Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy

Sponsor
Masonic Cancer Center, University of Minnesota (Other)
Overall Status
Terminated
CT.gov ID
NCT00303719
Collaborator
(none)
342
Enrollment
1
Location
2
Arms
205.4
Actual Duration (Months)
1.7
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy, or that have become cancer. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclophosphamide and fludarabine together with total-body irradiation followed by cyclosporine and mycophenolate mofetil before the transplant may stop this from happening.

PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with radiation therapy followed by cyclosporine and mycophenolate mofetil works in treating patients who are undergoing a donor stem cell transplant for hematologic cancer, metastatic breast cancer, or kidney cancer.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

OBJECTIVES:
  • Determine if a nonmyeloablative regimen comprising cyclophosphamide, fludarabine, and radiotherapy followed by cyclosporine and mycophenolate mofetil provides a prompt and durable donor engraftment in patients with hematologic malignancies or kidney cancer who are undergoing allogeneic stem cell transplantation.

  • Determine the safety of this nonmyeloablative transplantation regimen in these patients.

  • Determine the risk of graft-versus-host-disease in patients treated with this regimen.

  • Determine the antineoplastic potency of nonmyeloablative stem cell transplantation in patients treated with this regimen.

  • Determine the effect of lower doses of daily fludarabine on treatment-related mortality (TRM) OUTLINE: Patients are stratified according to risk (standard vs high).

  • Preparative regimen*: Patients receive cyclophosphamide intravenously (IV) over 2 hours on day -6 and fludarabine IV over 1 hour on days -6 to -2. Patients undergo total body irradiation on day -1. Some patients also receive anti-thymocyte globulin (ATG)** IV every 12 hours on days -6 to -4. Patients who receive ATG* include the following:

  • Related donor recipients who have not received combination chemotherapy within the past 6 months

  • Unrelated donor recipients who have not received combination chemotherapy within the past 3 months

  • Unrelated donor recipients who have received only 1 induction course for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or blastic phase chronic myelogenous leukemia (CML) NOTE: **Patients who underwent prior autologous stem cell transplantation in the past year do not receive ATG.

  • Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0.

  • Graft-versus-host-disease prophylaxis: Patients receive cyclosporine IV over 2 hours beginning on day -3 and continuing until at least day 100. Patients also receive mycophenolate mofetil IV or orally twice daily on days -3 to 30.

  • Donor lymphocyte infusion (DLI): Patients without active GVHD but deteriorating donor chimerism may receive DLI IV over 2 hours.

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

PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.

Study Design

Study Type:
Interventional
Actual Enrollment :
342 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy
Actual Study Start Date :
Mar 26, 2002
Actual Primary Completion Date :
May 8, 2019
Actual Study Completion Date :
May 8, 2019

Arms and Interventions

ArmIntervention/Treatment
Experimental: High Risk Patients

Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim.

Biological: anti-thymocyte globulin
ATG dose is 15 mg/kg intravenous (IV) every 12 hours for 6 doses on days -6, -5, and -4. Those that should/will receive ATG in the preparative regimen: Related donor recipients who have not had exposure to combination chemotherapy in the 6 months preceding transplant should Unrelated donor recipients who have not had exposure to combination chemotherapy in the 3 months preceding transplant will Unrelated donor recipients who have had only a single induction cycle for the treatment of ALL/AML or MDS or CML blast crisis should Recipients with a prior autologous transplant in the year prior to second transplant do not require ATG.
Other Names:
  • ATG
  • Drug: cyclophosphamide
    Cyclophosphamide will be given in a two hour infusion, total dose 50 mg/kg on day -6.
    Other Names:
  • Cytoxan
  • Drug: cyclosporine
    Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a level of >200. For adults the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours. Patients will receive CSA until day +100.
    Other Names:
  • CSA
  • Drug: fludarabine
    Fludarabine 30 mg/m^2/day intravenous (IV) on day -6 through day -2., total dose 150 mg/m^2 for 5 days.
    Other Names:
  • Fludara
  • Drug: mycophenolate mofetil
    Mycophenolate mofetil (MMF) 1.5 gram twice a day (BID) or if < 50 kg will be given 15 mg/kg orally(po) BID,beginning on day -3, and discontinue at day +30 or 7 days after engraftment (3 consecutive days of absolute neutrophil count (ANC) > 0.5 x 109 /L).
    Other Names:
  • MMF
  • Procedure: stem cell transplantation
    On day 0, if related donor, stem cells are infused via central line. If unrelated donor, marrow/PBSC is infused after arrival and processing on day 0.
    Other Names:
  • peripheral blood stem cell transplantation
  • bone marrow transplant
  • Radiation: total body irradiation
    The dose of TBI will be 200 cGy given in a single fraction on day -1.
    Other Names:
  • TBI
  • Drug: filgrastim
    Patients with white blood cell (WBC) counts < 2500 any time after stem cell infusion will be started on G-CSF support at Day +5 at a dose of 5 mcg/kg intravenously or subcutaneously (IV/SQ) daily rounded to vial size until absolute neutrophil count (ANC) > 2500 for 2 consecutive days.
    Other Names:
  • G-CSF
  • Experimental: Standard Risk Patients

    Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim.

    Biological: anti-thymocyte globulin
    ATG dose is 15 mg/kg intravenous (IV) every 12 hours for 6 doses on days -6, -5, and -4. Those that should/will receive ATG in the preparative regimen: Related donor recipients who have not had exposure to combination chemotherapy in the 6 months preceding transplant should Unrelated donor recipients who have not had exposure to combination chemotherapy in the 3 months preceding transplant will Unrelated donor recipients who have had only a single induction cycle for the treatment of ALL/AML or MDS or CML blast crisis should Recipients with a prior autologous transplant in the year prior to second transplant do not require ATG.
    Other Names:
  • ATG
  • Drug: cyclophosphamide
    Cyclophosphamide will be given in a two hour infusion, total dose 50 mg/kg on day -6.
    Other Names:
  • Cytoxan
  • Drug: cyclosporine
    Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a level of >200. For adults the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours. Patients will receive CSA until day +100.
    Other Names:
  • CSA
  • Drug: fludarabine
    Fludarabine 30 mg/m^2/day intravenous (IV) on day -6 through day -2., total dose 150 mg/m^2 for 5 days.
    Other Names:
  • Fludara
  • Drug: mycophenolate mofetil
    Mycophenolate mofetil (MMF) 1.5 gram twice a day (BID) or if < 50 kg will be given 15 mg/kg orally(po) BID,beginning on day -3, and discontinue at day +30 or 7 days after engraftment (3 consecutive days of absolute neutrophil count (ANC) > 0.5 x 109 /L).
    Other Names:
  • MMF
  • Procedure: stem cell transplantation
    On day 0, if related donor, stem cells are infused via central line. If unrelated donor, marrow/PBSC is infused after arrival and processing on day 0.
    Other Names:
  • peripheral blood stem cell transplantation
  • bone marrow transplant
  • Radiation: total body irradiation
    The dose of TBI will be 200 cGy given in a single fraction on day -1.
    Other Names:
  • TBI
  • Drug: filgrastim
    Patients with white blood cell (WBC) counts < 2500 any time after stem cell infusion will be started on G-CSF support at Day +5 at a dose of 5 mcg/kg intravenously or subcutaneously (IV/SQ) daily rounded to vial size until absolute neutrophil count (ANC) > 2500 for 2 consecutive days.
    Other Names:
  • G-CSF
  • Outcome Measures

    Primary Outcome Measures

    1. Neutrophil and Donor Cell Engraftment [Day 42 and Day 100]

      Successful sustained engraftment is defined as primary neutrophil engraftment by day 42 and e90% donor cells at day 100, with or without DLI. Engraftment based on absolute neutrophil count of donor origin > 0.5 x 10e9 /L for 3 days by day 42

    Secondary Outcome Measures

    1. Serious Adverse Events [Day 100]

      Safety by development of severe adverse events within 100 days of transplant

    2. Transplant Related Mortality [Day 100]

      > 30% transplant related mortality at 100 days (non-relapse).

    3. Overall Survival [1 year]

    4. Acute Graft-Versus-Host Disease [Day 100]

      Grade III-IV graft versus host disease

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    Standard patients will be enrolled into Arms 1-6. High risk patients (transplant with aplasia) will be considered separately in Arm 7.

