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| ID | Type | Description | Link |
|---|---|---|---|
| NCI-2012-00800 | Registry Identifier | NCI Clinical Trials Reporting Program (CTRP) |
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Triggering of futility rule; Interim analysis suggested no statistical superiority over historic controls
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with Myeloid Malignancies | Experimental |
| |
| Patients with Non-Malignancies | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Alemtuzumab | Drug | 0.5 mg/kg (max 15 mg or max 6 mg), IV, Day -12 to Day -10 pre-HCT |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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%. | Up to 5 years on average |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Patients must be ≥ 3 months and ≤30 years of age.
Stratum A: Non-Malignant Diseases, including:
Stratum B: Myeloid Malignancies, including:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Christopher C Dvorak, MD | University of California, San Francisco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, San Francisco | San Francisco | California | 94143 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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-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 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 7, 2013 |
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| Busulfan | Drug | 0.8 mg/kg/dose q6hrs or 1.1 mg/kg/dose q6hrs, IV, Day -9 to Day -6 pre-HCT |
|
|
| Fludarabine | Drug | 40 mg/m2 or 1.33 mg/kg, IV, Day -5 to Day -2 pre-HCT |
|
|
| Clofarabine | Drug | 10 mg/m2 or 0.33 mg/kg, IV, Day -5 to Day -2 pre-HCT |
|
|
| 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. |
| 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. | Participants will have peripheral blood chimerism assessed at Day 100 post hematopoietic stem cell transplant and then monthly until stable. |
| 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 | Pharmacokinetics (PK) blood sampling Days -5 to -2 pre-hematopoietic stem cell transplant. |
| FG001 | 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 |
| COMPLETED |
|
| NOT COMPLETED |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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 |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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%. | Posted | Number | participants | Up to 5 years on average |
|
|
| |||||||||||||||||||||||||||||||||||||
| 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. | 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. | Posted | Number | percentage of participants | 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. |
|
| |||||||||||||||||||||||||||||||||||||
| 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. | Posted | Number | percentage of participants | Participants will have peripheral blood chimerism assessed at Day 100 post hematopoietic stem cell transplant and then monthly until stable. |
|
| ||||||||||||||||||||||||||||||||||||||
| 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 | PK Data not collected | Posted | Pharmacokinetics (PK) blood sampling Days -5 to -2 pre-hematopoietic stem cell transplant. |
|
|
Up to 5 years
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 | 1 | 10 | 1 | 10 | 10 | 10 |
| EG001 | 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 | 6 | 1 | 6 | 6 | 6 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Veno-occlusive disease (VOD) | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Stridor | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Anemia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Mucositis oral | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Lung Infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
| |
| Lymph Gland Infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
|
Study closed prior to completion. Interim analysis suggested treatments would not demonstrate statistical superiority over historic controls.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Christopher Dvorak, MD | University of California, San Francisco | (415) 476-0554 | Christopher.Dvorak@ucsf.edu |
| Feb 7, 2020 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form: Minor-Parental | Apr 10, 2014 | Feb 7, 2020 | ICF_001.pdf |
| ICF | No | No | Yes | Informed Consent Form: Assent (Ages 7-12) | Apr 10, 2014 | Feb 7, 2020 | ICF_002.pdf |
| ICF | No | No | Yes | Informed Consent Form: Adult Adolescent | Apr 10, 2014 | Feb 7, 2020 | ICF_003.pdf |
| ID | Term |
|---|---|
| D000080983 | Bone Marrow Failure Disorders |
| D008659 | Metabolic Diseases |
| ID | Term |
|---|---|
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000074323 | Alemtuzumab |
| D002066 | Busulfan |
| C024352 | fludarabine |
| C042382 | fludarabine phosphate |
| D000077866 | Clofarabine |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D002072 | Butylene Glycols |
| D006018 | Glycols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D008698 | Mesylates |
| D000476 | Alkanesulfonates |
| D017738 | Alkanesulfonic Acids |
| D000473 | Alkanes |
| D006839 | Hydrocarbons, Acyclic |
| D006838 | Hydrocarbons |
| D013451 | Sulfonic Acids |
| D013456 | Sulfur Acids |
| D013457 | Sulfur Compounds |
| D000227 | Adenine Nucleotides |
| D011685 | Purine Nucleotides |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D001087 | Arabinonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D009711 | Nucleotides |
| D012265 | Ribonucleotides |
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| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
|
|
| Participants |
|