Pilot Trial of Clofarabine Added to Standard Busulfan and Fludarabine for Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation

Sponsor
University of California, San Francisco (Other)
Overall Status
Terminated
CT.gov ID
NCT01596699
Collaborator
(none)
16
Enrollment
1
Location
2
Arms
84.2
Actual Duration (Months)
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to find out what effects, good and/or bad, the addition of clofarabine, a new chemotherapy agent, to a standard busulfan and fludarabine conditioning treatment has. The study will also look at what causes some people to have high drug levels of these medications in their body compared to other people that may have low drug levels even if they all receive the same dose of medication.

Study Design

Study Type:
Interventional
Actual Enrollment :
16 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Pilot Trial of Clofarabine Added to Standard Busulfan and Fludarabine for Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation
Actual Study Start Date :
May 24, 2012
Actual Primary Completion Date :
Jun 1, 2019
Actual Study Completion Date :
Jun 1, 2019

Arms and Interventions

ArmIntervention/Treatment
Experimental: Patients with Myeloid Malignancies

Drug: Busulfan
0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT
Other Names:
  • Busulfex
  • Drug: Fludarabine
    40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
    Other Names:
  • Fludara
  • Drug: Clofarabine
    10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
    Other Names:
  • Clolar
  • Experimental: Patients with Non-Malignancies

    Drug: Alemtuzumab
    0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-HCT
    Other Names:
  • Campath
  • Drug: Busulfan
    0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT
    Other Names:
  • Busulfex
  • Drug: Fludarabine
    40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
    Other Names:
  • Fludara
  • Drug: Clofarabine
    10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
    Other Names:
  • Clolar
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Treatment-Related Adverse Events as a Measure of Safety and Tolerability [Up to 5 years on average]

      Severe Toxicity will be defined as death or Grade IV by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 pulmonary or hepatic failure (including moderate veno-occlusive disease(VOD) related to the transplant conditioning regimen within 100 days post-HCT. VOD will be defined by standard criteria. Patients must have Bilirubin >2.0 plus Hepatomegaly and/or Right upper quadrant (RUQ) pain plus Weight gain >5%.

    Secondary Outcome Measures

    1. Engraftment Rate of Patients With Non-malignant Diseases (Stratum A) [Participants will have engraftment blood studies starting approximately Day 30 post hematopoietic stem cell transplant and then monthly until stable. Average study participation is approximately 5 years.]

      Engraftment will be defined as the development of an Absolute Neutrophil Count (ANC) >500 for 3 consecutive days plus donor CD14/15 cells >70%. The engraftment rate in the population used for historical control is 40%. If 3 patients in Stratum A experience graft rejection, this stratum will close early for failing to achieve superior engraftment compared to standard-of-care.

    2. Mixed-donor Chimerism Rate of Patients With High-risk Myeloid Malignancies (Stratum B) [Participants will have peripheral blood chimerism assessed at Day 100 post hematopoietic stem cell transplant and then monthly until stable.]

      Full-donor chimerism will be defined by as ≥99% donor cells by Short Tandem Repeat (STR) analysis in all cell lines (CD3, CD14/15, and CD19) in peripheral blood. The historic control for Stratum B was determined using the 20 patients who were transplanted from 2005 - 2010 with Busulfan (BU)-based regimens and who retrospectively would have been eligible for the current trial. Of these 20 patients, at 100 days post-HCT, only 8 (40%) patients had full-donor chimerism. If 5 patients in Stratum B experienced mixed-donor chimerism at Day 100, we will close this stratum early for failing to achieve superior donor cell engraftment compared to standard-of-care.

    3. Serum Concentrations and Potential for Drug-drug Interaction of Fludarabine and Clofarabine [Pharmacokinetics (PK) blood sampling Days -5 to -2 pre-hematopoietic stem cell transplant.]

      Fludarabine and clofarabine drug levels and potential covariates influencing drug exposure such as renal function and genetic variants involved in drug metabolism, distribution, and activation will be analyzed using standard population pharmacokinetic methods using non-linear mixed effects modeling (NONMEM) software

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    3 Months to 30 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients must be ≥ 3 months and ≤30 years of age.

    • Stratum A: Non-Malignant Diseases, including:

    • Bone Marrow Failure Syndromes

    • Hemoglobinopathies or transfusion-dependent red blood cell (RBC) defects

    • Congenital Immunodeficiencies

    • Metabolic Diseases known to be treatable with Hematopoietic cell transplantation (HCT) (e.g. Hurler's)

    • Other Bone Marrow Stem Cell Defects (e.g. Osteopetrosis)

    • Severe Immune Dysregulation / Autoimmune Syndromes with at least transient prior response to immunosuppressive therapy

    • Stratum B: Myeloid Malignancies, including:

    • acute myeloid leukemia (AML), in greater than first clinical remission, or in CR1 but with detectable disease (≥0.1% Blasts by minimal residual disease (MRD) or Flow, or Positive Cytogenetics), or in CR1 but with a matched sibling Umbilical cord blood (UCB) donor.

    • Myelodysplastic syndromes (MDS)

    • Juvenile myelomonocytic leukemia (JMML)

    • Chronic myeloid leukemia (CML), with detectable disease by polymerase chain reaction (PCR)

    • Patients must have a suitable donor based on the University of California, San Francisco (UCSF) Pediatric Bone Marrow Transplant (BMT) standard operating procedures (SOP). 10/10 (HLA-A, -B, -C, -DR, -DQ) matching will be done for related and adult unrelated donors; 8/8 (HLA-A, -B, -C, -DR) for umbilical cord blood donors. Patients with non-malignant diseases will generally be eligible only if they have a mismatched donor, or an accepted clinical reason to be considered high-risk for rejection.

    • Liver transaminases (aspartate aminotransferase (AST)/alanine aminotransferase (ALT)) and Direct Bilirubin less than twice the upper limit of normal within 2 weeks of admission.

    • Cardiac Shortening Fraction ≥27% within 4 weeks of admission.

    • Creatinine clearance by Schwartz formula, glomerular filtration rate (GFR) or 24 hr urine collection ≥50 cc/min/1.73 m2, within 4 weeks of admission.

    • Pulmonary diffusion capacity ≥50% of predicted corrected for anemia/lung volume within 4 weeks of admission. If unable to do Pulmonary function testing(PFTs), then no active lung disease by chest x-ray (CXR) and/or oxygen (O2) Saturation ≥90% on room air.

    Exclusion Criteria:
    • Fanconi Anemia

    • Dyskeratosis Congenita

    • A known syndrome with increased sensitivity to radiation or alkylating agents

    • Severe Combined Immunodeficiency Disease eligible for a non-myeloablative HCT Trial

    • A mismatched donor for whom ex vivo T-cell depletion of the donor stem cells is planned

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1University of California, San FranciscoSan FranciscoCaliforniaUnited States94143

    Sponsors and Collaborators

    • University of California, San Francisco

    Investigators

    • Principal Investigator: Christopher C Dvorak, MD, University of California, San Francisco

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    University of California, San Francisco
    ClinicalTrials.gov Identifier:
    NCT01596699
    Other Study ID Numbers:
    • 110819
    • NCI-2012-00800
    First Posted:
    May 11, 2012
    Last Update Posted:
    Feb 26, 2020
    Last Verified:
    Feb 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by University of California, San Francisco
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleStratum A: Patients With Non-MalignanciesStratum B: Patients With Myeloid Malignancies
    Arm/Group DescriptionAlemtuzumab: 0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-Hematopoietic cell transplantation (HCT) Busulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCTBusulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
    Period Title: Overall Study
    STARTED106
    COMPLETED106
    NOT COMPLETED00

    Baseline Characteristics

    Arm/Group TitleStratum A: Patients With Non-MalignanciesStratum B: Patients With Myeloid MalignanciesTotal
    Arm/Group DescriptionAlemtuzumab: 0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-HCT Busulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCTBusulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCTTotal of all reporting groups
    Overall Participants10616
    Age, Customized (Count of Participants)
    0-9 years old
    10
    100%
    6
    100%
    16
    100%
    Sex: Female, Male (Count of Participants)
    Female
    4
    40%
    0
    0%
    4
    25%
    Male
    6
    60%
    6
    100%
    12
    75%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    4
    40%
    0
    0%
    4
    25%
    Not Hispanic or Latino
    6
    60%
    6
    100%
    12
    75%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    2
    20%
    2
    33.3%
    4
    25%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    1
    16.7%
    1
    6.3%
    White
    7
    70%
    3
    50%
    10
    62.5%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    1
    10%
    0
    0%
    1
    6.3%
    Region of Enrollment (participants) [Number]
    United States
    10
    100%
    6
    100%
    16
    100%

    Outcome Measures

    1. Primary Outcome
    TitleNumber of Participants With Treatment-Related Adverse Events as a Measure of Safety and Tolerability
    DescriptionSevere Toxicity will be defined as death or Grade IV by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 pulmonary or hepatic failure (including moderate veno-occlusive disease(VOD) related to the transplant conditioning regimen within 100 days post-HCT. VOD will be defined by standard criteria. Patients must have Bilirubin >2.0 plus Hepatomegaly and/or Right upper quadrant (RUQ) pain plus Weight gain >5%.
    Time FrameUp to 5 years on average

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleStratum A: Patients With Non-MalignanciesStratum B: Patients With Myeloid Malignancies
    Arm/Group DescriptionAlemtuzumab: 0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-HCT Busulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCTBusulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
    Measure Participants106
    Death
    1
    10%
    0
    0%
    Veno-occlusive disease(VOD)
    1
    10%
    1
    16.7%
    2. Secondary Outcome
    TitleEngraftment Rate of Patients With Non-malignant Diseases (Stratum A)
    DescriptionEngraftment will be defined as the development of an Absolute Neutrophil Count (ANC) >500 for 3 consecutive days plus donor CD14/15 cells >70%. The engraftment rate in the population used for historical control is 40%. If 3 patients in Stratum A experience graft rejection, this stratum will close early for failing to achieve superior engraftment compared to standard-of-care.
    Time FrameParticipants will have engraftment blood studies starting approximately Day 30 post hematopoietic stem cell transplant and then monthly until stable. Average study participation is approximately 5 years.

