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

This study is currently recruiting participants.
Verified November 2017 by City of Hope Medical Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT03118492
First Posted: April 18, 2017
Last Update Posted: November 14, 2017
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.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center
  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.

Condition Intervention 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

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • Incidence of adverse events assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [ Time Frame: Up to 100 days post-HCT ]
    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.

  • Incidence of unacceptable adverse event assessed by NCI CTCAE version 4.0 [ Time Frame: Up to 2 years ]
    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:
  • Cumulative incidence of acute GvHD assessed by Keystone Consensus criteria [ Time Frame: Up to day 100 post-HCT ]
    Time to the first day of acute GvHD onset (of any grade) will be used to estimate the cumulative incidence.

  • Cumulative incidence of chronic GvHD assessed by NIH Consensus Criteria [ Time Frame: Up to 2 years post-HCT ]
    Time to the first day of chronic GvHD onset (of any grade) will be used to estimate the cumulative incidence.

  • 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).

  • 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.

  • 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.

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

  • 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.

  • 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.

  • 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.


Estimated Enrollment: 12
Actual Study Start Date: June 21, 2017
Estimated Study Completion Date: October 2020
Estimated Primary Completion Date: October 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 stem cell transplantation
  • HSC
  • HSCT
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
  • 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:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
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 =< 10% or after progression to acute myeloid leukemia (AML) and achieved =< 5% BM blasts (morphologic complete remission [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
  • 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
  • > 10% bone marrow blasts at transplant if no history of AML and > 5% if had previous progression to AML (in a bone marrow biopsy 4 weeks prior to start of conditioning on study)
  • 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
  Contacts and Locations
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
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Monzr M. Al Malki, MD    626-256-4673 ext 62405    malmalki@coh.org   
Principal Investigator: Monzr M. Al Malki, MD         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Monzr Al Malki, MD City of Hope Medical Center
  More Information

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT03118492     History of Changes
Other Study ID Numbers: 16420
NCI-2017-00613 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
16420 ( Other Identifier: City of Hope Medical Center )
First Submitted: April 13, 2017
First Posted: April 18, 2017
Last Update Posted: November 14, 2017
Last Verified: November 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Neoplasm Metastasis
Primary Myelofibrosis
Neoplastic Processes
Neoplasms
Pathologic Processes
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Cyclophosphamide
Tacrolimus
Fludarabine phosphate
Melphalan
Mechlorethamine
Nitrogen Mustard Compounds
Fludarabine
Mycophenolic Acid
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
Antimetabolites, Antineoplastic
Antimetabolites
Antibiotics, Antineoplastic