Allogeneic Blood and Marrow Transplantation (BMT)Phase 2NCT01487577
Pharmacokinetics-based Mycophenolate Mofetil Dosing for GVHD Prevention
A Phase 2 study testing Mycophenolate mofetil in people with Allogeneic Blood and Marrow Transplantation (BMT) and Graft Versus Host Disease, run by University of Pittsburgh at 1 site in United States.
Trial summary
Bone marrow transplantation (BMT) is used to successfully treat high-risk forms of leukemia, lymphoma, and other childhood cancers that were once considered incurable. A major barrier to the application of this life-saving treatment is acute graft-versus-host disease (GVHD) which develops in approximately 30-80% of… Read more about this study
- Who is it for?
- Ages 6 months to 21 years
- Conditions the study is for
- Allogeneic Blood and Marrow Transplantation (BMT), Graft Versus Host Disease
- What is being tested?
- Mycophenolate mofetil
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 19 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2010to Jan 2016
- Phase
- Phase 2
- 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 6 months to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Patients must be between 6 months and 21 years of age.
- Recipients of an allogeneic blood and marrow transplant (BMT).
- Stem cell sources should be bone marrow or umbilical cord blood.
- Bone marrow or cord blood unit: Sibling should be HLA matched at A, B and DRB1 loci. Unrelated cord blood unit should be at a minimum 4/6 matched at allele level on HLA A, B and DRB1 loci. Unrelated donor should be HLA allele level matched at A, B, C and DRB1 loci.
- Minimum prefreezing nucleated cell dose for cord blood units: 3x10^7/kg for malignant diseases and 5x10^7/kg for nonmalignant diseases.
- Conditioning regimen must be myeloablative in intensity. Examples include but are not limited to Cy/TBI, BuCy 200, etc.
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- Patients ≥ 16 years old must have a Karnofsky score ≥ 70%, and patients < 16 years old must have a Lansky score ≥ 70%.
- Renal: Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2.
- Hepatic: Total bilirubin ≤ 2.5 mg/dL unless the increase in bilirubin is attributable to Gilbert's syndrome; and SGOT (AST), SGPT (ALT), and Alkaline Phosphatase < 5 x upper limit of normal (ULN) for age.
- Cardiac: Left ventricular ejection fraction at rest > 40%, or shortening fraction > 26%, by echocardiogram or radionuclide scan.
- Pulmonary: FEV1, FVC, and DLCO (diffusion capacity) > 50% of predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation > 92% of room air.
Who cannot join
- Patients with a known hypersensitivity to MMF.
- Prior autologous or allogeneic BMT < 12 months prior to enrollment.
- Mismatched related donor.
- Mismatched unrelated marrow donor.
- Peripheral blood stem cell source.
- Reduced intensity conditioning.
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- Uncontrolled bacterial, viral, fungal or other infection.
- Evidence of HIV infection or HIV positive serology.
- Requirement of supplemental oxygen.
- Patients who are pregnant (B-hCG positive) or breastfeeding. All females of 11 years of age or older and/or who have begun menstruating will be screened for hCG by either urinalysis or a blood sample in order to screen for pregnancy status, as per institutional BMT policy.
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, 15224
About this study
Official title: A Pilot Study of Pharmacokinetics-based Mycophenolate Mofetil Dosing for Graft-Versus-Host-Disease Prophylaxis in Pediatric Blood and Marrow Transplantation
Bone marrow transplantation (BMT) is used to successfully treat high-risk forms of leukemia, lymphoma, and other childhood cancers that were once considered incurable. A major barrier to the application of this life-saving treatment is acute graft-versus-host disease (GVHD) which develops in approximately 30-80% of patients and is a leading cause of death from transplant complications. Current GVHD prevention methods are not very efficacious and lead to unacceptable side effects. Mycophenolate mofetil (MMF), an anti-rejection medication used in solid organ transplants, has shown great promise in BMT recipients. The effectiveness of MMF depends on blood levels of mycophenolic acid (MPA, the active form of MMF). Different patients have been found to have different blood levels of MPA when they are given the same dose of MMF. The purpose of this study is to study a novel method of giving MMF based on its metabolism (pharmacokinetics) to achieve desired blood levels of MPA for prevention of GVHD. Non-invasive ways of monitoring the drug exposure will also be studied. The ultimate goal of this study is to improve approaches to GVHD prevention and improve outcomes of BMT in children.
Read the detailed description
Graft-versus-host disease (GVHD) remains a major barrier to the success of allogeneic blood and marrow transplant (BMT) therapy. Acute GVHD is seen in 30-80% of patients and once established, often responds poorly to therapy and is associated with chronic disease and increased risk of death. Although combination of methotrexate (MTX) and a calcineurin inhibitor has been the "standard of care" for more than a quarter of a century, there is little consensus on the most effective and least toxic approach to GVHD prevention. MTX use is associated with painful mucositis, delay in engraftment and potential pulmonary toxicity. For cord blood transplants, commonly, a calcineurin inhibitor is used with corticosteroids and antithymocyte globulin. Steroid therapy is frequently complicated by high rates of infection, hyperglycemia and hypertension.
Mycophenolate mofetil (MMF), whose metabolite mycophenolic acid (MPA) inhibits proliferation of lymphocytes, is approved for prevention of organ transplant rejection. MMF in combination with CsA is widely used for GVHD prevention in patients receiving reduced-intensity conditioning BMT. It has also been successfully used in primary and salvage therapy of acute GVHD. In myeloablative transplants, while the GVHD outcomes appear comparable, this regimen appears to have superior toxicity profile in comparison to CsA and MTX with faster hematopoietic engraftment and reduced severity and duration of mucositis.
One challenge with MMF use in BMT recipients is a significantly lower MPA exposure in the immediate post-conditioning period when compared to organ transplant recipients. This has been shown in a number of pharmacokinetics studies including our preliminary data on pediatric myeloablative transplants. Low total and unbound MPA trough concentrations are associated with higher rates of acute GVHD and graft rejection, and lower response rates in treatment of acute GVHD. There is also poor correlation between MPA trough concentration and area under the concentration curve (AUC). While most previous studies have used fixed MMF dosing, one recent study in adults has shown feasibility of AUC-based individualized MMF dosing.
This protocol is based on the premise that optimization of MPA exposure in the immediate post-transplant phase will lead to better acute GVHD prevention. It will study an AUC-based targeting of MMF in pediatric patients undergoing myeloablative allogeneic BMT. We propose a novel continuous infusion method for MMF administration to achieve total MPA steady state concentration. Salient findings emerging from this study will be examined and in replicate cohorts of pediatric and adult patients undergoing allo-BMT.
- Being tested
- Mycophenolate mofetil
- Keywords
- Allogeneic blood and marrow transplantation (BMT), Graft versus host disease, Mycophenolate mofetil, Pharmacokinetics
- Medical subject headings
- Graft vs Host Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Also called Cellcept, MMF
Based on individual pharmacokinetics data, mycophenolate mofetil will be administered by continuous infusion to target a desired AUC exposure
| Study group | Role | What they receive |
|---|---|---|
| Mycophenolate mofetil | Experimental | Pharmacokinetics-based targeting of mycophenolate mofetil Receives: Drug: Mycophenolate mofetil |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Grade ≥3 Toxicities Scored According to the CTCAE Version 4.0.
Measured: 100 days
Number of Participants With Acute Grade II-IV GVHD, Acute Grade III-IV GVHD, and Chronic GVHD.
Acute GVHD will be graded according to the Modified Glucksberg Staging Criteria. Chronic GVHD will be graded according to NIH Chronic GVHD Consensus Guidelines.
Measured: 1 year
Secondary outcomes (7)
Number of Participants With Neutrophil and Platelet Engraftment.
Neutrophil and platelet engraftment definitions as defined by the CIBMTR Data Management Manual.
Measured: 100 days
Number of Participants Who Experienced Relapse.
Measured: 1 year
Number of Participants Who Experienced Nonrelapse Mortality.
Measured: 1 year
Number of Participants in Overall Survival.
Measured: 1 year
Pharmacokinetic Analysis of MMF AUC to Evaluate MMF Dose Relationships to Drug Exposure.
Pharmacokinetic analysis includes, but is not limited to, area under the plasma concentration versus time curve (AUC).
Measured: 100 days
Pharmacokinetic Analysis of MMF Clearance to Evaluate MMF Dose Relationships to Drug Exposure.
Pharmacokinetic analysis includes, but is not limited to, clearance.
Measured: 100 days
Pharmacokinetic Analysis of MMF Steady State Concentration to Evaluate MMF Dose Relationships to Drug Exposure.
Pharmacokinetic analysis includes, but is not limited to, steady-state concentrations.
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 Dec 2011 (estimated)
- Study startJun 2010
- Primary completionDec 2014
- Study completionJan 2016
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.
- Other trials for Allogeneic Blood and Marrow Transplantation (BMT)Studies of the same condition, open and under way.
- More trials run by University of PittsburghThe 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pittsburgh
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Randy Windreich, University of Pittsburgh
- Investigators
- Randy M Windreich, MD, Principal investigator, University of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01487577
- Sponsor's protocol ID
- CHP_BMT_MMF_10
- Status last verified
- May 2016
- First submitted
- 23 Nov 2011
- Last updated
- 21 Jun 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 21 Jun 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study of Pharmacokinetics-based Mycophenolate Mofetil Dosing for Graft-Versus-Host-Disease Prophylaxis in Pediatric Blood and Marrow Transplantation
- ClinicalTrials.gov ID
- NCT01487577
- Acronym / sponsor ID
- CHP_BMT_MMF_10
- Keywords
- Allogeneic blood and marrow transplantation (BMT), Graft versus host disease, Mycophenolate mofetil, Pharmacokinetics
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- University of PittsburghUniversity, hospital or other
- Study start
- Jun 2010
- Primary completion
- Dec 2014 (actual)
- Study completion
- Jan 2016 (actual)
- First posted
- 7 Dec 2011 (estimated)
- Results
- Posted 21 Jun 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Bone marrow transplantation (BMT) is used to successfully treat high-risk forms of leukemia, lymphoma, and other childhood cancers that were once considered incurable. A major barrier to the application of this life-saving treatment is acute graft-versus-host disease (GVHD) which develops in approximately 30-80% of patients and is a leading cause of death from transplant complications. Current GVHD prevention methods are not very efficacious and lead to unacceptable side effects. Mycophenolate mofetil (MMF), an anti-rejection medication used in solid organ transplants, has shown great promise in BMT recipients. The effectiveness of MMF depends on blood levels of mycophenolic acid (MPA, the active form of MMF). Different patients have been found to have different blood levels of MPA when they are given the same dose of MMF. The purpose of this study is to study a novel method of giving MMF based on its metabolism (pharmacokinetics) to achieve desired blood levels of MPA for prevention of GVHD. Non-invasive ways of monitoring the drug exposure will also be studied. The ultimate goal of this study is to improve approaches to GVHD prevention and improve outcomes of BMT in children.
Detailed description
Graft-versus-host disease (GVHD) remains a major barrier to the success of allogeneic blood and marrow transplant (BMT) therapy. Acute GVHD is seen in 30-80% of patients and once established, often responds poorly to therapy and is associated with chronic disease and increased risk of death. Although combination of methotrexate (MTX) and a calcineurin inhibitor has been the "standard of care" for more than a quarter of a century, there is little consensus on the most effective and least toxic approach to GVHD prevention. MTX use is associated with painful mucositis, delay in engraftment and potential pulmonary toxicity. For cord blood transplants, commonly, a calcineurin inhibitor is used with corticosteroids and antithymocyte globulin. Steroid therapy is frequently complicated by high rates of infection, hyperglycemia and hypertension.
Mycophenolate mofetil (MMF), whose metabolite mycophenolic acid (MPA) inhibits proliferation of lymphocytes, is approved for prevention of organ transplant rejection. MMF in combination with CsA is widely used for GVHD prevention in patients receiving reduced-intensity conditioning BMT. It has also been successfully used in primary and salvage therapy of acute GVHD. In myeloablative transplants, while the GVHD outcomes appear comparable, this regimen appears to have superior toxicity profile in comparison to CsA and MTX with faster hematopoietic engraftment and reduced severity and duration of mucositis.
One challenge with MMF use in BMT recipients is a significantly lower MPA exposure in the immediate post-conditioning period when compared to organ transplant recipients. This has been shown in a number of pharmacokinetics studies including our preliminary data on pediatric myeloablative transplants. Low total and unbound MPA trough concentrations are associated with higher rates of acute GVHD and graft rejection, and lower response rates in treatment of acute GVHD. There is also poor correlation between MPA trough concentration and area under the concentration curve (AUC). While most previous studies have used fixed MMF dosing, one recent study in adults has shown feasibility of AUC-based individualized MMF dosing.
This protocol is based on the premise that optimization of MPA exposure in the immediate post-transplant phase will lead to better acute GVHD prevention. It will study an AUC-based targeting of MMF in pediatric patients undergoing myeloablative allogeneic BMT. We propose a novel continuous infusion method for MMF administration to achieve total MPA steady state concentration. Salient findings emerging from this study will be examined and in replicate cohorts of pediatric and adult patients undergoing allo-BMT.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Mycophenolate mofetil | Experimental | Drug: Mycophenolate mofetilPharmacokinetics-based targeting of mycophenolate mofetil |
Who may qualify
- Ages
- 6 months to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (11 listed)
- Patients must be between 6 months and 21 years of age.
- Recipients of an allogeneic blood and marrow transplant (BMT).
- Stem cell sources should be bone marrow or umbilical cord blood.
- Bone marrow or cord blood unit: Sibling should be HLA matched at A, B and DRB1 loci. Unrelated cord blood unit should be at a minimum 4/6 matched at allele level on HLA A, B and DRB1 loci. Unrelated donor should be HLA allele level matched at A, B, C and DRB1 loci.
- Minimum prefreezing nucleated cell dose for cord blood units: 3x10^7/kg for malignant diseases and 5x10^7/kg for nonmalignant diseases.
Key exclusion criteria (10 listed)
- Patients with a known hypersensitivity to MMF.
- Prior autologous or allogeneic BMT < 12 months prior to enrollment.
- Mismatched related donor.
- Mismatched unrelated marrow donor.
- Peripheral blood stem cell source.
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 |
|---|---|---|
| Mycophenolate mofetilAlso: Cellcept, MMFBased on individual pharmacokinetics data, mycophenolate mofetil will be administered by continuous infusion to target a desired AUC exposure | Drug | Mycophenolate mofetil |
Primary outcome
Number of Participants With Grade ≥3 Toxicities Scored According to the CTCAE Version 4.0.
Time frame: 100 days
Number of Participants With Acute Grade II-IV GVHD, Acute Grade III-IV GVHD, and Chronic GVHD.
Time frame: 1 year
Acute GVHD will be graded according to the Modified Glucksberg Staging Criteria. Chronic GVHD will be graded according to NIH Chronic GVHD Consensus Guidelines.
7 secondary outcomes
Number of Participants With Neutrophil and Platelet Engraftment.
Time frame: 100 days
Number of Participants Who Experienced Relapse.
Time frame: 1 year
Number of Participants Who Experienced Nonrelapse Mortality.
Time frame: 1 year
Number of Participants in Overall Survival.
Time frame: 1 year
Pharmacokinetic Analysis of MMF AUC to Evaluate MMF Dose Relationships to Drug Exposure.
Time frame: 100 days
Pharmacokinetic Analysis of MMF Clearance to Evaluate MMF Dose Relationships to Drug Exposure.
Time frame: 100 days
Pharmacokinetic Analysis of MMF Steady State Concentration to Evaluate MMF Dose Relationships to Drug Exposure.
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 21 Jun 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Randy M Windreich, MD principal investigator
University of Pittsburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Mycophenolate mofetil in people with Allogeneic Blood and Marrow Transplantation (BMT) and Graft Versus Host Disease, run by University of Pittsburgh 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 11 inclusion and 10 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 21 Jun 2016. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 21 Jun 2016). 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?
Number of Participants With Grade ≥3 Toxicities Scored According to the CTCAE Version 4.0. (time frame: 100 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 21 Jun 2016.