Busulfan, Fludarabine Phosphate, and Post-Transplant Cyclophosphamide in Treating Patients With Blood Cancer Undergoing Donor Stem Cell Transplant

Myelodysplastic Syndrome Clinical Trial

Official title:

Timed Sequential Busulfan and Post Transplant Cyclophosphamide for Allogeneic Transplantation

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02861417
• Other study ID #: 2016-0137
• Secondary ID: NCI-2017-0061420
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: August 5, 2016
• Est. completion date: August 31, 2025

Study information

• Verified date: December 2023
• Source: M.D. Anderson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 204
• Est. completion date: August 31, 2025
• Est. primary completion date: August 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Hematopoietic and Lymphoid Cell Neoplasm
• High Risk Acute Myeloid Leukemia
• High Risk Myelodysplastic Syndrome
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Lymphoma
• Lymphoproliferative Disorder
• Lymphoproliferative Disorders
• Multiple Myeloma
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasm
• Myeloproliferative Disorders
• Neoplasms
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia
• Recurrence
• Recurrent Acute Lymphoblastic Leukemia
• Recurrent Acute Myeloid Leukemia
• Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
• Recurrent High Risk Myelodysplastic Syndrome
• Recurrent Hodgkin Lymphoma
• Recurrent Myelodysplastic Syndrome
• Recurrent Non-Hodgkin Lymphoma
• Recurrent Plasma Cell Myeloma
• Syndrome

Intervention

Procedure:
• Allogeneic Hematopoietic Stem Cell Transplantation
Undergo stem cell transplantation

Drug:
• Busulfan
Given IV
• Cyclophosphamide
Given IV
• Fludarabine
Given IV
• Fludarabine Phosphate
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Mycophenolate Mofetil
Given PO

Other:
• Pharmacological Study
Correlative studies

Drug:
• Tacrolimus
Given IV or PO
• Thiotepa
Given IV

Locations

Country	Name	City	State
United States	M D Anderson Cancer Center	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
M.D. Anderson Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	100 days
Secondary	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.	Up to 3 years
Secondary	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.	Up to 3 years
Secondary	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.	Up to 3 years
Secondary	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.	Up to 3 years
Secondary	Relapse rate	Will be observed.	Up to 3 years
Secondary	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.	Up to 3 years
Secondary	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.	Up to 3 years
Secondary	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.	Up to 3 years

External Links

•   MD Anderson Cancer Center