Busulfan, Fludarabine Phosphate, and Post-Transplant Cyclophosphamide in Treating Patients With Blood Cancer Undergoing Donor Stem Cell Transplant
December 12, 2023 updated by: M.D. Anderson Cancer Center
Timed Sequential Busulfan and Post Transplant Cyclophosphamide for Allogeneic Transplantation
This phase II trial studies the side effect of busulfan, fludarabine phosphate, and post-transplant cyclophosphamide in treating patients with blood cancer undergoing donor stem cell transplant.
Drugs used in chemotherapy, such as busulfan, fludarabine phosphate and cyclophosphamide work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Giving chemotherapy such as busulfan and fludarabine phosphate before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells.
Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease).
Giving cyclophosphamide after the transplant may stop this from happening.
Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them.
Study Overview
Status
Active, not recruiting
Conditions
- Hematopoietic and Lymphoid Cell Neoplasm
- Recurrent Hodgkin Lymphoma
- Myelodysplastic Syndrome
- Recurrent Acute Myeloid Leukemia
- Recurrent Myelodysplastic Syndrome
- High Risk Myelodysplastic Syndrome
- Recurrent Non-Hodgkin Lymphoma
- Recurrent Acute Lymphoblastic Leukemia
- Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
- Recurrent Plasma Cell Myeloma
- Myelodysplastic/Myeloproliferative Neoplasm
- Lymphoproliferative Disorder
- Recurrent High Risk Myelodysplastic Syndrome
- High Risk Acute Myeloid Leukemia
Detailed Description
PRIMARY OBJECTIVE:
I. To assess safety of timed sequential busulfan and fludarabine conditioning regimen and post transplant cyclophosphamide as determined by day 100 non-relapse mortality in patients undergoing allogeneic transplantation: from matched donors; from mismatched (haploidentical) donors.
SECONDARY OBJECTIVE:
I. To evaluate efficacy of this therapy and to compare outcomes between recipients of matched and mismatched donors by studying the following endpoints: graft versus host disease (GVHD)-free/relapse free survival; relapse-free survival; overall survival; non-relapse mortality; relapse rate; time to neutrophil and platelet engraftment; incidence of acute and chronic GVHD; grade 3 and 4 adverse events.
TERTIARY OBJECTIVE:
I. To study impact of timed sequential busulfan therapy and post-transplant cyclophosphamide on immune reconstitution and cytokines levels post-transplant.
OUTLINE: Patients are assigned to 1 of 4 groups.
GROUP I (FROM HAPLOIDENTICAL DONOR): Patients receive busulfan intravenously (IV) over 3 hours on days -13, -12, and -6 to -3, thiotepa IV over 4 hours on day -7, fludarabine phosphate IV over 1 hour on days -6 to -3. Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or orally (PO) twice daily (BID) for up to 3 months and mycophenolate mofetil PO thrice daily (TID).
GROUP II (FROM MATCHED DONOR): Patients receive busulfan IV over 3 hours on days -13, -12, and -6 to -3, fludarabine phosphate IV over 1 hour on days -6 to -3. Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or PO BID for up to 3 months.
GROUP III and GROUP IV: Patients receiving haploidentical related donor transplant, diagnosis of myelofibrosis, > 60 years old, or patients with comorbidity scores > 3 will go in Group 3 or 4. If patients with comorbidity score > 3, then the principal investigator is the final arbiter of eligibility for comorbidity score > 3. Busulfan is administered at the dose calculated to achieve a total (including first two doses delivered on day -20 and day -13) system exposure of 20,000 +/- 12% uMol-min based on the pharmacokinetic studies.
GROUP V and GROUP VI: Patients receive busulfan IV over 3 hours on days -20, -13, and -6 to -3, a lower dose of thiotepa IV over 4 hours on day -7, fludarabine phosphate IV over 1 hour on days -6 to -3. Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or PO BID for up to 3 months and mycophenolate mofetil PO TID.
