Transplants and ImplantsPhase 1/2NCT02522572
Quantitating the Impact of Plerixafor
A Phase 1/2 study testing plerixafor, Bortezomib and plasmapheresis in people with Transplants and Implants, run by E. Steve Woodle at 2 sites in United States.
Trial summary
The primary objective of this study is to conduct a proof of concept pilot study that will provide a preliminary evaluation of the safety of plerixafor alone or in combination with bortezomib on plasma cell mobilization, Human Leukocyte Antigen (HLA) antibody levels and toxicity profile in sensitized patients awaiting… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Transplants and Implants
- What is being tested?
- plerixafor, Bortezomib and plasmapheresis
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 2 sitesUnited States
- Study dates
- Aug 2015to Oct 2020
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
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 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male and female patients between 18 and 65 years of age (inclusive) with end-stage renal disease awaiting kidney transplantation.
- Patient with eligible living donor will have: donor specific antibody (DSA) against living donor of >5,000 mean fluorescence intensity (MFI) or a positive T or B cell flow cytometry crossmatch.
- Patient that is on the kidney transplant waiting list awaiting a deceased donor transplant and has an immunodominant antibody (iAb) of >8,000MFI or has a current or peak calculated panel reactive antibody (cPRA) >20%.
- Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
- Female subject is either postmenopausal for at least 1 year prior to initiation of study treatment, is surgically sterilized, or if of childbearing potential, agrees to practice 2 effective methods of contraception from the time of signing the informed consent form through 3 months after the last dose of plerixafor and/or bortezomib, or agrees to completely abstain from heterosexual intercourse. Women of childbearing potential must have a negative serum pregnancy test within the last 48 hours prior to receiving study medication.
- Male subjects, even if surgically sterilized (i.e. status post-vasectomy) must agree to 1 of the following effective contraception through 3 months after end of study.
- Review of pre-transplant medical clearance by the patient's transplant nephrologist to assure the patient is medically acceptable for study entry.
- Cardiac evaluation by transplant nephrologist with clearance documented in writing to participate in the study.
Who cannot join
- Known hypersensitivity to bortezomib, boron or mannitol, plerixafor or any of its components.
- Actual body weight exceeds 175% of ideal body mass.
- Subjects judged by the investigator to be at significant risk of failing to comply with the requirements of the protocol or unable to cooperate or communicate with the investigator.
- Abnormal electrocardiogram (ECG) with clinically significant ventricular arrhythmias or other conduction abnormality that in the opinion of the investigator warrants exclusion of the subject from the trial.
- Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (Appendix A), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
- Patient has Grade 2 peripheral neuropathy by Common Toxicity Criteria for Adverse Effects (CTCAE) criteria within 14 days before enrollment.
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- Patients with an absolute neutrophil count < 1,000/mm3 or platelet count < 75,000/mm3 within 30 days of consent.
- Patient has received other investigational drugs within 14 days prior to initiation of study treatment.
- Receipt of a live vaccine within 4 weeks prior to initiation of study treatment.
- Received blood transfusions within 30 days prior to trial entry.
- Serious medical (other than renal disease) or psychiatric illness likely to interfere with participation in this clinical study.
- Patients who are anti-HIV-positive, anti-Hepatitis C Virus (HCV) positive with a detectable viral load, or HBsAg-positive on testing performed within one year of consent.
- History of malignancy within the past 5 years that is not considered to be cured, with the exception of localized basal cell carcinoma of the skin (excised ≥ 2 years prior to randomization).
- Evidence of severe liver disease with abnormal liver profile (aspartate aminotransferase (AST), alanine aminotransferase (ALT) or total bilirubin > 1.5 times upper limit of normal (ULN)) on testing performed within 30 days of consent.
- Patients with current or severe systemic infections.
- Pregnant or nursing (lactating) women and women who might become pregnant during the study.
Trial locations and contacts
2 sites in 1 country.
United States2 sites, 2 recruiting
- Recruiting
The Christ Hospital
Cincinnati, Ohio, 45219
E. Steve Woodle, MD, 513-558-6001, Woodlees@uc.edu
Adele Rike-Shields, PharmD
- Recruiting
University of Cincinnati
Cincinnati, Ohio, 45267
E. Steve Woodle, MD, 513-558-6001, Woodlees@uc.edu
Rita R Alloway, PharmD
About this study
Official title: Quantitating the Impact of Plerixafor Alone or in Combination With Bortezomib on Plasma Cell Mobilization and the Subsequent Impact on HLA Antibody Levels
The primary objective of this study is to conduct a proof of concept pilot study that will provide a preliminary evaluation of the safety of plerixafor alone or in combination with bortezomib on plasma cell mobilization, Human Leukocyte Antigen (HLA) antibody levels and toxicity profile in sensitized patients awaiting kidney transplantation.
The secondary objective of this study is to conduct additional analyses of the study regimen on HLA antibody levels using multiple different assays and statistical analysis.
Read the detailed description
The investigators have previously demonstrated that proteasome inhibition (with bortezomib) provides effective antihumoral therapy for antibody-mediated rejection (AMR) and for desensitization in kidney transplant recipients and candidates. These studies have also demonstrated that plasma cell populations exhibit significant heterogeneity. Newly produced plasma blasts and plasma cells, whether from a primary or anamnestic immunologic response, during an acute AMR, are very sensitive to proteasome inhibitor-based therapy. Of the plasma cell populations we have examined, those that demonstrate the greatest degree of resistance to proteasome inhibitor therapy are those that reside within bone marrow niches. These long lived bone marrow niche resident plasma cell (LLBMNRPC) populations demonstrate a significant degree of resistance to bortezomib therapy. This concept of plasma cell niche providing long term survival signals is supported by substantial literature from murine models. A number of signals are involved that derive from the plasma cell niche which are thought to contribute to long lived plasma cell survival including CXC-chemokine receptor 4 (CXCR4)/chemokine (C-X-C motif) ligand 12 (CXCL12) interactions, Interleukin-6 (IL-6), B cell activating factor (BAFF), and cluster of differentiation 44 (CD44). In addition, a number of cells have been demonstrated to be involved in the plasma cell niche in either human or murine models, including eosinophils, osteoclasts, bone marrow reticular cells, amongst others.
Interruption of CXCR4/CXCL12 interactions with plerixafor has been used to induce cluster of differentiation 34+ (CD34+) bone marrow stem cell mobilization into the peripheral blood. Since the CXCR4/CXCL12 interaction is also thought to be responsible for plasma cells homing to the bone marrow niche, it has been hypothesized that plerixafor may also provide systemic mobilization of bone marrow niche resident plasma cells, or alternatively, may induce a local mobilization from the bone marrow niche of plasma cells. Given that previous studies have indicated that mobilization of long lived plasma cells is thought to result in short term (less than 72 hour) survival of long lived plasma cells, this represents a significant potential for enhancement of proteasome inhibitor-based plasma cell targeting therapies. Indeed, a previous abstract from the oncology literature has provided preliminary evidence that combined plerixafor and bortezomib therapy may be of use in mobilizing the malignant myeloma cell from its bone marrow niche, thereby enhancing sensitivity to bortezomib.
The purpose of the proposed study is to conduct a proof of concept and preliminary safety evaluation of plerixafor alone and also combined therapy with plerixafor and bortezomib. The investigators have prospectively conducted a meticulous assessment of bortezomib-related toxicities in both the transplant recipient AMR and the transplant candidate desensitization populations and recently published this in Transplantation. This experience, which now includes over 100 treated patients, indicates that the toxicity profile of bortezomib is quite comparable to that which is observed in the myeloma population. The investigators' preliminary analysis of plerixafor and bortezomib based toxicities demonstrates that there is no significant degree of overlap in the toxicities and no significant reasons to have concerns regarding combinatorial toxicities a priori.
The investigators' extensive phase I/II study of bortezomib-based desensitization with and without rituximab-based memory B-cell depletion and/or plasmapheresis has provided a substantial experience as a first line approach for first generation plasma cell targeted therapies for desensitization in kidney transplant candidates. The current proposal is the first in the initiation of second generation plasma cell targeting protocols which have substantial potential for applications beyond kidney transplant candidates. These types of regimens may also lend themselves to AMR and desensitization in kidney transplant recipients and also in heart and other solid organ transplant recipients. It is also possible that such second generation plasma cell targeted protocols may also be of use for desensitization in kidney transplant, heart transplant, and other solid organ transplant populations. Finally, these plasma cell targeted therapies may also be of use in autoimmune diseases where autoantibodies are thought to represent a major pathogenetic factor.
- Conditions
- Transplants and Implants
- Being tested
- plerixafor, Bortezomib, plasmapheresis
- Keywords
- Renal Transplantation, Desensitization, plerixafor, bortezomib
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
plerixaforDrug
Also called Mozobil
Plerixafor will be dosed subcutaneously and administered based on group assignment.
BortezomibDrug
Also called Velcade
Bortezomib will be given via IV push over 3-5 seconds and administered based on group assignment.
plasmapheresisOther
Plasmapheresis will be administered based on group assignment.
| Study group | Role | What they receive |
|---|---|---|
| Group A | Experimental | 4 doses of plerixafor and plasmapheresis Receives: Drug: plerixafor; Other: plasmapheresis |
| Group B | Experimental | 4 doses of plerixafor, 1 dose of bortezomib, and plasmapheresis Receives: Drug: plerixafor; Drug: Bortezomib; Other: plasmapheresis |
| Group C | Experimental | 6 doses of plerixafor, 2 doses of bortezomib, and plasmapheresis Receives: Drug: plerixafor; Drug: Bortezomib; Other: plasmapheresis |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent reduction in immunodominant Donor Specific Antibody (iDSA) [highest titer DSA (MFI)] and/or immunodominant antibody (iAb)
Measured: Up to 44 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Aug 2015 (estimated)
- Study startAug 2015
- Primary completionSep 2020 (estimated)
- Study completionOct 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Transplants and ImplantsStudies of the same condition, open and under way.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- E. Steve Woodle
- Sponsor type
- University, hospital or other
- Collaborators
- Sanofi-Synthelabo
- Responsible party
- Sponsor-investigator, E. Steve Woodle, University of Cincinnati
- Investigators
- Ervin S Woodle, MD, Principal investigator, University of Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02522572
- Sponsor's protocol ID
- Mozobil Sanofi
- Status last verified
- Jun 2020
- First submitted
- 6 Aug 2015
- Last updated
- 30 Jun 2020
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 30 Jun 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Quantitating the Impact of Plerixafor Alone or in Combination With Bortezomib on Plasma Cell Mobilization and the Subsequent Impact on HLA Antibody Levels
- ClinicalTrials.gov ID
- NCT02522572
- Acronym / sponsor ID
- Mozobil Sanofi
- Conditions
- Transplants and Implants
- Keywords
- Renal Transplantation, Desensitization, plerixafor, bortezomib
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- E. Steve WoodleUniversity, hospital or other
- Collaborators
- Sanofi-Synthelabo
- Study start
- Aug 2015
- Primary completion
- Sep 2020 (estimated)
- Study completion
- Oct 2020 (estimated)
- First posted
- 13 Aug 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective of this study is to conduct a proof of concept pilot study that will provide a preliminary evaluation of the safety of plerixafor alone or in combination with bortezomib on plasma cell mobilization, Human Leukocyte Antigen (HLA) antibody levels and toxicity profile in sensitized patients awaiting kidney transplantation.
The secondary objective of this study is to conduct additional analyses of the study regimen on HLA antibody levels using multiple different assays and statistical analysis.
Detailed description
The investigators have previously demonstrated that proteasome inhibition (with bortezomib) provides effective antihumoral therapy for antibody-mediated rejection (AMR) and for desensitization in kidney transplant recipients and candidates. These studies have also demonstrated that plasma cell populations exhibit significant heterogeneity. Newly produced plasma blasts and plasma cells, whether from a primary or anamnestic immunologic response, during an acute AMR, are very sensitive to proteasome inhibitor-based therapy. Of the plasma cell populations we have examined, those that demonstrate the greatest degree of resistance to proteasome inhibitor therapy are those that reside within bone marrow niches. These long lived bone marrow niche resident plasma cell (LLBMNRPC) populations demonstrate a significant degree of resistance to bortezomib therapy. This concept of plasma cell niche providing long term survival signals is supported by substantial literature from murine models. A number of signals are involved that derive from the plasma cell niche which are thought to contribute to long lived plasma cell survival including CXC-chemokine receptor 4 (CXCR4)/chemokine (C-X-C motif) ligand 12 (CXCL12) interactions, Interleukin-6 (IL-6), B cell activating factor (BAFF), and cluster of differentiation 44 (CD44). In addition, a number of cells have been demonstrated to be involved in the plasma cell niche in either human or murine models, including eosinophils, osteoclasts, bone marrow reticular cells, amongst others.
Interruption of CXCR4/CXCL12 interactions with plerixafor has been used to induce cluster of differentiation 34+ (CD34+) bone marrow stem cell mobilization into the peripheral blood. Since the CXCR4/CXCL12 interaction is also thought to be responsible for plasma cells homing to the bone marrow niche, it has been hypothesized that plerixafor may also provide systemic mobilization of bone marrow niche resident plasma cells, or alternatively, may induce a local mobilization from the bone marrow niche of plasma cells. Given that previous studies have indicated that mobilization of long lived plasma cells is thought to result in short term (less than 72 hour) survival of long lived plasma cells, this represents a significant potential for enhancement of proteasome inhibitor-based plasma cell targeting therapies. Indeed, a previous abstract from the oncology literature has provided preliminary evidence that combined plerixafor and bortezomib therapy may be of use in mobilizing the malignant myeloma cell from its bone marrow niche, thereby enhancing sensitivity to bortezomib.
The purpose of the proposed study is to conduct a proof of concept and preliminary safety evaluation of plerixafor alone and also combined therapy with plerixafor and bortezomib. The investigators have prospectively conducted a meticulous assessment of bortezomib-related toxicities in both the transplant recipient AMR and the transplant candidate desensitization populations and recently published this in Transplantation. This experience, which now includes over 100 treated patients, indicates that the toxicity profile of bortezomib is quite comparable to that which is observed in the myeloma population. The investigators' preliminary analysis of plerixafor and bortezomib based toxicities demonstrates that there is no significant degree of overlap in the toxicities and no significant reasons to have concerns regarding combinatorial toxicities a priori.
The investigators' extensive phase I/II study of bortezomib-based desensitization with and without rituximab-based memory B-cell depletion and/or plasmapheresis has provided a substantial experience as a first line approach for first generation plasma cell targeted therapies for desensitization in kidney transplant candidates. The current proposal is the first in the initiation of second generation plasma cell targeting protocols which have substantial potential for applications beyond kidney transplant candidates. These types of regimens may also lend themselves to AMR and desensitization in kidney transplant recipients and also in heart and other solid organ transplant recipients. It is also possible that such second generation plasma cell targeted protocols may also be of use for desensitization in kidney transplant, heart transplant, and other solid organ transplant populations. Finally, these plasma cell targeted therapies may also be of use in autoimmune diseases where autoantibodies are thought to represent a major pathogenetic factor.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Group A | Experimental | Drug: plerixafor, Other: plasmapheresis4 doses of plerixafor and plasmapheresis |
| Group B | Experimental | Drug: plerixafor, Drug: Bortezomib, Other: plasmapheresis4 doses of plerixafor, 1 dose of bortezomib, and plasmapheresis |
| Group C | Experimental | Drug: plerixafor, Drug: Bortezomib, Other: plasmapheresis6 doses of plerixafor, 2 doses of bortezomib, and plasmapheresis |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Male and female patients between 18 and 65 years of age (inclusive) with end-stage renal disease awaiting kidney transplantation.
- Patient with eligible living donor will have: donor specific antibody (DSA) against living donor of >5,000 mean fluorescence intensity (MFI) or a positive T or B cell flow cytometry crossmatch.
- Patient that is on the kidney transplant waiting list awaiting a deceased donor transplant and has an immunodominant antibody (iAb) of >8,000MFI or has a current or peak calculated panel reactive antibody (cPRA) >20%.
- Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
- Female subject is either postmenopausal for at least 1 year prior to initiation of study treatment, is surgically sterilized, or if of childbearing potential, agrees to practice 2 effective methods of contraception from the time of signing the informed consent form through 3 months after the last dose of plerixafor and/or bortezomib, or agrees to completely abstain from heterosexual intercourse. Women of childbearing potential must have a negative serum pregnancy test within the last 48 hours prior to receiving study medication.
Key exclusion criteria (16 listed)
- Known hypersensitivity to bortezomib, boron or mannitol, plerixafor or any of its components.
- Actual body weight exceeds 175% of ideal body mass.
- Subjects judged by the investigator to be at significant risk of failing to comply with the requirements of the protocol or unable to cooperate or communicate with the investigator.
- Abnormal electrocardiogram (ECG) with clinically significant ventricular arrhythmias or other conduction abnormality that in the opinion of the investigator warrants exclusion of the subject from the trial.
- Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (Appendix A), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
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 |
|---|---|---|
| plerixaforAlso: MozobilPlerixafor will be dosed subcutaneously and administered based on group assignment. | Drug | Group A, Group B, Group C |
| BortezomibAlso: VelcadeBortezomib will be given via IV push over 3-5 seconds and administered based on group assignment. | Drug | Group B, Group C |
| plasmapheresisPlasmapheresis will be administered based on group assignment. | Other | Group A, Group B, Group C |
Primary outcome
Percent reduction in immunodominant Donor Specific Antibody (iDSA) [highest titer DSA (MFI)] and/or immunodominant antibody (iAb)
Time frame: Up to 44 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jun 2020.
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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.
Ervin S Woodle, MD principal investigator
University of Cincinnati
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing plerixafor, Bortezomib and plasmapheresis in people with Transplants and Implants, run by E. Steve Woodle at 2 sites 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 8 inclusion and 16 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: status not confirmed, as of the sponsor's last update on 30 Jun 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact E. Steve Woodle, MD (513-558-6001, Woodlees@uc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent reduction in immunodominant Donor Specific Antibody (iDSA) [highest titer DSA (MFI)] and/or immunodominant antibody (iAb) (time frame: Up to 44 days). 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 30 Jun 2020.