Myelodysplastic SyndromesPhase 4NCT00361140
Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
A Phase 4 study testing Busulfan and Fludarabine in people with Myelodysplastic Syndromes and Myeloproliferative Disorders, run by H. Lee Moffitt Cancer Center and Research Institute at 1 site in United States.
Trial summary
Pre-transplant conditioning will include Fludarabine and dose-escalated Busulfan on days -6, -5, -4, and -3. Daily treatment doses will be adjusted to achieve target area under the plasma concentration time curve (AUC). Day 0 is the day of hematopoietic progenitor cell reinfusion. Read more about this study
- Who is it for?
- Ages 16 to 65 years
- Conditions the study is for
- Myelodysplastic Syndromes, Myeloproliferative Disorders, Leukemia, Lymphocytic
- What is being tested?
- Busulfan and Fludarabine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 72 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2005to Feb 2012
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 16 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor. HLA-DQ mismatches are not considered ie they are allowed in addition to these.
- Histologically confirmed diagnosis by pathologic review
- Diagnosis of any of the following:
- Acute myelogenous leukemia (AML), Acute lymphoblastic leukemia (ALL), or Non-Hodgkin's Leukemia (NHL), in first remission with high risk of relapse, refractory to primary chemotherapy, or after first relapse; acute biphenotypic or undifferentiated leukemia is also included
- Myelodysplastic Syndrome (MDS), with IPSS >1
- Chronic myelogenous leukemia (CML), with GleevecR-refractory or intolerant chronic phase, or beyond chronic phase by morphology or cytogenetics
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- Myeloproliferative disorders, including Ph-negative CML, myelofibrosis and chronic myelomonocytic leukemia (CMML)
- Multiple myeloma, refractory to two or more lines of therapy.
- Chronic lymphocytic leukemia (CLL), refractory to fludarabine
- Hodgkin's disease, refractory to primary chemotherapy or after first relapse
- Karnofsky performance status 70-100%
- Organ function:
- Pulmonary: Diffusing capacity of lung for carbon monoxide (DLCO) greater than 50%
- Cardiac: Left ventricular ejection fraction greater than 45%
- Renal: Creatinine clearance (measured or calculated) equal or greater than 50 ml/min
- Hepatic: Total bilirubin less than or equal to 2 mg/dL, (Gilbert and other syndromes with increased indirect bilirubin should be allowed); serum transaminases less than two times the upper limit of normal.
- Signed informed consent form in accordance with institutional policies
Who cannot join
- Pregnant or lactating women
- HIV or seropositive, confirmed by nucleic acid test (NAT)
- Active central nervous system (CNS) malignancy
- Patients with current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings) are ineligible.
- Unfavorable psychosocial evaluation or history of poor compliance to prescribed medical care
- Current use of metronidazole or acetominophen, unless medically necessary; patients must discontinue use of these agents at least 7 days prior to the start of BusulfexR administration
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- Prior use of MylotargR (gemtuzumab ozogamicin)
- Prior Hematopoietic Cell Transplantation (HCT)
- Prior chest or abdominal irradiation with greater than 1800 cGy
- Presence of any of the following comorbid conditions:
- History of myocardial infarction or coronary artery disease requiring catheterization or stent placements less than six months prior to enrollment. All participants with history of myocardial infarction or coronary artery disease must have clearance by a cardiologist to be enrolled.
- Congestive heart failure (even if symptomatically controlled)
- Peripheral vascular disease (including intermittent claudication or history of bypass for arterial insufficiency)
- Untreated thoracic or abdominal aneurysm (6 cm or more)
- History of any cerebrovascular accident including transient ischemic attacks
- Dementia
- Connective tissue/rheumatologic disorders with active disease
- Diabetes uncontrolled by medication (including insulin)
- Hemiplegia/paraplegia
- History of prior malignancy (excluding nonmelanoma skin or cervical carcinoma after curative resection) less than 5 years from enrollment with the following exception. Cancer treated with curative intent less than 5 years will be reviewed on a case-by-case basis by the Principal Investigator.
