Hematopoietic and Lymphoid Cell NeoplasmPhase 2NCT02861417
Busulfan, Fludarabine Phosphate, and Post-Transplant Cyclophosphamide in Treating Patients With Blood Cancer Undergoing Donor Stem Cell Transplant
A Phase 2 study testing Allogeneic Hematopoietic Stem Cell Transplantation, Busulfan and Cyclophosphamide in people with Hematopoietic and Lymphoid Cell Neoplasm and High Risk Acute Myeloid Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 12 to 75 years
- Conditions the study is for
- Hematopoietic and Lymphoid Cell Neoplasm, High Risk Acute Myeloid Leukemia, High Risk Myelodysplastic Syndrome
- What is being tested?
- Allogeneic Hematopoietic Stem Cell Transplantation, Busulfan and Cyclophosphamide
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 204 participants
- Where
- 1 siteUnited States
- Study dates
- 5 Aug 2016to 31 Aug 2028
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 75 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the detailed description
PRIMARY OBJECTIVE:
- 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:
- 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:
- 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.
- Conditions
- Hematopoietic and Lymphoid Cell Neoplasm, High Risk Acute Myeloid Leukemia, High Risk Myelodysplastic Syndrome, Lymphoproliferative Disorder, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm
- Being tested
- Allogeneic Hematopoietic Stem Cell Transplantation, Busulfan, Cyclophosphamide, Fludarabine, Fludarabine Phosphate
- Medical subject headings
- Hematologic Neoplasms, Lymphoproliferative Disorders, Myelodysplastic Syndromes, Myelodysplastic-Myeloproliferative Diseases, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myeloid, Acute, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Hodgkin Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Allogeneic Hematopoietic Stem Cell TransplantationProcedure or surgery
Also called Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT
Undergo stem cell transplantation
BusulfanDrug
Also called 1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum
Given IV
CyclophosphamideDrug
Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida
Given IV
FludarabineDrug
Also called Fluradosa
Given IV
Also called 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara
Given IV
Laboratory Biomarker AnalysisOther
Correlative studies
Also called Cellcept, MMF
Given PO
Correlative studies
TacrolimusDrug
Also called FK 506, Fujimycin, Hecoria, Prograf
Given IV or PO
ThiotepaDrug
Also called 1,1'',1''''-Phosphinothioylidynetrisaziridine, Girostan, N,N'', N''''-Triethylenethiophosphoramide, Oncotiotepa
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Group I (haploidentical donor transplant, chemotherapy) | Experimental | 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. Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Busulfan; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Other: Pharmacological Study; Drug: Tacrolimus; Drug: Thiotepa |
| Group II (matched donor transplant, chemotherapy) | Experimental | 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. Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Busulfan; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Tacrolimus |
| Group III (haploidentical donor transplant, chemotherapy) | Experimental | 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. Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Busulfan; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Other: Pharmacological Study; Drug: Tacrolimus; Drug: Thiotepa |
| Group IV (matched donor transplant, chemotherapy) | Experimental | 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. Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Busulfan; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Tacrolimus |
| Group V (haploidentical donor transplant, chemotherapy) | Experimental | 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. Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Busulfan; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Other: Pharmacological Study; Drug: Tacrolimus; Drug: Thiotepa |
| Group VI (matched or haploidentical transplant, chemotherapy) | Experimental | 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. Receives: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Busulfan; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Other: Pharmacological Study; Drug: Tacrolimus; Drug: Thiotepa |
What is being measured
The primary outcome is the main question the study is designed to answer.
Non-relapse mortality rate
The proportion of patients with non-relapse mortality will be reported separately by arm, along with the corresponding 95% Bayesian credible interval.
Measured: 100 days
Secondary outcomes (8)
Graft versus host disease-free survival/relapse free survival
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.
Measured: Up to 3 years
Relapse-free survival
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.
Measured: Up to 3 years
Overall survival
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.
Measured: Up to 3 years
Non-relapse mortality
The proportion of patients with non-relapse mortality will be reported separately by arm, along with the corresponding 95% Bayesian credible interval.
Measured: Up to 3 years
Relapse rate
Will be observed.
Measured: Up to 3 years
Time to platelet and neutrophil engraftment
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.
Measured: Up to 3 years
Incidence of acute and chronic graft versus host disease
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.
Measured: Up to 3 years
Incidence of grade 3 and 4 adverse events
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.
Measured: Up to 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Aug 2016 (estimated)
- Study start5 Aug 2016
- Primary completion31 Aug 2028 (estimated)
- Study completion31 Aug 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hematopoietic and Lymphoid Cell NeoplasmStudies of the same condition, open and under way.
- More trials run by M.D. Anderson Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 204 participants (actual)
Sponsor and investigators
- Lead sponsor
- M.D. Anderson Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Uday R Popat, MD, Principal investigator, M.D. Anderson Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02861417
- Sponsor's protocol ID
- 2016-0137
- Other IDs
- NCI-2017-00614, 2016-0137
- Status last verified
- Aug 2026
- First submitted
- 5 Aug 2016
- Last updated
- 6 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Popat UR, Pasvolsky O, Bassett R Jr, Mehta RS, Olson A, Chen J, Alousi AM, Al-Atrash G, Bashir Q, Gulbis AM, Hosing CM, Im JS, Kebriaei P, Khouri I, Marin D, Nieto Y, Oran B, Saini N, Shigle TL, Srour SA, Ramdial JL, Rezvani K, Qazilbash MH, Andersson BS, Champlin RE, Shpall EJ. Myeloablative fractionated busulfan for allogeneic stem cell transplant in older patients or patients with comorbidities. Blood Adv. 2023 Oct 24;7(20):6196-6205. doi: 10.1182/bloodadvances.2023010850.
PubMed 37611156