Hematologic MalignanciesPhase 1/2NCT00810602
Vorinostat to Prevent Graft Versus Host Disease Following Reduced Intensity, Related Donor Stem Cell Transplant
A Phase 1/2 study testing reduced intensity, related donor stem cell transplant, tacrolimus (standard GVHD prophylaxis) and mycophenolate (standard GVHD prophylaxis) in people with Hematologic Malignancies and Graft vs Host Disease, run by Pavan Reddy, MD at 2 sites in United States.
Trial summary
The proposed research study is to test the drug vorinostat, in a new use as an additional medication, with other standard treatments for the prevention of severe acute graft versus host disease (GVHD). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hematologic Malignancies, Graft vs Host Disease
- What is being tested?
- reduced intensity, related donor stem cell transplant, tacrolimus (standard GVHD prophylaxis) and mycophenolate (standard GVHD prophylaxis)
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 61 participants
- Where
- 2 sitesUnited States
- Study dates
- Jan 2009to Jul 2013
- Phase
- Phase 1/2
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Have a 7/8 or 8/8 HLA A, B, C and DR, HLA-matched related donor willing and able to donate allogeneic stem cells.
- For patients with multiple myeloma, CLL, and lymphoma: must be in CR, PR, or stable disease.
- For MDS, acute leukemia or CML: must have <20% blasts on marrow exam.
- For all other diseases: must have non-refractory disease.
- and meet at least ONE of the next three criteria:
- Any patient ≥ 18 years of age with a hematological malignancy and not considered a candidate for allogeneic myeloablative transplant due to illness and/or age (≥55 years).
- Any patient ≥ 18 years of age who has relapsed following prior autologous or allogeneic transplant for a hematologic malignancy.
- Any patient ≥ 18 years of age diagnosed with a hematological malignancy for which reduced intensity transplant is institutionally preferred over myeloablative transplant (eg, chronic lymphocytic leukemia).
Who cannot join
- Less than 18 years of age.
- Currently taking any HDAC inhibitors, or have taken an HDAC inhibitor within 30 days of the trial.
- Positive serum tests for HIV, HTLV1 / HTLV2.
- Detectable hepatitis B virus (HBV), hepatitis C (HCV) or Epstein-Barr (EBV).
- Pregnancy.
- One or more of the following organ system function criteria
Show all 13Show fewer
- Cardiac: Ejection fraction ≤ 40%
- Renal: Estimated or actual GFR ≤ 40 ml/min (corrected for BSA)
- Pulmonary: FEV1, FVC, or DLCO ≤ 40% predicted
- Hepatic: Total bilirubin ≥3 mg% and AST/ALT >5 x institutional normal for age
- Karnofsky score ≤50 (Requires considerable assistance and frequent medical care).
- Persistent invasive infections not controlled by antimicrobial medication.
- Any physical or psychological condition that, in the opinion of the investigator, would pose unacceptable risk to the patient.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of Michigan Cancer Center
Ann Arbor, Michigan, 48109
Washington University School of Medicine
St Louis, Missouri, 63110
About this study
Official title: Phase II Trial of Vorinostat Plus Tacrolimus & Mycophenolate to Prevent Graft Versus Host Disease Following Reduced Intensity Conditioning Related Donor Allogeneic Transplant
The proposed research study is to test the drug vorinostat, in a new use as an additional medication, with other standard treatments for the prevention of severe acute graft versus host disease (GVHD).
If this treatment is safe and effective, when combined with a reduced intensity transplant, the research may achieve a more effective therapy for patients with high-risk, blood cell related cancers.
Read more
All subjects will receive an identical, known treatment to test if the treatment is safe and effective (a phase II trial). For patients to take part they must have a high-risk, blood cell cancer, be suitable candidates to receive a reduced intensity transplant and have a matched, related donor.
Adult subjects (age 18 years and older) will be considered as subjects provided, as detailed in the protocol, they meet additional criteria and are not excluded from participating. About fifty (50) subjects will be enrolled in this study at the University of Michigan.
Patients who receive blood stem cell transplants (HSCT), also called bone marrow transplants, to treat their cancer are at risk for serious complications, which may sometimes be fatal. The more common, serious ones are relapse (return of their disease), body organ injury from the intensity of the chemotherapy given prior to their transplant, and a serious complication called graft versus host disease (GVHD). GVHD is a form of rejection, where the transplanted cells of the donor attack the recipient's body as foreign, and do damage to organs and tissues.
To decrease the side effects of the chemotherapy given before a transplant, reduced intensity treatment plans(regimens)have recently been developed at a number of transplant centers. A decrease in the side effects of chemotherapy (called toxicities) has been achieved; however, this success with "less intensive" treatments has been partially offset by less successful results in controlling the patient's cancer.