    • Age and Graft criteria (all patients)

    • Patient's < or = 75 years old with a 5/6 or 6/6 related donor match are eligible.

    • Patient's < or = 75 years who have a 7-8/8 HLA-A,B,C,DRB1 allele matched unrelated volunteer marrow and/or peripheral blood stem cell (PBSC) donor match are eligible.

    • Disease Criteria (standard risk patients)

    • Acute myelogenous leukemia

    • Acute lymphocytic leukemia

    • Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis in chronic phase is eligible).

    • Non-Hodgkins lymphoma (NHL), Hodgkins, chronic lymphocytic leukemia, multiple myeloma demonstrating chemosensitive disease

    • Acquired bone marrow failure syndromes

    • Myelodysplastic syndrome of all subtypes including refractory anemia (RA) or all IPSS categories if severe pancytopenia, transfusion requirements not responsive to therapy, or high risk cytogenetics. Blasts must be less than 5%. If >5% requires therapy (induction or Hypomethylating agents) pre-transplant to decrease disease burden.

    • Renal cell cancer,

    • Chronic myeloproliferative disorder, i.e. myelofibrosis

    • Disease Criteria (High risk patients on Arm 7)

    • Patients with refractory leukemia or MDS may be taken to transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody. These high risk patients will be analyzed separately in Arm 7.

    • Adequate organ function and performance status (all patients)

    Exclusion Criteria:
    • Pregnancy or breast feeding

    • Evidence of HIV infection or known HIV positive serology

    • Active serious infection

    • Congenital bone marrow failure syndrome

    • Previous irradiation that precludes the safe administration of an additional dose of 200 cGy of total body irradiation (TBI)

    • Chronic myelogenous leukemia (CML) in refractory blast crisis

    • Intermediate or high grade NHL, mantle cell NHL, and Hodgkins disease that is progressive on salvage therapy. Stable disease is acceptable to move forward provided it is non-bulky.

    • Multiple Myeloma progressive on salvage chemotherapy.

    DONOR ELIGIBILITY

    • Related will undergo apheresis - if donor is unable to undergo apheresis, a bone marrow harvest is acceptable; unrelated volunteer donors must be able to undergo bone marrow harvest or apheresis.

    • All donors must be able to give informed consent.

    • Donors weighing less than 40 kg (children) will need evaluation by a pediatrician for suitability of the apheresis procedure. Informed consent must be obtained from parent or guardian as applicable for minors.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Masonic Cancer Center, University of MinnesotaMinneapolisMinnesotaUnited States55455

    Sponsors and Collaborators

    • Masonic Cancer Center, University of Minnesota

    Investigators

    • Principal Investigator: Erica Warlick, MD, Masonic Cancer Center, University of Minnesota

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Masonic Cancer Center, University of Minnesota
    ClinicalTrials.gov Identifier:
    NCT00303719
    Other Study ID Numbers:
    • 2001LS058
    • UMN-MT2001-10
    • 0108M06725
    First Posted:
    Mar 17, 2006
    Last Update Posted:
    May 12, 2020
    Last Verified:
    Apr 1, 2020

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleHigh Risk PatientsStandard Risk Patients
    Arm/Group DescriptionPatients with refractory leukemia or MDSPatients with Disease criteria: Acute myelogenous leukemia , Acute lymphocytic leukemia, Chronic myelogenous leukemia , NHL, Hodgkins, chronic lymphocytic leukemia, multiple myeloma, Acquired bone marrow failure syndromes, Myelodysplastic syndrome, Renal cell cancer,Chronic myeloproliferative disorder
    Period Title: Overall Study
    STARTED13329
    COMPLETED13292
    NOT COMPLETED037

