relapse mortality (NRM) [ Time Frame: After transplant up to 2 years ]
    The event is death from causes other than relapse or progression. NRM described post-start of protocol treatment and post-HCT. Disease relapse/progression are considered competing risks.
  • Cumulative Incidence of Acute GvHD [ Time Frame: From Day 0 up to Day +100 post-HCT. ]
    Acute GvHD assessed and graded according to the Keystone Consensus on GVHD scoring system (Przepiorka, Weisdorf et al. Acute GvHD described post-HCT. Time to the first day of acute GvHD onset (of any grade) used to estimate the cumulative incidence.
  • Cumulative Incidence of Chronic GvHD: [ Time Frame: Day 100 up to 2 years post-HCT ]
    Chronic GvHD assessed and graded according to the NIH Consensus Criteria. Time to the first day of chronic GvHD onset (of any grade) used to estimate the cumulative incidence.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combination Chemotherapy, Total Body Irradiation, and Donor Blood Stem Cell Transplant in Treating Patients With Primary or Secondary Myelofibrosis
Official Title  ICMJE A Pilot Study of Reduced Intensity HLA-Haploidentical Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide in Patients With Advanced Myelofibrosis
Brief Summary 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.
Detailed Description

PRIMARY OBJECTIVE:

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:

Patients receive melphalan intravenously (IV) over 30 minutes on days -5, fludarabine phosphate IV over 1 hour on days -5 to -2. Patients undergo total body irradiation (TBI) on day -1 and hematopoietic stem cell transplant (HCT) on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning on day 5, patients 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, patients are followed up at 1, 3, 6, 9, 12 and 24 months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Primary Myelofibrosis
  • Secondary Myelofibrosis
Intervention  ICMJE
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-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- 138719
  • Biological: Filgrastim
    Given SC
    Other Names:
    • G-CSF
    • Neupogen
    • r-metHuG-CSF
    • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
    • rG-CSF
    • Tevagrastim
  • Drug: Fludarabine Phosphate
    Given IV
    Other Names:
    • 2-F-ara-AMP
    • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
    • Beneflur
    • Fludara
    • SH T 586
  • Procedure: Hematopoietic Cell Transplantation
    Undergo HCT
    Other Names:
    • HCT
    • Hematopoietic Stem Cell Transplantation
    • HSCT
    • Stem Cell Transplant
    • stem cell transplantation
  • Drug: Melphalan
    Given IV
    Other Names:
    • Alanine 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-19813
  • Drug: Mycophenolate Mofetil
    Given PO
    Other Names:
    • Cellcept
    • MMF
  • Drug: Tacrolimus
    IV or PO
    Other Names:
    • FK 506
    • Fujimycin
    • Hecoria
    • Prograf
    • Protopic
  • Radiation: Total-Body Irradiation
    Undergo TBI
    Other Names:
    • TBI
    • TOTAL BODY IRRADIATION
    • Whole Body Irradiation
    • Whole-Body Irradiation
Study Arms  ICMJE Experimental: Treatment (combination chemotherapy, TBI, HCT)
Patients receive melphalan IV over 30 minutes on days -5, fludarabine phosphate IV over 1 hour on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning on day 5, patients 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.
Interventions:
  • Drug: Cyclophosphamide
  • Biological: Filgrastim
  • Drug: Fludarabine Phosphate
  • Procedure: Hematopoietic Cell Transplantation
  • Drug: Melphalan
  • Drug: Mycophenolate Mofetil
  • Drug: Tacrolimus
  • Radiation: Total-Body Irradiation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 2, 2018)
12
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 30, 2020
Estimated Primary Completion Date November 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of primary or secondary Myelofibrosis with transplant indication by DIPSS-plus (> intermediate -1);
  • Age 18-70; patients >/= age 50 must have an comorbidity score (HCT-CI) </= 4 (Sorror). The Principal Investigator is the final arbiter for comorbidity;
  • Patients can be in chronic phase (CP) with BM blast count </= 10% or after progression to AML and achieved </= 5% BM blasts (morphologic CR prior to transplant);
  • Lack of an 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;
  • Adequate organ function: ALT/AST/billirubin </= 5X UNL, creatinine clearance > 50mls/min (calculated with Cockroft-Gault formula); LVEF >/= 50%, 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:

  • 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;

  • HIV positive; active hepatitis B or C;
  • Patients with active infections. The PI is the final arbiter of the eligibility;
  • Liver cirrhosis;
  • Prior 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 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. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Stefan Ciurea, MD 713-792-8750 sciurea@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03426969
Other Study ID Numbers  ICMJE 2017-0375
NCI-2018-00910 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0375 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Stefan O Ciurea M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP