Pilot Trial of Clofarabine Added to Standard Busulfan and Fludarabine for Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/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:
Drug: Fludarabine
40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
Other Names:
Drug: Clofarabine
10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
Other Names:
|
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:
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:
Drug: Fludarabine
40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
Other Names:
Drug: Clofarabine
10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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
- 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
Eligibility Criteria
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University of California, San Francisco | San Francisco | California | United States | 94143 |
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.- 110819
- NCI-2012-00800
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Stratum A: Patients With Non-Malignancies | Stratum B: Patients With Myeloid Malignancies |
---|---|---|
Arm/Group Description | Alemtuzumab: 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-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 |
Period Title: Overall Study | ||
STARTED | 10 | 6 |
COMPLETED | 10 | 6 |
NOT COMPLETED | 0 | 0 |
Baseline Characteristics
Arm/Group Title | Stratum A: Patients With Non-Malignancies | Stratum B: Patients With Myeloid Malignancies | Total |
---|---|---|---|
Arm/Group Description | 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 | 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 | Total of all reporting groups |
Overall Participants | 10 | 6 | 16 |
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
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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Stratum A: Patients With Non-Malignancies | Stratum B: Patients With Myeloid Malignancies |
---|---|---|
Arm/Group Description | 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 | 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 Participants | 10 | 6 |
Death |
1
10%
|
0
0%
|
Veno-occlusive disease(VOD) |
1
10%
|
1
16.7%
|
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. |
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 Title | Stratum A: Patients With Non-Malignancies |
---|---|
Arm/Group Description | 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 |
Measure Participants | 9 |
Number [percentage of participants] |
66.67
666.7%
|
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. |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Stratum B: Patients With Myeloid Malignancies |
---|---|
Arm/Group Description | 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 Participants | 6 |
Number [percentage of participants] |
66.67
666.7%
|
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. |
Outcome Measure Data
Analysis Population Description |
---|
PK Data not collected |
Arm/Group Title | Stratum A: Patients With Non-Malignancies | Stratum B: Patients With Myeloid Malignancies |
---|---|---|
Arm/Group Description | 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 | 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 Participants | 0 | 0 |
Adverse Events
Time Frame | Up 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 Title | Stratum A: Patients With Non-Malignancies | Stratum B: Patients With Myeloid Malignancies | ||
Arm/Group Description | 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 | 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 | ||
All Cause Mortality |
||||
Stratum A: Patients With Non-Malignancies | Stratum B: Patients With Myeloid Malignancies | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 1/10 (10%) | 6/6 (100%) | ||
Serious Adverse Events |
||||
Stratum A: Patients With Non-Malignancies | Stratum B: Patients With Myeloid Malignancies | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 1/10 (10%) | 1/6 (16.7%) | ||
General disorders | ||||
Veno-occlusive disease (VOD) | 1/10 (10%) | 1 | 1/6 (16.7%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
Stratum A: Patients With Non-Malignancies | Stratum B: Patients With Myeloid Malignancies | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 10/10 (100%) | 6/6 (100%) | ||
Blood and lymphatic system disorders | ||||
Febrile neutropenia | 10/10 (100%) | 10 | 6/6 (100%) | 6 |
Anemia | 10/10 (100%) | 10 | 6/6 (100%) | 6 |
Gastrointestinal disorders | ||||
Mucositis oral | 10/10 (100%) | 10 | 6/6 (100%) | 6 |
Infections and infestations | ||||
Lung Infection | 0/10 (0%) | 0 | 1/6 (16.7%) | 1 |
Lymph Gland Infection | 0/10 (0%) | 0 | 1/6 (16.7%) | 1 |
Respiratory, thoracic and mediastinal disorders | ||||
Stridor | 1/10 (10%) | 1 | 0/6 (0%) | 0 |
Limitations/Caveats
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/Title | Dr. Christopher Dvorak, MD |
---|---|
Organization | University of California, San Francisco |
Phone | (415) 476-0554 |
Christopher.Dvorak@ucsf.edu |
- 110819
- NCI-2012-00800