Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT

Sponsor
H. Lee Moffitt Cancer Center and Research Institute (Other)
Overall Status
Completed
CT.gov ID
NCT03018223
Collaborator
(none)
32
Enrollment
1
Location
1
Arm
49.5
Actual Duration (Months)
0.6
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to find out if a combination of drugs (these are called:

cyclophosphamide, sirolimus, and mycophenolate mofetil) will protect participants better against graft vs. host disease (GVHD) after receiving a hematopoietic cell transplant from a related partially matched (haploidentical) donor. As part of the treatment for their blood cancer, participants need a hematopoietic cell transplantation (HCT) to improve their chances of cure. In any HCT, after the stem cell infusion is given, a combination of drugs is needed to prevent GVHD and facilitate acceptance of the graft.

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: Fludarabine
  • Drug: Busulfan
  • Drug: Cyclophosphamide
  • Radiation: Total body irradiation (TBI)
  • Procedure: Peripheral Blood Hematopoietic Cell Transplantation (HCT)
  • Drug: Sirolimus (SIR)
  • Drug: Mycophenolate mofetil (MMF)
  • Drug: Granulocyte-colony stimulating factor (G-CSF)
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
32 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Prevention
Official Title:
A Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haploidentical Peripheral Blood Stem Cell Transplantation
Actual Study Start Date :
Jan 31, 2017
Actual Primary Completion Date :
Dec 15, 2018
Actual Study Completion Date :
Mar 18, 2021

Arms and Interventions

ArmIntervention/Treatment
Experimental: Conditioning/HCT/GVHD Prophylaxis

Pre-HCT Conditioning, HCT, GVHD Prophylaxis. Conditioning regimen: To reduce heterogeneity, two commonly used myeloablative (MAC) and reduced intensity (RIC) regimens are permitted on this trial. Myeloablative conditioning: fludarabine, busulfan. Reduced intensity conditioning: fludarabine, cyclophosphamide, total body irradiation. Peripheral blood hematopoietic cell transplantation Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. Growth factor support: G-CSF

Drug: Fludarabine
Myeloablative conditioning: 40 mg/m^2 daily for 4 days. Dose will be adjusted for estimated creatinine clearance. Reduced intensity conditioning: 30 mg/m^2 daily on days -6, -5, -4, -3 and -2. Dose will be adjusted for estimated creatinine clearance.
Other Names:
  • Fludara, Oforta
  • Drug: Busulfan
    Myeloablative conditioning: IV dosing targeted for a daily total area under curve (AUC) 5300 mmol*min/L for 4 days. Busulfan AUC will be pharmacokinetically targeted. An AUC 3500 mmol*min/l may be considered in patients over 60 years of age or with multiple comorbidities. Chemotherapy may start on day -6 or day -5 depending on the day of admission (-6 for Wednesday admission, -5 for Sunday admission).
    Other Names:
  • Busulfex, Myleran
  • Drug: Cyclophosphamide
    Reduced intensity conditioning: 14.5 mg/kg/day on days -6, -5. GVHD prophylaxis: 50 mg/kg ideal body weight (IBW) daily dose will be given on days +3 and +4 post-transplant as an IV infusion over 1-2 hours.
    Other Names:
  • Cytoxan
  • Radiation: Total body irradiation (TBI)
    Reduced intensity conditioning: 200 centigray (cGy) on day -1.
    Other Names:
  • radiotherapy
  • Procedure: Peripheral Blood Hematopoietic Cell Transplantation (HCT)
    On day 0, patients will receive a peripheral blood hematopoietic cell graft.
    Other Names:
  • cell graft
  • Drug: Sirolimus (SIR)
    GVHD prophylaxis: SIR will be administered as a 9 mg oral loading dose on day +5, followed by maintenance. SIR levels will be monitored and maintenance dosing adjusted as needed for a target trough level 8 to 14 ng/ml, per Moffitt BMT program standard practice. In the absence of acute GVHD, sirolimus taper will start on day +90 (+/- 10 days) and it is suggested to finish by day +180.
    Other Names:
  • Rapamune
  • Drug: Mycophenolate mofetil (MMF)
    GVHD prophylaxis: MMF will start on day +5 at a dose of 15 mg/kg every 8 hours IV with the maximum daily dose not to exceed 3 gm. MMF will be changed to orally (PO) and discontinued on day +35 (without taper) in the absence of acute GVHD.
    Other Names:
  • CellCept
  • Drug: Granulocyte-colony stimulating factor (G-CSF)
    Growth factor support: G-CSF will be given beginning on day 5 at a dose of 5 mcg/kg/day (rounding to the nearest vial dose), until absolute granulocyte count (ANC) is > 1,000/mm^3 for three consecutive days. G-CSF may be given IV or subcutaneously.
    Other Names:
  • Neupogen, Filgrastim
  • Outcome Measures