- History of renal failure requiring renal replacement therapy (e.g., hemodialysis, peritoneal dialysis, etc.)
Trial locations and contacts
1 site in 1 country.
United States1 site
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, 33612
About this study
Official title: Busulfan Dose Escalation Study Based on AUC in the Setting of Busulfan/Fludarabine Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation (HCT)
Pre-transplant conditioning will include Fludarabine and dose-escalated Busulfan on days -6, -5, -4, and -3. Daily treatment doses will be adjusted to achieve target area under the plasma concentration time curve (AUC). Day 0 is the day of hematopoietic progenitor cell reinfusion. Supportive care will be based on institutional guidelines. Blood samples will be collected for dose modification based on the AUC levels. Dose escalation will proceed to determine the maximally tolerated level or AUC to evaluate the potential therapeutic benefit of higher doses of busulfan.
Read the detailed description
Patients will receive anti-seizure prophylaxis beginning on day -7. Pre-transplant conditioning will include Fludarabine and dose-escalated Busulfan on days -6, -5, -4, and -3. Daily treatment doses will be adjusted to achieve target AUCs (area under the plasma concentration time curve). Day 0 is the day of hematopoietic progenitor cell reinfusion.
Supportive care will be based on institutional guidelines. In an effort to prevent hepatotoxicity, ursodiol will be given to patients. During chemotherapy patients will not receive concurrent metronidazole, itraconazole, or be given acetaminophen.
Blood samples will be collected at specific times after Dose 1 and Dose 4 and dose modification will be determined or based on the desired AUC levels. Doses 3 and/or 4 will be adjusted to achieve an average daily Busulfan AUC over the 4 treatment days.
Dose escalation will proceed through 3 dose levels to determine the maximally tolerated level or AUC to evaluate the potential therapeutic benefit of higher doses of busulfan.
Graft assessment, processing, and characterization will be done as per institutional guidelines. Donor-recipient chimerism (two genetically distinct types of blood cells) will be characterized by samples obtained pre-transplant and on days 30+/- 7, 90+/-7 and 360+/-30 post-transplant.
- Conditions
- Myelodysplastic Syndromes, Myeloproliferative Disorders, Leukemia, Lymphocytic, Myeloma, Lymphoma
- Being tested
- Busulfan, Fludarabine
- Keywords
- Busulfan, Fludarabine, Chimerism, Allogeneic stem cell transplantation (HCT), Myelodysplastic Syndromes, Leukemia Myeloproliferative disorders (MPD), Leukemia, Lymphocytic, Myeloma, Lymphoma, AUC, Hematologic malignancies
- Medical subject headings
- Myelodysplastic Syndromes, Myeloproliferative Disorders, Leukemia, Lymphoid, Neoplasms, Plasma Cell, Lymphoma, Hematologic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BusulfanDrug
Also called Busulfex(R)
Bu IV (BusulfexR) over 3 hours on days -6, -5, -4, and -3. Day -6 and -5 doses for patients on Level 1 will be 170mg/m2. This dose is based on the dose used by DeLima (2004) adjusted proportionately to achieve an AUC of 6000uM-min. Subsequent daily doses for patients on Level 1 will be adjusted to achieve an average AUC of 6000uM-min.
Day -6 and -5 doses for patients on Level 2 will be based on the mean dose required on Level 1 to achieve target AUC then adjusted proportionally for new target AUC.
Subsequent daily doses will be adjusted to achieve target AUCs.
FludarabineDrug
Also called Fludarabine Phosphate
Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3
| Study group | Role | What they receive |
|---|---|---|
| AUC 6000 | Experimental | Busulfan AUC Level 1: 6000 +/- 600 uM-min
Fludarabine 40mg/m2 IV over 1 hour Receives: Drug: Busulfan; Drug: Fludarabine |
| AUC 7500 | Experimental | Busulfan AUC Level 2: 7500 +/- 750 uM-min
Fludarabine 40mg/m2 IV over 1 hour Receives: Drug: Busulfan; Drug: Fludarabine |
| AUC 9000 | Experimental | AUC Level 3: 9000 +/- 900 uM-min
Fludarabine 40mg/m2 IV over 1 hour Receives: Drug: Busulfan; Drug: Fludarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Non-relapse Mortality
The number of participants dead due to causes unrelated to relapse within the first 100 days post transplant.
