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

Primary Purpose

Myeloid Malignancy, Bone Marrow Failure Syndrome, Transfusion-dependent Red Blood Cell (RBC) Defect

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Alemtuzumab
Busulfan
Fludarabine
Clofarabine
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myeloid Malignancy focused on measuring conditioning, allogeneic, hematopoietic, cell, transplantation, HCT

Eligibility Criteria

3 Months - 30 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California, San Francisco

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Patients with Myeloid Malignancies

Patients with Non-Malignancies

Arm Description

Outcomes

Primary Outcome Measures

Number of Participants With Treatment-Related Adverse Events as a Measure of Safety and Tolerability
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

Engraftment Rate of Patients With Non-malignant Diseases (Stratum A)
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.
Mixed-donor Chimerism Rate of Patients With High-risk Myeloid Malignancies (Stratum B)
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.
Serum Concentrations and Potential for Drug-drug Interaction of Fludarabine and Clofarabine
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

Full Information

First Posted
May 7, 2012
Last Updated
February 25, 2020
Sponsor
University of California, San Francisco
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1. Study Identification

Unique Protocol Identification Number
NCT01596699
Brief Title
Pilot Trial of Clofarabine Added to Standard Busulfan and Fludarabine for Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation
Official Title
A Pilot Trial of Clofarabine Added to Standard Busulfan and Fludarabine for Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Terminated
Why Stopped
Triggering of futility rule; Interim analysis suggested no statistical superiority over historic controls
Study Start Date
May 24, 2012 (Actual)
Primary Completion Date
June 2019 (Actual)
Study Completion Date
June 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myeloid Malignancy, Bone Marrow Failure Syndrome, Transfusion-dependent Red Blood Cell (RBC) Defect, Congenital Immunodeficiency, Metabolic Disease, Severe Immune Dysregulation
Keywords
conditioning, allogeneic, hematopoietic, cell, transplantation, HCT

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Patients with Myeloid Malignancies
Arm Type
Experimental
Arm Title
Patients with Non-Malignancies
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Alemtuzumab
Other Intervention Name(s)
Campath
Intervention Description
0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-HCT
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
Busulfex
Intervention Description
0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
Intervention Type
Drug
Intervention Name(s)
Clofarabine
Other Intervention Name(s)
Clolar
Intervention Description
10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-Related Adverse Events as a Measure of Safety and Tolerability
Description
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%.
Time Frame
Up to 5 years on average
Secondary Outcome Measure Information:
Title
Engraftment Rate of Patients With Non-malignant Diseases (Stratum A)
Description
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.
Time Frame
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.
Title
Mixed-donor Chimerism Rate of Patients With High-risk Myeloid Malignancies (Stratum B)
Description
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.
Time Frame
Participants will have peripheral blood chimerism assessed at Day 100 post hematopoietic stem cell transplant and then monthly until stable.
Title
Serum Concentrations and Potential for Drug-drug Interaction of Fludarabine and Clofarabine
Description
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
Time Frame
Pharmacokinetics (PK) blood sampling Days -5 to -2 pre-hematopoietic stem cell transplant.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Months
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christopher C Dvorak, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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