    Baseline Characteristics

    Arm/Group TitleHigh Risk PatientsStandard Risk PatientsTotal
    Arm/Group DescriptionPatients with refractory leukemia or MDSPatients with Disease criteria: Acute myelogenous leukemia , Acute lymphocytic leukemia, Chronic myelogenous leukemia , NHL, Hodgkins, chronic lymphocytic leukemia, multiple myeloma, Acquired bone marrow failure syndromes, Myelodysplastic syndrome, Renal cell cancer,Chronic myeloproliferative disorderTotal of all reporting groups
    Overall Participants13292305
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    4
    30.8%
    184
    63%
    188
    61.6%
    >=65 years
    9
    69.2%
    108
    37%
    117
    38.4%
    Sex: Female, Male (Count of Participants)
    Female
    4
    30.8%
    112
    38.4%
    116
    38%
    Male
    9
    69.2%
    180
    61.6%
    189
    62%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    7.7%
    3
    1%
    4
    1.3%
    Not Hispanic or Latino
    10
    76.9%
    250
    85.6%
    260
    85.2%
    Unknown or Not Reported
    2
    15.4%
    39
    13.4%
    41
    13.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    2
    0.7%
    2
    0.7%
    Asian
    0
    0%
    4
    1.4%
    4
    1.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    5
    1.7%
    5
    1.6%
    White
    12
    92.3%
    259
    88.7%
    271
    88.9%
    More than one race
    0
    0%
    6
    2.1%
    6
    2%
    Unknown or Not Reported
    1
    7.7%
    16
    5.5%
    17
    5.6%

    Outcome Measures

    1. Primary Outcome
    TitleNeutrophil and Donor Cell Engraftment
    DescriptionSuccessful sustained engraftment is defined as primary neutrophil engraftment by day 42 and e90% donor cells at day 100, with or without DLI. Engraftment based on absolute neutrophil count of donor origin > 0.5 x 10e9 /L for 3 days by day 42
    Time FrameDay 42 and Day 100

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleHigh Risk PatientsStandard Risk Patients
    Arm/Group DescriptionPatients with refractory leukemia or MDSPatients with Disease criteria: Acute myelogenous leukemia , Acute lymphocytic leukemia, Chronic myelogenous leukemia , NHL, Hodgkins, chronic lymphocytic leukemia, multiple myeloma, Acquired bone marrow failure syndromes, Myelodysplastic syndrome, Renal cell cancer,Chronic myeloproliferative disorder
    Measure Participants13292
    Count of Participants [Participants]
    12
    92.3%
    289
    99%
    2. Secondary Outcome
    TitleSerious Adverse Events
    DescriptionSafety by development of severe adverse events within 100 days of transplant
    Time FrameDay 100

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleHigh Risk PatientsStandard Risk Patients
    Arm/Group DescriptionPatients with refractory leukemia or MDSPatients with Disease criteria: Acute myelogenous leukemia , Acute lymphocytic leukemia, Chronic myelogenous leukemia , NHL, Hodgkins, chronic lymphocytic leukemia, multiple myeloma, Acquired bone marrow failure syndromes, Myelodysplastic syndrome, Renal cell cancer,Chronic myeloproliferative disorder
    Measure Participants13292
    Count of Participants [Participants]
    0
    0%
    47
    16.1%
    3. Secondary Outcome
    TitleTransplant Related Mortality
    Description> 30% transplant related mortality at 100 days (non-relapse).
    Time FrameDay 100

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleHigh Risk PatientsStandard Risk Patients
    Arm/Group DescriptionPatients with refractory leukemia or MDSPatients with Disease criteria: Acute myelogenous leukemia , Acute lymphocytic leukemia, Chronic myelogenous leukemia , NHL, Hodgkins, chronic lymphocytic leukemia, multiple myeloma, Acquired bone marrow failure syndromes, Myelodysplastic syndrome,Chronic myeloproliferative disorder
    Measure Participants13292
    Count of Participants [Participants]
    2
    15.4%
    40
    13.7%
    4. Secondary Outcome
    TitleOverall Survival
    Description
    Time Frame1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleHigh Risk PatientsStandard Risk Patients
    Arm/Group DescriptionPatients with refractory leukemia or MDSPatients with Disease criteria: Acute myelogenous leukemia , Acute lymphocytic leukemia, Chronic myelogenous leukemia , NHL, Hodgkins, chronic lymphocytic leukemia, multiple myeloma, Acquired bone marrow failure syndromes, Myelodysplastic syndrome,Chronic myeloproliferative disorder
    Measure Participants13292
    Count of Participants [Participants]
    8
    61.5%
    181
    62%
    5. Secondary Outcome
    TitleAcute Graft-Versus-Host Disease
    DescriptionGrade III-IV graft versus host disease
    Time FrameDay 100