Measured: 100 days
Secondary outcomes (1)
Severe Venous Occlusive Disease (VOD)/ Sinusoidal Obstructive Syndrome (SOS)
The number of subjects with severe VOD / SOS; severity staged according to criteria set forth by McDonald G.B., Hinds M.S., Fisher L.D., et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255-267. Assessed within the first 100 days post transplant.
Measured: 100 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Aug 2006 (estimated)
- Study startAug 2005
- Primary completionFeb 2012
- Study completionFeb 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Myelodysplastic SyndromesStudies of the same condition, open and under way.
- More trials run by H. Lee Moffitt Cancer Center and Research InstituteThe 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 4
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 72 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Teresa Field, PhD, MD, Principal investigator, H. Lee Moffitt Cancer Center and Research InstituteJanelle Perkins, PharmD, Principal investigator, H. Lee Moffitt Cancer Center and Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00361140
- Sponsor's protocol ID
- MCC-14178
- Status last verified
- Jun 2013
- First submitted
- 3 Aug 2006
- Last updated
- 3 Mar 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Perkins JB, Kim J, Anasetti C, Fernandez HF, Perez LE, Ayala E, Kharfan-Dabaja MA, Tomblyn MR, Sullivan DM, Pidala JA, Field TL. Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012 Jul;18(7):1099-107. doi: 10.1016/j.bbmt.2011.12.584. Epub 2011 Dec 23.
PubMed 22198540
Study at a glance
From the registry record, last updated by the sponsor on 3 Mar 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Busulfan Dose Escalation Study Based on AUC in the Setting of Busulfan/Fludarabine Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation (HCT)
- ClinicalTrials.gov ID
- NCT00361140
- Acronym / sponsor ID
- MCC-14178
- Conditions
- Myelodysplastic Syndromes, Myeloproliferative Disorders, Leukemia, Lymphocytic, Myeloma, Lymphoma
- Keywords
- Busulfan, Fludarabine, Chimerism, Allogeneic stem cell transplantation (HCT), Myelodysplastic Syndromes, Leukemia Myeloproliferative disorders (MPD), Leukemia, Lymphocytic, Myeloma
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 72 participants (actual)
- Lead sponsor
- H. Lee Moffitt Cancer Center and Research InstituteUniversity, hospital or other
- Study start
- Aug 2005
- Primary completion
- Feb 2012 (actual)
- Study completion
- Feb 2012 (actual)
- First posted
- 7 Aug 2006 (estimated)
- Results
- Posted 27 Jun 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Pre-transplant conditioning will include Fludarabine and dose-escalated Busulfan on days -6, -5, -4, and -3. Daily treatment doses will be adjusted to achieve target area under the plasma concentration time curve (AUC). Day 0 is the day of hematopoietic progenitor cell reinfusion. Supportive care will be based on institutional guidelines. Blood samples will be collected for dose modification based on the AUC levels. Dose escalation will proceed to determine the maximally tolerated level or AUC to evaluate the potential therapeutic benefit of higher doses of busulfan.
Detailed description
Patients will receive anti-seizure prophylaxis beginning on day -7. Pre-transplant conditioning will include Fludarabine and dose-escalated Busulfan on days -6, -5, -4, and -3. Daily treatment doses will be adjusted to achieve target AUCs (area under the plasma concentration time curve). Day 0 is the day of hematopoietic progenitor cell reinfusion.
Supportive care will be based on institutional guidelines. In an effort to prevent hepatotoxicity, ursodiol will be given to patients. During chemotherapy patients will not receive concurrent metronidazole, itraconazole, or be given acetaminophen.
