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

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ClinicalTrials.gov Identifier: NCT03118492
Recruitment Status : Recruiting
First Posted : April 18, 2017
Last Update Posted : July 13, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
This pilot phase I 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.

Condition or disease Intervention/treatment Phase
Secondary Myelofibrosis Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Cyclophosphamide Drug: Fludarabine Biological: Glycosylated Recombinant Human G-CSF AVI-014 Other: Laboratory Biomarker Analysis Drug: Melphalan Drug: Mycophenolate Mofetil Drug: Tacrolimus Radiation: Total-Body Irradiation Phase 1

Detailed Description:

PRIMARY OBJECTIVE:

I. To evaluate the safety and tolerability of reduced-intensity (fludarabine/melphalan) 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 evaluate and describe cytokine release syndrome (CRS) post haploidentical HCT in the setting of advanced myelofibrosis, as assessed by grade, frequency, severity, duration and reversibility (outcome).

III. To estimate graft failure-free survival (GFS) at 100-days post-transplant. IV. 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.

V. 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).

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

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

EXPLORATORY OBJECTIVE:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 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 : May 24, 2017
Estimated Primary Completion Date : May 24, 2021
Estimated Study Completion Date : May 24, 2021


Arm Intervention/treatment
Experimental: Treatment (combination chemotherapy, TBI, HCT)
Patients 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.
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo HCT
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT
  • Stem Cell Transplantation, Allogeneic

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

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Biological: Glycosylated Recombinant Human G-CSF AVI-014
Given IV
Other Name: AVI-014

Other: Laboratory Biomarker Analysis
Correlative studies

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
Given 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 100 days post-hematopoietic cell transplantation (HCT) ]
    Assessed by Bearman Toxicity Scale and National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version (CTCAE) 4.03. 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.

  2. Incidence of unacceptable toxicity [ Time Frame: Up to 2 years ]
    Assessed by Bearman Toxicity Scale and NCI CTCAE version 4.03. 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 :
  1. Neutrophil recovery [ Time Frame: Up to 2 years ]
    Defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of >= 500/uL after conditioning.

  2. Platelet recovery [ Time Frame: Up to 2 years ]
    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.

  3. Incidence of cytokine release syndrome (CRS) [ Time Frame: After haploidentical HCT, assessed up to 2 years ]
    Defined and graded per American Society for Transplantation and Cellular Therapy (ASTCT) criteria.

  4. 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 ]
    Will be calculated using Kaplan-Meier product-limit method, 95% confidence intervals will be calculated.

  5. 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 ]
    Will be calculated using Kaplan-Meier product-limit method, 95% confidence intervals will be calculated.

  6. 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 ]
    Will be calculated using Kaplan-Meier product-limit method, 95% confidence intervals will be calculated.

  7. Cumulative incidence of relapse/progression [ Time Frame: Up to 2 years ]
    The cumulative incidence of relapse/progression will be estimated using the method described by Gooley et al. (1999).

  8. Non-relapse mortality (NRM) [ Time Frame: Up to 2 years ]
    The cumulative incidence of NRM will be estimated using the method described by Gooley et al. (1999).

  9. Cumulative incidence of acute graft versus host disease (GvHD) [ Time Frame: Up to day 100 post-HCT ]
    Assessed by Keystone Consensus criteria. Time to the first day of acute GvHD onset (of any grade) will be used to estimate the cumulative incidence.

  10. Cumulative incidence of chronic graft versus host disease GvHD [ Time Frame: Up to 2 years post-HCT ]
    Assessed by National Institutes of Health Consensus Criteria. Time to the first day of chronic GvHD onset (of any grade) will be used to estimate the cumulative incidence.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 DSA < MFI of 2000 prior to conditioning at discretion of 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 PI is the final arbiter of the eligibility
  • Patients with evidence of severe pulmonary hypertension by echocardiogram and confirmed by a subsequent right side cardiac catheterization pre-enrollment
  • Liver cirrhosis
  • Prior central nervous system (CNS) involvement by tumor cells
  • 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
  • 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

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): NCT03118492


Locations
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United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Monzr M. Al Malki    626-256-4673 ext 62405    malmalki@coh.org   
Principal Investigator: Monzr M. Al Malki         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Monzr M Al Malki City of Hope Comprehensive Cancer Center
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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT03118492    
Other Study ID Numbers: 16420
NCI-2017-00613 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
16420 ( Other Identifier: City of Hope Medical Center )
P30CA033572 ( U.S. NIH Grant/Contract )
First Posted: April 18, 2017    Key Record Dates
Last Update Posted: July 13, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: No
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
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Calcineurin Inhibitors
Enzyme Inhibitors
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents