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)
• Enrollment: 16
• Location: 1
• Arms: 2
• Actual Duration (Months): 84.2
• Patients Per Site Per Month: 0.2

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
Myeloid Malignancy; Bone Marrow Failure Syndrome; Transfusion-dependent Red Blood Cell (RBC) Defect; Congenital Immunodeficiency; Metabolic Disease; Severe Immune Dysregulation	Drug: Alemtuzumab; Drug: Busulfan; Drug: Fludarabine; Drug: Clofarabine	Phase 2

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

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: 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

	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)

• Study Protocol and Statistical Analysis Plan - Jun 7, 2013
• Informed Consent Form: Minor-Parental - Apr 10, 2014
• Informed Consent Form: Assent (Ages 7-12) - Apr 10, 2014
• Informed Consent Form: Adult Adolescent - Apr 10, 2014

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: conditioning; allogeneic; hematopoietic; cell; transplantation; HCT
• Additional relevant MeSH terms: Bone Marrow Failure Disorders; Pancytopenia; Metabolic Diseases; Fludarabine; Busulfan; Alemtuzumab; Clofarabine

Study Results

Participant Flow

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

1. Primary Outcome

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%

2. Secondary Outcome

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%

3. Secondary Outcome

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%

4. Secondary Outcome

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

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.