Study Type
Interventional
Enrollment (Actual)
204
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Texas
-
Houston, Texas, United States, 77030
- M D Anderson Cancer Center
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
12 years to 75 years (Child, Adult, Older Adult)
Accepts Healthy Volunteers
No
Description
Inclusion Criteria:
- Patients with high-risk hematologic malignancies with anticipated poor prognosis with non transplant therapy, including those in remission or with induction failure and after treated or untreated relapse; Diagnoses to be included a) Acute myeloid leukemia; b) Acute lymphocytic leukemia; c) Chronic myeloid leukemia; d) Chronic lymphoproliferative disorder; e) Myelodysplastic syndrome; f) Myeloproliferative syndromes; g) Non-Hodgkin's lymphoma; h) Hodgkin's Lymphoma; i) Multiple myeloma
- Patients must have a haploidentical related donor or a fully matched related or unrelated donor
- Performance score of >= 70 by Karnofsky/Lansky or performance score (PS) 0 to 1 (Eastern Cooperative Oncology Group [ECOG] =< 1)
- Left ventricular ejection fraction >= 50%
- Adequate pulmonary function with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% of expected corrected for hemoglobin and/or volume; children unable to perform pulmonary function tests (e.g., less than 7 years old) pulse oximetry of >= 92% on room air
- Creatinine clearance (calculated creatinine clearance by Cockcroft-Gault using adjusted body weight if actual body weight is 20% greater than ideal is permitted) should be > 50 ml/min
- Bilirubin =< 2 x the upper limit of normal (except with patients high indirect bilirubin due to Gilbert's syndrome, hypersplenism, or hemolysis)
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 200
- Negative beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization; women of child bearing potential must be willing to use an effective contraceptive measure while on study
- Patient or patient's legal representative able to sign informed consent
Exclusion Criteria:
- Human immunodeficiency virus (HIV) seropositivity
- Uncontrolled infections
- Patients with comorbidity score > 3; the principal investigator is the final arbiter of eligibility for comorbidity score > 3
- Prior allogeneic transplant
- Patients with active hepatitis B and C
- Patients with prior coronary artery disease
- Patients who received inotuzumab and/or gemtuzumab in the past
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Group I (haploidentical donor transplant, chemotherapy)
Patients receive busulfan IV over 3 hours on days -13, -12, and -6 to -3, thiotepa IV over 4 hours on day -7, fludarabine phosphate IV over 1 hour on days -6 to -3.
Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or PO BID for up to 3 months and mycophenolate mofetil PO TID.
|
Correlative studies
Correlative studies
Given IV
Other Names:
Given IV
Other Names:
Undergo stem cell transplantation
Other Names:
Given PO
Other Names:
Given IV
Other Names:
Given IV or PO
Other Names:
Given IV
Other Names:
Given IV
Other Names:
|
|
Experimental: Group II (matched donor transplant, chemotherapy)
Patients receive busulfan IV over 3 hours on days -13, -12, and -6 to -3, fludarabine phosphate IV over 1 hour on days -6 to -3.
Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or PO BID for up to 3 months.
|
Correlative studies
Correlative studies
Given IV
Other Names:
Given IV
Other Names:
Undergo stem cell transplantation
Other Names:
Given IV
Other Names:
Given IV or PO
Other Names:
Given IV
Other Names:
|
|
Experimental: Group III (haploidentical donor transplant, chemotherapy)
Patients receiving haploidentical related donor transplant, diagnosis of myelofibrosis, > 60 years old, or patients with comorbidity scores > 3 will go in Group 3 or 4. If patients with comorbidity score > 3, then the principal investigator is the final arbiter of eligibility for comorbidity score > 3. Busulfan is administered at the dose calculated to achieve a total (including first two doses delivered on day -20 and day -13) system exposure of 20,000 +/- 12% uMol-min based on the pharmacokinetic studies.
|
Correlative studies
Correlative studies
Given IV
Other Names:
Given IV
Other Names:
Undergo stem cell transplantation
Other Names:
Given PO
Other Names:
Given IV
Other Names:
Given IV or PO
Other Names:
Given IV
Other Names:
Given IV
Other Names:
|
|
Experimental: Group IV (matched donor transplant, chemotherapy)
Patients receiving haploidentical related donor transplant, diagnosis of myelofibrosis, > 60 years old, or patients with comorbidity scores > 3 will go in Group 3 or 4. If patients with comorbidity score >3, then the principal investigator is the final arbiter of eligibility for comorbidity score > 3. Busulfan is administered at the dose calculated to achieve a total (including first two doses delivered on day -20 and day -13) system exposure of 20,000 +/- 12% uMol-min based on the pharmacokinetic studies.
|
Correlative studies
Correlative studies
Given IV
Other Names:
Given IV
Other Names:
Undergo stem cell transplantation
Other Names:
Given IV
Other Names:
Given IV or PO
Other Names:
Given IV
Other Names:
|
|
Experimental: Group V (haploidentical donor transplant, chemotherapy)
Patients receive busulfan IV over 3 hours on days -20, -13, and -6 to -3, a lower dose of thiotepa IV over 4 hours on day -7, fludarabine phosphate IV over 1 hour on days -6 to -3.
Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or PO BID for up to 3 months and mycophenolate mofetil PO TID.
|
Correlative studies
Correlative studies
Given IV
Other Names:
Given IV
Other Names:
Undergo stem cell transplantation
Other Names:
Given PO
Other Names:
Given IV
Other Names:
Given IV or PO
Other Names:
Given IV
Other Names:
Given IV
Other Names:
|
|
Experimental: Group VI (matched or haploidentical transplant, chemotherapy)
Patients receiving fully matched or haploidentical donor transplant receive busulfan IV over 3 hours on days -20, -13, and -6 to -3, a lower dose of thiotepa IV over 4 hours on day -7, fludarabine phosphate IV over 1 hour on days -6 to -3.
Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or PO BID for up to 3 months and mycophenolate mofetil PO TID.
|
Correlative studies
Correlative studies
Given IV
Other Names:
Given IV
Other Names:
Undergo stem cell transplantation
Other Names:
Given PO
Other Names:
Given IV
Other Names:
Given IV or PO
Other Names:
Given IV
Other Names:
Given IV
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Non-relapse mortality rate
Time Frame: 100 days
|
The proportion of patients with non-relapse mortality will be reported separately by arm, along with the corresponding 95% Bayesian credible interval.
|
100 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Graft versus host disease-free survival/relapse free survival
Time Frame: Up to 3 years
|
Will be calculated from the time of transplant by the method of Kaplan and Meier.
Patients with matched donors will be compared to patients with mismatched donors by the log-rank test.
Cox proportional hazards regression analysis will be used to assess the association between these survival parameters and clinical and treatment covariates of interest.
|
Up to 3 years
|
|
Relapse-free survival
Time Frame: Up to 3 years
|
Will be calculated from the time of transplant by the method of Kaplan and Meier.
Patients with matched donors will be compared to patients with mismatched donors by the log-rank test.
Cox proportional hazards regression analysis will be used to assess the association between these survival parameters and clinical and treatment covariates of interest.
|
Up to 3 years
|
|
Overall survival
Time Frame: Up to 3 years
|
Will be calculated from the time of transplant by the method of Kaplan and Meier.
Patients with matched donors will be compared to patients with mismatched donors by the log-rank test.
Cox proportional hazards regression analysis will be used to assess the association between these survival parameters and clinical and treatment covariates of interest.
|
Up to 3 years
|
|
Non-relapse mortality
Time Frame: Up to 3 years
|
The proportion of patients with non-relapse mortality will be reported separately by arm, along with the corresponding 95% Bayesian credible interval.
|
Up to 3 years
|
|
Relapse rate
Time Frame: Up to 3 years
|
Will be observed.
|
Up to 3 years
|
|
Time to platelet and neutrophil engraftment
Time Frame: Up to 3 years
|
Will be calculated from the time of transplant and estimated by the Kaplan-Meier method.
Distributions will be compared between patients with matched and mismatched donors via the log-rank test.
|
Up to 3 years
|
|
Incidence of acute and chronic graft versus host disease
Time Frame: Up to 3 years
|
Will be estimated using the method of Gooley, and the method of Fine and Gray will be used to model the incidence by disease and clinical characteristics of interest, including matched versus mismatched donors.
|
Up to 3 years
|
|
Incidence of grade 3 and 4 adverse events
Time Frame: Up to 3 years
|
Descriptive statistics will be used to summarize adverse events by treatment arm.
The number and proportion of subjects with treatment emergent adverse events will be reported and compared between patients with matched and mismatched donors by using Fisher's exact test.
Frequency counts and percentages will also be presented of subjects with serious adverse events and adverse events leading to withdrawal.
Graphical summaries will be used where appropriate.
|
Up to 3 years
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Uday R Popat, MD, M.D. Anderson Cancer Center
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Helpful Links
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
August 5, 2016
Primary Completion (Estimated)
August 31, 2024
Study Completion (Estimated)
August 31, 2024
Study Registration Dates
First Submitted
August 5, 2016
First Submitted That Met QC Criteria
August 5, 2016
First Posted (Estimated)
August 10, 2016
Study Record Updates
Last Update Posted (Estimated)
December 13, 2023
Last Update Submitted That Met QC Criteria
December 12, 2023
Last Verified
December 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Immune System Diseases
- Neoplasms by Histologic Type
- Lymphatic Diseases
- Immunoproliferative Disorders
- Disease Attributes
- Disease
- Bone Marrow Diseases
- Hematologic Diseases
- Hemorrhagic Disorders
- Hemostatic Disorders
- Paraproteinemias
- Blood Protein Disorders
- Neoplasms, Plasma Cell
- Precancerous Conditions
- Leukemia, Lymphoid
- Chronic Disease
- Neoplasms
- Lymphoma
- Syndrome
- Myelodysplastic Syndromes
- Multiple Myeloma
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Recurrence
- Preleukemia
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Lymphoproliferative Disorders
- Myeloproliferative Disorders
- Myelodysplastic-Myeloproliferative Diseases
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Enzyme Inhibitors
- Antirheumatic Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antitubercular Agents
- Antibiotics, Antitubercular
- Calcineurin Inhibitors
- Cyclophosphamide
- Fludarabine
- Fludarabine phosphate
- Tacrolimus
- Mycophenolic Acid
- Thiotepa
- Busulfan
- Vidarabine
Other Study ID Numbers
- 2016-0137 (Other Identifier: M D Anderson Cancer Center)
- NCI-2017-00614 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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