Symptoms and General Pathology

All Conditions

Nutritional and Metabolic Diseases

Immune System Diseases

Blood and Lymph Conditions

Syndrome

Metabolic Diseases

Immunologic Deficiency Syndromes

Bone Marrow Failure Disorders

Pancytopenia

Bone Marrow Diseases

Hematologic Diseases

Cytopenia

Antineoplastic Agents

All Drugs and Chemicals

Fludarabine

Fludarabine phosphate

Busulfan

Alemtuzumab

Clofarabine

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Alkylating Agents

Antineoplastic Agents, Alkylating

Antineoplastic Agents, Immunological

0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-HCT

0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT

40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT

10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT

Christopher C Dvorak, MD

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.

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

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

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%.

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.

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.

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

University of California, San Francisco

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.

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

Stratum A: Patients With Non-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

Stratum B: Patients With Myeloid Malignancies

Total

0-9 years old

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

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

Dr. Christopher Dvorak, MD

Death

Veno-occlusive disease(VOD)

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

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.

Engraftment Rate of Patients With Non-malignant Diseases (Stratum A)

Mixed-donor Chimerism Rate of Patients With High-risk Myeloid Malignancies (Stratum B)

Serum Concentrations and Potential for Drug-drug Interaction of Fludarabine and Clofarabine

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

Spots Global Cancer Trial Database for congenital immunodeficiency