Bone Marrow Failure Syndrome, Congenital Immunodeficiency, Metabolic Disease, Myeloid Malignancy, Severe Immune Dysregulation, Transfusion-dependent Red Blood Cell (RBC) Defect
Conditions
Keywords
conditioning, allogeneic, hematopoietic, cell, transplantation, HCT
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.
Interventions
DRUGAlemtuzumab
0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-HCT
DRUGBusulfan
0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT
DRUGFludarabine
40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
DRUGClofarabine
10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
Sponsors
University of California, San Francisco
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 30 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stratum A: Patients With Non-Malignancies Alemtuzumab: 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 | 10 |
| Stratum B: Patients With Myeloid Malignancies 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 | 6 |
| Total | 16 |
Baseline characteristics
| Characteristic | Total | Stratum A: Patients With Non-Malignancies | Stratum B: Patients With Myeloid Malignancies |
|---|---|---|---|
| Age, Customized 0-9 years old | 16 Participants | 10 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 4 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 6 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 7 Participants | 3 Participants |
| Region of Enrollment United States | 16 participants | 10 participants | 6 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 10 | 6 / 6 |
| other Total, other adverse events | 10 / 10 | 6 / 6 |
| serious Total, serious adverse events | 1 / 10 | 1 / 6 |
Outcome results
Primary
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%.
Time frame: Up to 5 years on average
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum A: Patients With Non-Malignancies | Number of Participants With Treatment-Related Adverse Events as a Measure of Safety and Tolerability | Death | 1 participants |
| Stratum A: Patients With Non-Malignancies | Number of Participants With Treatment-Related Adverse Events as a Measure of Safety and Tolerability | Veno-occlusive disease(VOD) | 1 participants |
| Stratum B: Patients With Myeloid Malignancies | Number of Participants With Treatment-Related Adverse Events as a Measure of Safety and Tolerability | Death | 0 participants |
| Stratum B: Patients With Myeloid Malignancies | Number of Participants With Treatment-Related Adverse Events as a Measure of Safety and Tolerability | Veno-occlusive disease(VOD) | 1 participants |
Secondary
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.
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.
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Stratum A: Patients With Non-Malignancies | Engraftment Rate of Patients With Non-malignant Diseases (Stratum A) | 66.67 percentage of participants |
Secondary
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.
Time frame: Participants will have peripheral blood chimerism assessed at Day 100 post hematopoietic stem cell transplant and then monthly until stable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum A: Patients With Non-Malignancies | Mixed-donor Chimerism Rate of Patients With High-risk Myeloid Malignancies (Stratum B) | 66.67 percentage of participants |
Secondary
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
Time frame: Pharmacokinetics (PK) blood sampling Days -5 to -2 pre-hematopoietic stem cell transplant.
Population: PK Data not collected