    Primary Outcome Measures

    1. Incidence of Grade II-IV Acute Graft vs. Host Disease (GVHD) [100 days post hematopoietic cell transplant (HCT)]

      Cumulative incidence of grade II-IV acute GVHD by day 100 after HCT. Acute GVHD organ staging and assessment of overall grade will use standard consensus criteria. The cumulative incidence of acute and chronic GVHD will be estimated, considering malignancy relapse and non-relapse death as competing risk events.

    Secondary Outcome Measures

    1. Incidence of Chronic GVHD [1 year post HCT]

      Cumulative incidence of chronic GVHD by 1 year. Chronic GVHD diagnosis follow National Institutes of Health (NIH) Consensus guidelines.

    2. Overall Survival (OS) [Up to 1 year post HCT]

      Overall survival is defined as time from transplant to death or last follow-up, and is reported as percentage of surviving participants.

    3. Progression Free Survival (PFS) [Up to 1 year post HCT]

      Progression-free survival defined by the time interval from transplant to relapse/recurrence, to death or to last follow-up. Reported as percentage of participants who are disease free one year post HCT.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:
    Patient Participants:
    • Age: Must be older than 18 years, no upper age limit.

    • Karnofsky performance status: Full intensity conditioning, 80-100%; reduced intensity conditioning, 60-100%.

    • Vital organ function: a) Cardiac: Left ventricular ejection fraction must be > 45% assessed by multigated acquisition (MUGA) scan or echocardiogram. No myocardial infarction within 6 months of transplant evaluation. b) Pulmonary: forced expiratory volume at one second (FEV1), forced vital capacity (FVC), and adjusted diffusing capacity of the lungs for carbon monoxide (DLCO) must be ≥ 50% of predicted values. c) Liver: Transaminases (AST, ALT) less than 2 times upper limit of normal values. d) Kidney: Estimated creatinine clearance ≥ 50 cc/min.

    • Signed informed consent.

    • Included disease conditions and remission status: a) Acute leukemia in First Complete Remission (CR1) or second/subsequent CR. b) Chronic myeloid leukemia, primary myelofibrosis, chronic myelomonocytic leukemia. c) Int-2 or high risk myelodysplastic syndrome (MDS). d) Hodgkin lymphoma beyond CR1 with chemosensitive disease, Stable Disease (SD) may be included if no mass >3 cm. e) Non-Hodgkin lymphoma in high risk CR1 or subsequent CR (by clinical, cytogenetic or molecular criteria), primary induction failure (PIF) or relapsed with chemosensitive disease. SD may be included if no mass >3 cm. f) Multiple myeloma in CR/Very Good Partial Response (VGPR).

    Donor Participants:
    • Per Moffitt Cancer Center (MCC) Blood and Marrow Transplant (BMT) program practices, an allele level matched (8/8 HLA A, B, C and DR) sibling or unrelated donor is preferred. If a matched donor is not found, mismatched unrelated or haploidentical donors may be considered.

    • If a haploidentical donor is considered, parents, children, full siblings and in selected cases, extended family, will have high resolution typing at the MCC HLA laboratory. A familiar haploidentical donor is chosen among those who share at least one HLA-A, B, C, DRB1 and DQB1 haplotype with the patient.

