A Phase 2 interventional study of Busulfan and Cyclophosphamide in Acute Leukemia, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Chronic Myelogenous Leukemia, BCR-ABL1 Positive, sponsored by City of Hope Medical Center. Completed at 1 site in United States. Open to participants aged 5 Years to 75 Years. Per ClinicalTrials.gov, last updated 2024-01-09.
Sponsored by City of Hope Medical Center · Phase 2, Interventional, and Supportive care
This pilot phase II trial studies how well high dose cyclophosphamide, tacrolimus, and mycophenolate mofetil work in preventing graft versus host disease in patients with hematological malignancies undergoing myeloablative or reduced intensity donor stem cell transplant. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft versus host disease). Giving high dose cyclophosphamide, tacrolimus, and mycophenolate mofetil after the transplant may stop this from happening.
PRIMARY OBJECTIVES:
I. To estimate the graft versus host disease (GVHD)-free relapse/progression-free survival (GRFS) at one-year post hematopoietic cell transplantation (HCT) and to evaluate the clinical activity of post-transplant high dose cyclophosphamide (PTCy).
SECONDARY OBJECTIVES:
I. To summarize toxicities/complications/infections including type, frequency, severity, attribution, time course and duration through 100 days post-transplant.
II. To estimate the cumulative incidence (CI) of acute and chronic GVHD. III. To characterize the time course of neutrophil and platelet recovery/engraftment.
IV. To estimate overall survival (OS), progression-free survival (PFS), CI of relapse/progression and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.
V. To describe quality of life at 100 days, 6 months, 1 and 2 years. VI. To characterize immune cell reconstitution and T cell repertoire post high dose cyclophosphamide in mismatched donor HCT.
VII. To characterize quality of life.
OUTLINE:
CONDITIONING REGIMEN: Patients are assigned to 1 of 3 conditioning regimens at the discretion of the attending physician and principal investigator.
REGIMEN A (REDUCED INTENSITY CONDITIONING): Patients receive fludarabine phosphate intravenously (IV) over 60 minutes on days -7 to -3 and melphalan hydrochloride IV over 20 minutes on day -2.
REGIMEN B (MYELOABLATIVE CONDITIONING [MAC]): Patients receive fludarabine phosphate IV over 1-3 hours and busulfan IV over 3 hour on days -5 to -2.
REGIMEN C (MAC): Patients receive fludarabine phosphate IV over 60 minutes on days -7 to -5 and total body irradiation (TBI) twice daily (BID) on days -4 to -1.
TRANSPLANT: Patients undergo peripheral blood stem cell (PBSC) hematopoietic cell transplantation (HCT) on day 0.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, mycophenolate mofetil IV or orally (PO) thrice daily (TID) beginning on day 5 and stopping on day 35 if no severe GVHD is present, and tacrolimus IV continuously on days 5-180 with a taper beginning on day 90 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up twice weekly for 100 days, twice monthly for 6 months, monthly until no evidence of GVHD, and then yearly for up to 2 years.
5,578 studies on the registry are indexed under Lymphoma; 825 are open to participants now.
This study's enrollment of 38 is close to the median of 40 across 4,508 interventional studies indexed under Lymphoma.
Browse Lymphoma studies →City of Hope Medical Center is the lead sponsor of 670 studies on the registry; 181 are open to participants now.
Of its 30 completed or terminated interventional studies of FDA-regulated products, 12 (40%) have results posted.
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DONOR INCLUSION CRITERIA
Exclusion Criteria:
Patients receive fludarabine phosphate IV over 60 minutes on days -7 to -3 and melphalan hydrochloride IV over 20 minutes on day -2. Patients undergo PBSC HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, mycophenolate mofetil IV or PO TID beginning on days 5 and stopping on day 35 if no severe GVHD is present-35, and tacrolimus IV continuously on days 5-180 with a taper beginning on day 90 in the absence of disease progression or unacceptable toxicity.
Drug: Cyclophosphamide · Drug: Fludarabine Phosphate · Procedure: Hematopoietic Cell Transplantation · Other: Laboratory Biomarker Analysis · Drug: Melphalan Hydrochloride · Drug: Mycophenolate Mofetil · Procedure: Peripheral Blood Stem Cell Transplantation · Other: Quality-of-Life Assessment · Drug: Tacrolimus
Patients receive fludarabine phosphate IV over 1-3 hours and busulfan IV over 3 hour on days -5 to -2. Patients undergo PBSC HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, mycophenolate mofetil IV or PO TID beginning on days 5 and stopping on day 35 if no severe GVHD is present-35, and tacrolimus IV continuously on days 5-180 with a taper beginning on day 90 in the absence of disease progression or unacceptable toxicity.
Drug: Busulfan · Drug: Cyclophosphamide · Drug: Fludarabine Phosphate · Procedure: Hematopoietic Cell Transplantation · Other: Laboratory Biomarker Analysis · Drug: Mycophenolate Mofetil · Procedure: Peripheral Blood Stem Cell Transplantation · Other: Quality-of-Life Assessment · Drug: Tacrolimus
Patients receive fludarabine phosphate IV over 60 minutes on days -7 to -5 and TBI BID on days -4 to -1. Patients undergo PBSC HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, mycophenolate mofetil IV or PO TID beginning on days 5 and stopping on day 35 if no severe GVHD is present-35, and tacrolimus IV continuously on days 5-180 with a taper beginning on day 90 in the absence of disease progression or unacceptable toxicity.
Drug: Cyclophosphamide · Drug: Fludarabine Phosphate · Procedure: Hematopoietic Cell Transplantation · Other: Laboratory Biomarker Analysis · Drug: Mycophenolate Mofetil · Procedure: Peripheral Blood Stem Cell Transplantation · Other: Quality-of-Life Assessment · Drug: Tacrolimus · Radiation: Total-Body Irradiation
Given IV
Also known as: 1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508
Given IV
Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
Given IV
Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Undergo PBSC HCT
Also known as: HCT, Hematopoietic Stem Cell Transplantation, HSCT, stem cell transplantation
Correlative studies
Given IV
Also known as: Alkeran, Alkerana, Evomela
Given IV or PO
Also known as: Cellcept, MMF
Undergo PBSC HCT
Also known as: PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation
Ancillary studies
Also known as: Quality of Life Assessment
Given IV
Also known as: FK 506, Fujimycin, Hecoria, Prograf, Protopic
Undergo TBI
Also known as: TOTAL BODY IRRADIATION, Whole-Body Irradiation
Graft-Versus-Host Disease-Free, Relapse-Free Survival (GRFS) at 1 Year
Estimates will be calculated using the Kaplan-Meier method, Greenwood formula will be used to calculate standard error (SE), and log-log transformation method will be used to construct 95% confidence intervals. Graft versus host disease (GVHD, acute and chronic), disease status and vital status will be monitored per clinical standard operating procedure. For this endpoint failure is defined as the first occurrence of grade 3 or 4 acute GVHD, or moderate/severe chronic GVHD, or disease relapse (for patients in complete remission at the start of conditioning) or disease progression (for patients with active disease at the start of conditioning) or death (from any cause). Patients not experiencing any of these will be censored at his/her date of last contact.
Time frame: From stem cell infusion to grade 3-4 acute graft versus host disease (GVHD), moderate-severe chronic GVHD, relapse, progression or death (from any cause), whichever occurs first, assessed for up to 1 year.
Acute Graft Versus Host Disease (aGVHD) of Grades 2-4 According to the Consensus Grading
Acute graft versus host disease is graded according to the 1994 Keystone Consensus Grading. aGVHD grade was evaluated from day 0 through 100 days post-transplant. The first day of acute GVHD onset at grades 2-4 was used to calculate the cumulative incidence. Relapse/death prior to onset was considered competing events.
Time frame: Up to 100 days post-stem cell infusion
Overall Survival (OS) at 1 Year
Estimates was calculated using the Kaplan-Meier method, Greenwood formula was used to calculate SE, and log-log transformation method was used to construct 95% confidence intervals. Each patient's vital status was monitored per clinical standard operating procedure. For this endpoint failure is defined as death (from any cause). Patients not experiencing a death event was censored at his/her date of last contact.
Time frame: From start of transplant to death, or last follow up, whichever occurs first, assessed for up to 1 year.
| Milestone | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen B (Fludarabine, Busulfan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) |
|---|---|---|---|
| Started | 19 | 0 | 19 |
| Completed | 19 | 0 | 19 |
| Not completed | 0 | 0 | 0 |
Estimates will be calculated using the Kaplan-Meier method, Greenwood formula will be used to calculate standard error (SE), and log-log transformation method will be used to construct 95% confidence intervals. Graft versus host disease (GVHD, acute and chronic), disease status and vital status will be monitored per clinical standard operating procedure. For this endpoint failure is defined as the first occurrence of grade 3 or 4 acute GVHD, or moderate/severe chronic GVHD, or disease relapse (for patients in complete remission at the start of conditioning) or disease progression (for patients with active disease at the start of conditioning) or death (from any cause). Patients not experiencing any of these will be censored at his/her date of last contact.
| percentage of survival probability | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) |
|---|---|---|
| Graft-Versus-Host Disease-Free, Relapse-Free Survival (GRFS) at 1 Year | 53 (29 to 72) | 84 (59 to 95) |
Acute graft versus host disease is graded according to the 1994 Keystone Consensus Grading. aGVHD grade was evaluated from day 0 through 100 days post-transplant. The first day of acute GVHD onset at grades 2-4 was used to calculate the cumulative incidence. Relapse/death prior to onset was considered competing events.