    Outcome Measure Data

    Analysis Population Description
    Three patients in Stratum A experienced graft rejection which met the criteria for failing to achieve superior engraftment compared to standard-of-care. One patient was not evaluable.
    Arm/Group TitleStratum A: Patients With Non-Malignancies
    Arm/Group DescriptionAlemtuzumab: 0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-HCT Busulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
    Measure Participants9
    Number [percentage of participants]
    66.67
    666.7%
    3. Secondary Outcome
    TitleMixed-donor Chimerism Rate of Patients With High-risk Myeloid Malignancies (Stratum B)
    DescriptionFull-donor chimerism will be defined by as ≥99% donor cells by Short Tandem Repeat (STR) analysis in all cell lines (CD3, CD14/15, and CD19) in peripheral blood. The historic control for Stratum B was determined using the 20 patients who were transplanted from 2005 - 2010 with Busulfan (BU)-based regimens and who retrospectively would have been eligible for the current trial. Of these 20 patients, at 100 days post-HCT, only 8 (40%) patients had full-donor chimerism. If 5 patients in Stratum B experienced mixed-donor chimerism at Day 100, we will close this stratum early for failing to achieve superior donor cell engraftment compared to standard-of-care.
    Time FrameParticipants will have peripheral blood chimerism assessed at Day 100 post hematopoietic stem cell transplant and then monthly until stable.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleStratum B: Patients With Myeloid Malignancies
    Arm/Group DescriptionBusulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
    Measure Participants6
    Number [percentage of participants]
    66.67
    666.7%
    4. Secondary Outcome
    TitleSerum Concentrations and Potential for Drug-drug Interaction of Fludarabine and Clofarabine
    DescriptionFludarabine and clofarabine drug levels and potential covariates influencing drug exposure such as renal function and genetic variants involved in drug metabolism, distribution, and activation will be analyzed using standard population pharmacokinetic methods using non-linear mixed effects modeling (NONMEM) software
    Time FramePharmacokinetics (PK) blood sampling Days -5 to -2 pre-hematopoietic stem cell transplant.

    Outcome Measure Data

    Analysis Population Description
    PK Data not collected
    Arm/Group TitleStratum A: Patients With Non-MalignanciesStratum B: Patients With Myeloid Malignancies
    Arm/Group DescriptionAlemtuzumab: 0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-HCT Busulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCTBusulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
    Measure Participants00

    Adverse Events

    Time FrameUp to 5 years
    Adverse Event Reporting Description Bone Marrow Transplant (BMT) patients have a large number of toxicities as an expected part of the intervention. Some traditional adverse events are an intended part of the conditioning and therefore not considered an unexpected toxicity as part of the treatment regimen. All of the reported febrile neutropenia, anemia, and mucositis events were anticipated as part of bone marrow transplant.
    Arm/Group TitleStratum A: Patients With Non-MalignanciesStratum B: Patients With Myeloid Malignancies
    Arm/Group DescriptionAlemtuzumab: 0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-HCT Busulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCTBusulfan: 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT Fludarabine: 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT Clofarabine: 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
    All Cause Mortality
    Stratum A: Patients With Non-MalignanciesStratum B: Patients With Myeloid Malignancies
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total1/10 (10%) 6/6 (100%)
    Serious Adverse Events
    Stratum A: Patients With Non-MalignanciesStratum B: Patients With Myeloid Malignancies
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total1/10 (10%) 1/6 (16.7%)
    General disorders
    Veno-occlusive disease (VOD)1/10 (10%) 11/6 (16.7%) 1
    Other (Not Including Serious) Adverse Events
    Stratum A: Patients With Non-MalignanciesStratum B: Patients With Myeloid Malignancies
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total10/10 (100%) 6/6 (100%)
    Blood and lymphatic system disorders
    Febrile neutropenia10/10 (100%) 106/6 (100%) 6
    Anemia10/10 (100%) 106/6 (100%) 6
    Gastrointestinal disorders
    Mucositis oral10/10 (100%) 106/6 (100%) 6
    Infections and infestations
    Lung Infection0/10 (0%) 01/6 (16.7%) 1
    Lymph Gland Infection0/10 (0%) 01/6 (16.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Stridor1/10 (10%) 10/6 (0%) 0

    Limitations/Caveats

    Study closed prior to completion. Interim analysis suggested treatments would not demonstrate statistical superiority over historic controls.

    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/TitleDr. Christopher Dvorak, MD
    OrganizationUniversity of California, San Francisco
    Phone(415) 476-0554
    EmailChristopher.Dvorak@ucsf.edu
    Responsible Party:
    University of California, San Francisco
    ClinicalTrials.gov Identifier:
    NCT01596699
    Other Study ID Numbers:
    • 110819
    • NCI-2012-00800
    First Posted:
    May 11, 2012
    Last Update Posted:
    Feb 26, 2020
    Last Verified:
    Feb 1, 2020