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleHigh Risk PatientsStandard Risk Patients
    Arm/Group DescriptionPatients with refractory leukemia or MDSPatients with Disease criteria: Acute myelogenous leukemia , Acute lymphocytic leukemia, Chronic myelogenous leukemia , NHL, Hodgkins, chronic lymphocytic leukemia, multiple myeloma, Acquired bone marrow failure syndromes, Myelodysplastic syndrome, Renal cell cancer,Chronic myeloproliferative disorder
    Measure Participants13292
    Count of Participants [Participants]
    2
    15.4%
    79
    27.1%

    Adverse Events

    Time Frame2 years
    Adverse Event Reporting Description
    Arm/Group TitleHigh Risk PatientsStandard Risk Patients
    Arm/Group DescriptionPatients with refractory leukemia or MDSPatients with Disease criteria: Acute myelogenous leukemia , Acute lymphocytic leukemia, Chronic myelogenous leukemia , NHL, Hodgkins, chronic lymphocytic leukemia, multiple myeloma, Acquired bone marrow failure syndromes, Myelodysplastic syndrome, Renal cell cancer,Chronic myeloproliferative disorder
    All Cause Mortality
    High Risk PatientsStandard Risk Patients
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total6/13 (46.2%) 124/292 (42.5%)
    Serious Adverse Events
    High Risk PatientsStandard Risk Patients
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total1/13 (7.7%) 53/292 (18.2%)
    Immune system disorders
    Graft versus Host disease0/13 (0%) 28/292 (9.6%)
    Infections and infestations
    Infection0/13 (0%) 4/292 (1.4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Relapse1/13 (7.7%) 21/292 (7.2%)
    Progressive disease0/13 (0%) 0/292 (0%)
    Other (Not Including Serious) Adverse Events
    High Risk PatientsStandard Risk Patients
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total12/13 (92.3%) 272/292 (93.2%)
    Cardiac disorders
    Organ failure2/13 (15.4%) 417/292 (5.8%) 21
    Decrease cardiac function0/13 (0%) 028/292 (9.6%) 33
    pericardial effusion2/13 (15.4%) 345/292 (15.4%) 51
    Ear and labyrinth disorders
    Ear disorder2/13 (15.4%) 210/292 (3.4%) 10
    Eye disorders
    Eye disorder0/13 (0%) 031/292 (10.6%) 48
    Gastrointestinal disorders
    Bleeding2/13 (15.4%) 445/292 (15.4%) 56
    General disorders
    Other disorders9/13 (69.2%) 25179/292 (61.3%) 489
    Hepatobiliary disorders
    Abnormal liver0/13 (0%) 018/292 (6.2%) 20
    Infections and infestations
    Bacterial infection5/13 (38.5%) 15128/292 (43.8%) 334
    Infection (Etiology unknown)4/13 (30.8%) 896/292 (32.9%) 219
    Fungal infection4/13 (30.8%) 15122/292 (41.8%) 269
    Pnemonia8/13 (61.5%) 15149/292 (51%) 351
    Viral infection8/13 (61.5%) 15143/292 (49%) 291
    Nervous system disorders
    Neuropathy1/13 (7.7%) 143/292 (14.7%) 51
    Neurotoxicity0/13 (0%) 029/292 (9.9%) 37
    Renal and urinary disorders
    Cystitis1/13 (7.7%) 115/292 (5.1%) 18
    Hemodialysis2/13 (15.4%) 218/292 (6.2%) 21
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome (ARDS)0/13 (0%) 017/292 (5.8%) 18
    perihilar opacity1/13 (7.7%) 114/292 (4.8%) 20
    Increased oxygen requirement1/13 (7.7%) 161/292 (20.9%) 73
    Pulmonary hemorrhage0/13 (0%) 025/292 (8.6%) 25

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleErica Warlick, MD
    OrganizationMasonic Cancer Center, University of Minnesota
    Phone612-625-8942
    Emailewarlick@umn.edu
    Responsible Party:
    Masonic Cancer Center, University of Minnesota
    ClinicalTrials.gov Identifier:
    NCT00303719
    Other Study ID Numbers:
    • 2001LS058
    • UMN-MT2001-10
    • 0108M06725
    First Posted:
    Mar 17, 2006
    Last Update Posted:
    May 12, 2020
    Last Verified:
    Apr 1, 2020