| percentage of probability | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) |
|---|---|---|
| Acute Graft Versus Host Disease (aGVHD) of Grades 2-4 According to the Consensus Grading | 47 (29 to 76) | 53 (34 to 81) |
Estimates was calculated using the Kaplan-Meier method, Greenwood formula was used to calculate SE, and log-log transformation method was used to construct 95% confidence intervals. Each patient's vital status was monitored per clinical standard operating procedure. For this endpoint failure is defined as death (from any cause). Patients not experiencing a death event was censored at his/her date of last contact.
| percentage of probability | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) |
|---|---|---|
| Overall Survival (OS) at 1 Year | 68 (42 to 84) | 100 (NA to NA) |
Collected over Up to 2 years post-transplant.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | 9/19 (47.4%) | 12/19 (63.2%) | 19/19 (100%) |
| Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) | 0/19 (0%) | 6/19 (31.6%) | 19/19 (100%) |
| Event | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) |
|---|---|---|
| SEPSISInfections and infestations | 3/19 | 1/19 |
| VOMITINGGastrointestinal disorders | 0/19 | 2/19 |
| FEVERGeneral disorders | 0/19 | 2/19 |
| CMV VIREMIAInfections and infestations | 2/19 | 0/19 |
| RESPIRATORY FAILURERespiratory, thoracic and mediastinal disorders | 2/19 | 0/19 |
| FEBRILE NEUTROPENIABlood and lymphatic system disorders | 1/19 | 1/19 |
| HEMOLYSISBlood and lymphatic system disorders | 0/19 | 1/19 |
| ABDOMINAL PAINGastrointestinal disorders | 1/19 | 0/19 |
| DIARRHEAGastrointestinal disorders | 1/19 | 0/19 |
| NAUSEAGastrointestinal disorders | 0/19 | 1/19 |
| Event | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) |
|---|---|---|
| ANEMIABlood and lymphatic system disorders | 19/19 | 19/19 |
| DIARRHEAGastrointestinal disorders | 19/19 | 19/19 |
| NAUSEAGastrointestinal disorders | 19/19 | 19/19 |
| LYMPHOCYTE COUNT DECREASEDInvestigations | 19/19 | 19/19 |
| NEUTROPHIL COUNT DECREASEDInvestigations | 19/19 | 17/19 |
| PLATELET COUNT DECREASEDInvestigations | 18/19 | 19/19 |
| HYPOKALEMIAMetabolism and nutrition disorders | 19/19 | 18/19 |
| HYPOMAGNESEMIAMetabolism and nutrition disorders | 19/19 | 17/19 |
| HYPONATREMIAMetabolism and nutrition disorders | 19/19 | 19/19 |
| VOMITINGGastrointestinal disorders | 18/19 | 17/19 |
No subject enrolled onto Regimen B.
| Age, Continuous(years) | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen B (Fludarabine, Busulfan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) | Total |
|---|---|---|---|---|
| Median | 63 (33 to 72) | — | 44 (21 to 57) | 53 (21 to 72) |
| Sex: Female, Male(Participants) | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen B (Fludarabine, Busulfan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) | Total |
|---|---|---|---|---|
| Female | 8 | — | 11 | 19 |
| Male | 11 | — | 8 | 19 |
| Ethnicity (NIH/OMB)(Participants) | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen B (Fludarabine, Busulfan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) | Total |
|---|---|---|---|---|
| Hispanic or Latino | 3 | — | 8 | 11 |
| Not Hispanic or Latino | 15 | — | 11 | 26 |
| Unknown or Not Reported | 1 | — | 0 | 1 |
| Race (NIH/OMB)(Participants) | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen B (Fludarabine, Busulfan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | — | 0 | 0 |
| Asian | 4 | — | 4 | 8 |
| Native Hawaiian or Other Pacific Islander | 0 | — | 0 | 0 |
| Black or African American | 2 | — | 2 | 4 |
| White | 12 | — | 12 | 24 |
| More than one race | 0 | — | 0 | 0 |
| Unknown or Not Reported | 1 | — | 1 | 2 |
| Region of Enrollment(participants) | Regimen A (Fludarabine, Melphalan, PBSC HCT, GVHD Prophylaxis) | Regimen B (Fludarabine, Busulfan, PBSC HCT, GVHD Prophylaxis) | Regimen C (Fludarabine, TBI, PBSC HCT, GVHD Prophylaxis) | Total |
|---|---|---|---|---|
| United States | 19 | — | 19 | 38 |
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