    • Patient will be screened for antibodies targeting mismatched HLA antigens in potential haploidentical donors (donor specific antibodies, DSA). Antibody screen and confirmatory testing using Luminex single antigen-bead test will be done.

    • Among several potential donors, will choose in order of priority: a) Matched cytomegalovirus (CMV) immunoglobulin G (IgG) serologic status between donor and recipient. b) ABO blood group system-matched donor preferred, then minor ABO mismatch, then major ABO mismatch. c) Younger donor preferred: child, then sibling, and then parent. d) For male recipient, male donor will be preferred. Avoid mother as a donor unless no other choices.

    Exclusion Criteria:
    Patient Participants:
    • Uncontrolled active bacterial, viral, fungal infection.

    • Prior allogeneic HCT.

    • Unwilling to comply with study requirements.

    • Active, progressive or advanced disease based on diagnosis.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1H. Lee Moffitt Cancer Center and Research InstituteTampaFloridaUnited States33612

    Sponsors and Collaborators

    • H. Lee Moffitt Cancer Center and Research Institute

    Investigators

    • Principal Investigator: Nelli Bejanyan, M.D., H. Lee Moffitt Cancer Center and Research Institute

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    H. Lee Moffitt Cancer Center and Research Institute
    ClinicalTrials.gov Identifier:
    NCT03018223
    Other Study ID Numbers:
    • MCC-18766
    First Posted:
    Jan 11, 2017
    Last Update Posted:
    Sep 16, 2021
    Last Verified:
    Sep 1, 2021

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleConditioning/HCT/GVHD Prophylaxis
    Arm/Group DescriptionPre-HCT Conditioning, HCT, GVHD Prophylaxis.
    Period Title: Overall Study
    STARTED32
    COMPLETED32
    NOT COMPLETED0

    Baseline Characteristics

    Arm/Group TitleConditioning/HCT/GVHD Prophylaxis
    Arm/Group DescriptionPre-HCT Conditioning, HCT, GVHD Prophylaxis.
    Overall Participants32
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    27
    84.4%
    >=65 years
    5
    15.6%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    49.5
    Sex: Female, Male (Count of Participants)
    Female
    12
    37.5%
    Male
    20
    62.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    4
    12.5%
    Not Hispanic or Latino
    28
    87.5%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    3
    9.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    7
    21.9%
    White
    22
    68.8%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    32
    100%

    Outcome Measures

    1. Primary Outcome
    TitleIncidence of Grade II-IV Acute Graft vs. Host Disease (GVHD)
    DescriptionCumulative incidence of grade II-IV acute GVHD by day 100 after HCT. Acute GVHD organ staging and assessment of overall grade will use standard consensus criteria. The cumulative incidence of acute and chronic GVHD will be estimated, considering malignancy relapse and non-relapse death as competing risk events.
    Time Frame100 days post hematopoietic cell transplant (HCT)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleConditioning/HCT/GVHD Prophylaxis
    Arm/Group DescriptionPre-HCT Conditioning, HCT, GVHD Prophylaxis.
    Measure Participants32
    Number (95% Confidence Interval) [percentage of participants]
    18.8
    58.8%
    2. Secondary Outcome
    TitleIncidence of Chronic GVHD
    DescriptionCumulative incidence of chronic GVHD by 1 year. Chronic GVHD diagnosis follow National Institutes of Health (NIH) Consensus guidelines.
    Time Frame1 year post HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleConditioning/HCT/GVHD Prophylaxis
    Arm/Group DescriptionPre-HCT Conditioning, HCT, GVHD Prophylaxis.
    Measure Participants32
    Number (95% Confidence Interval) [percentage of participants]
    20.0
    62.5%
    3. Secondary Outcome
    TitleOverall Survival (OS)
    DescriptionOverall survival is defined as time from transplant to death or last follow-up, and is reported as percentage of surviving participants.
    Time FrameUp to 1 year post HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleConditioning/HCT/GVHD Prophylaxis
    Arm/Group DescriptionPre-HCT Conditioning, HCT, GVHD Prophylaxis.
    Measure Participants32
    Number (95% Confidence Interval) [percentage of participants]
    70.2
    219.4%
    4. Secondary Outcome
    TitleProgression Free Survival (PFS)
    DescriptionProgression-free survival defined by the time interval from transplant to relapse/recurrence, to death or to last follow-up. Reported as percentage of participants who are disease free one year post HCT.
    Time FrameUp to 1 year post HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleConditioning/HCT/GVHD Prophylaxis
    Arm/Group DescriptionPre-HCT Conditioning, HCT, GVHD Prophylaxis.
    Measure Participants32
    Number (95% Confidence Interval) [percentage of participants]
    56.6
    176.9%