Blood samples will be collected at specific times after Dose 1 and Dose 4 and dose modification will be determined or based on the desired AUC levels. Doses 3 and/or 4 will be adjusted to achieve an average daily Busulfan AUC over the 4 treatment days.
Dose escalation will proceed through 3 dose levels to determine the maximally tolerated level or AUC to evaluate the potential therapeutic benefit of higher doses of busulfan.
Graft assessment, processing, and characterization will be done as per institutional guidelines. Donor-recipient chimerism (two genetically distinct types of blood cells) will be characterized by samples obtained pre-transplant and on days 30+/- 7, 90+/-7 and 360+/-30 post-transplant.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| AUC 6000 | Experimental | Drug: Busulfan, Drug: FludarabineBusulfan AUC Level 1: 6000 +/- 600 uM-min Fludarabine 40mg/m2 IV over 1 hour |
| AUC 7500 | Experimental | Drug: Busulfan, Drug: FludarabineBusulfan AUC Level 2: 7500 +/- 750 uM-min Fludarabine 40mg/m2 IV over 1 hour |
| AUC 9000 | Experimental | Drug: Busulfan, Drug: FludarabineAUC Level 3: 9000 +/- 900 uM-min Fludarabine 40mg/m2 IV over 1 hour |
Who may qualify
- Ages
- 16 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (17 listed)
- HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor. HLA-DQ mismatches are not considered ie they are allowed in addition to these.
- Histologically confirmed diagnosis by pathologic review
- Diagnosis of any of the following:
- Organ function:
- Signed informed consent form in accordance with institutional policies
Key exclusion criteria (21 listed)
- Pregnant or lactating women
- HIV or seropositive, confirmed by nucleic acid test (NAT)
- Active central nervous system (CNS) malignancy
- Patients with current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings) are ineligible.
- Unfavorable psychosocial evaluation or history of poor compliance to prescribed medical care
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BusulfanAlso: Busulfex(R)Bu IV (BusulfexR) over 3 hours on days -6, -5, -4, and -3. Day -6 and -5 doses for patients on Level 1 will be 170mg/m2. This dose is based on the dose used by DeLima (2004) adjusted proportionately to achieve an AUC of 6000uM-min. Subsequent daily doses for patients on Level 1 will be adjusted to achieve an average AUC of 6000uM-min. Day -6 and -5 doses for patients on Level 2 will be based on the mean dose required on Level 1 to achieve target AUC then adjusted proportionally for new target AUC. Subsequent daily doses will be adjusted to achieve target AUCs. | Drug | AUC 6000, AUC 7500, AUC 9000 |
| FludarabineAlso: Fludarabine PhosphateFludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3 | Drug | AUC 6000, AUC 7500, AUC 9000 |
Primary outcome
Non-relapse Mortality
Time frame: 100 days
The number of participants dead due to causes unrelated to relapse within the first 100 days post transplant.
1 secondary outcome
Severe Venous Occlusive Disease (VOD)/ Sinusoidal Obstructive Syndrome (SOS)
Time frame: 100 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Mar 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 22198540Perkins JB, Kim J, Anasetti C, Fernandez HF, Perez LE, Ayala E, Kharfan-Dabaja MA, Tomblyn MR, Sullivan DM, Pidala JA, Field TL. Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012 Jul;18(7):1099-107. doi: 10.1016/j.bbmt.2011.12.584. Epub 2011 Dec 23.
- Moffitt Cancer Center Clinical Trials websiteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Teresa Field, PhD, MD principal investigator
H. Lee Moffitt Cancer Center and Research Institute
Janelle Perkins, PharmD principal investigator
H. Lee Moffitt Cancer Center and Research Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Busulfan and Fludarabine in people with Myelodysplastic Syndromes and Myeloproliferative Disorders, run by H. Lee Moffitt Cancer Center and Research Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Mar 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Jun 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Non-relapse Mortality (time frame: 100 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00361140, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Mar 2017.