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

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ClinicalTrials.gov Identifier: NCT03426969
Recruitment Status : Completed
First Posted : February 8, 2018
Last Update Posted : October 14, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

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.

Condition or disease Intervention/treatment Phase
Primary Myelofibrosis Secondary Myelofibrosis Drug: Cyclophosphamide Biological: Filgrastim Drug: Fludarabine Phosphate Procedure: Hematopoietic Cell Transplantation Drug: Melphalan Drug: Mycophenolate Mofetil Drug: Tacrolimus Radiation: Total-Body Irradiation Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of Reduced Intensity HLA-Haploidentical Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide in Patients With Advanced Myelofibrosis
Actual Study Start Date : January 31, 2018
Actual Primary Completion Date : September 21, 2020
Actual Study Completion Date : September 21, 2020


Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03426969


Locations
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United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Stefan O Ciurea M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03426969    
Other Study ID Numbers: 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 )
First Posted: February 8, 2018    Key Record Dates
Last Update Posted: October 14, 2020
Last Verified: October 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasm Metastasis
Primary Myelofibrosis
Neoplastic Processes
Neoplasms
Pathologic Processes
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Mycophenolic Acid
Cyclophosphamide
Melphalan
Mechlorethamine
Nitrogen Mustard Compounds
Fludarabine
Fludarabine phosphate
Tacrolimus
Lenograstim
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Adjuvants, Immunologic
Calcineurin Inhibitors