    Adverse Events

    Time Frame2 years, 7 months
    Adverse Event Reporting Description
    Arm/Group TitleConditioning/HCT/GVHD Prophylaxis
    Arm/Group DescriptionPre-HCT Conditioning, HCT, GVHD Prophylaxis.
    All Cause Mortality
    Conditioning/HCT/GVHD Prophylaxis
    Affected / at Risk (%)# Events
    Total5/32 (15.6%)
    Serious Adverse Events
    Conditioning/HCT/GVHD Prophylaxis
    Affected / at Risk (%)# Events
    Total17/32 (53.1%)
    Blood and lymphatic system disorders
    Anemia1/32 (3.1%) 1
    Blood and lymphatic system disorders -Other1/32 (3.1%) 1
    Cardiac disorders
    Cardiac disorders - Other1/32 (3.1%) 1
    Gastrointestinal disorders
    Colonic perforation2/32 (6.3%) 2
    Nausea1/32 (3.1%) 1
    Upper gastrointestinal hemorrhage1/32 (3.1%) 1
    Vomiting1/32 (3.1%) 1
    Fever1/32 (3.1%) 1
    Hepatobiliary disorders
    Hepatobiliary disorders - Other1/32 (3.1%) 1
    Immune system disorders
    Autoimmune disorder1/32 (3.1%) 1
    Immune system disorders - Other1/32 (3.1%) 1
    Infections and infestations
    Enterocolitis infectious1/32 (3.1%) 1
    Infections and infestations -Other3/32 (9.4%) 3
    Lung infection3/32 (9.4%) 3
    Sepsis2/32 (6.3%) 2
    Urinary tract infection1/32 (3.1%) 1
    Psychiatric disorders
    Confusion1/32 (3.1%) 1
    Renal and urinary disorders
    Portal vein thrombosis1/32 (3.1%) 1
    Cystitis noninfective1/32 (3.1%) 1
    Hematuria5/32 (15.6%) 5
    Respiratory, thoracic and mediastinal disorders
    Hypoxia1/32 (3.1%) 1
    Pleural effusion1/32 (3.1%) 1
    Pneumonitis1/32 (3.1%) 1
    Respiratory, thoracic and mediastinal disorders - Other1/32 (3.1%) 1
    Vascular disorders
    Thromboembolic event1/32 (3.1%) 1
    Other (Not Including Serious) Adverse Events
    Conditioning/HCT/GVHD Prophylaxis
    Affected / at Risk (%)# Events
    Total5/32 (15.6%)
    General disorders
    Fever4/32 (12.5%) 4
    Infections and infestations
    Infections and Infestations - Other1/32 (3.1%) 1

    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/TitleNelli Bejanyan, MD
    OrganizationMoffitt Cancer Center
    Phone813-745-7208
    EmailNellie.Bejanyan@moffitt.org
    Responsible Party:
    H. Lee Moffitt Cancer Center and Research Institute
    ClinicalTrials.gov Identifier:
    NCT03018223
    Other Study ID Numbers:
    • MCC-18766
    First Posted:
    Jan 11, 2017
    Last Update Posted:
    Sep 16, 2021
    Last Verified:
    Sep 1, 2021