As mentioned above, GVHD is a form of transplant rejection. GVHD can affect the digestive system, skin, liver and other body systems. GVHD can increase the risk of infection. After a matched, related donor stem cell transplant, GVHD when severe, is a major cause of discomfort, organ damage, and even death. When a graft vs host reaction develops, but is kept under control, studies show there may be a beneficial graft versus tumor effect, helping to destroy tumor cells in the patient, and thus providing a more effective control of their cancer.
The goal of this study is to try to maximize the potential benefits, of giving patients less intense chemotherapy to reduce the toxic effects, letting the graft vs host effect help in destroying tumor cells, but preventing acute severe GVHD by using the drug vorinostat, combined with standard medicines, to reduce the chance of serious GVHD-related complications.
- Conditions
- Hematologic Malignancies, Graft vs Host Disease
- Being tested
- reduced intensity, related donor stem cell transplant, tacrolimus (standard GVHD prophylaxis), mycophenolate (standard GVHD prophylaxis), vorinostat
- Medical subject headings
- Hematologic Neoplasms, Graft vs Host Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
reduced intensity, related donor stem cell transplantProcedure or surgery
Fludarabine /Busulfan(FluBu2)regimen
Fludarabine: 40 mg/m2/day in 0.9 NS, administered IV on days -5 to day -2 pre-transplant for a total of 4 doses. Busulfan: 3.2 mg/kg in 0.9 NS administered IV on days -5 and -4 for a total of 2 doses. Total body irradiation 200 cGy delivered in a single fraction will be given on day 0 for patients receiving an HLA-mismatched transplant.
tacrolimus (standard GVHD prophylaxis)Drug
Tacrolimus will begin on day -3, IV or oral. Target trough level for tacrolimus is 8-12 ng/ml. In the absence of GVHD, tacrolimus tapering will begin on day +56 post transplant
mycophenolate (standard GVHD prophylaxis)Drug
Mycophenolate will begin on day 0 at 10 mg/kg/dose (up to 1 gram per dose) every 8 hours orally or intravenously and will continue until day 28.
vorinostatDrug
Also called ZOLINZA
Vorinostat given at a dose 100 mg PO BID starting day -10. If tolerated, vorinostat will be continued until day 100 post-transplant,whether or not acute GVHD develops.
Dose escalation/ de-escalation
Ten subjects treated at a dose of 100 mg PO BID. If dosing modifications are not required, during the pre-engraftment period in more than 4 patients, AND no more than two observed drug related toxicities CTC grade 4 or higher [probably or definitely related to the drug] then vorinostat dose will be escalated to 200 mg PO BID.
If dose escalation does not occur due to failure to meet the above criteria,then the study will enroll at the 100 mg PO BID dosing, subject to the protocol stopping rules.
If dose escalation occurs, subjects will be treated at 200 mg PO BID dosing level. If the probability of unacceptable toxicity exceeds the rules in protocol, then the dose of vorinostat will be de-escalated to 100 mg PO BID for the remainder of study.
| Study group | Role | What they receive |
|---|---|---|
| Vorinostat prophylaxis | Experimental | Vorinostat,combined with standard GVHD prevention medications(tacrolimus, mycophenolate) for adults who received a reduced intensity, related donor stem cell transplant Receives: Procedure: reduced intensity, related donor stem cell transplant; Drug: tacrolimus (standard GVHD prophylaxis); Drug: mycophenolate (standard GVHD prophylaxis); Drug: vorinostat |
What is being measured
The primary outcome is the main question the study is designed to answer.
100-day Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD)
Assess if the addition of Vorinostat to standard GVHD prophylaxis regimen can reduce the rate of grades 2-4 acute GVHD when compared to 48% in a cohort of identically treated RIC HSCT patients without vorinostat. A reduction of incidence to less than 25% will be considered successful.
Measured: 100 days
Secondary outcomes (3)
Number of Serious Adverse Events
The safety and feasibility will be partially measured by the number of serious adverse events (SAE) recorded by participants receiving at least one dose of Vorinostat.
Measured: 100 days
Percent Cumulative Incidence of Relapse at 2 Years.
Determine the cumulative incidence of relapse at 2 years.
Measured: two years
Percent Survival at 2-years
To determine 2-year overall survival rate
Measured: two years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Dec 2008 (estimated)
- Study startJan 2009
- Primary completionApr 2013
- Study completionJul 2013
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 Hematologic MalignanciesStudies 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 61 participants (actual)
Sponsor and investigators
- Lead sponsor
- Pavan Reddy, MD
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Pavan Reddy, MD, University of Michigan Rogel Cancer Center
- Investigators
- Pavan Reddy, MD, Principal investigator, University of Michigan Rogel Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00810602
- Sponsor's protocol ID
- UMCC 2008.095
- Status last verified
- Mar 2014
- First submitted
- 17 Dec 2008
- Last updated
- 11 Apr 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Choi SW, Braun T, Chang L, Ferrara JL, Pawarode A, Magenau JM, Hou G, Beumer JH, Levine JE, Goldstein S, Couriel DR, Stockerl-Goldstein K, Krijanovski OI, Kitko C, Yanik GA, Lehmann MH, Tawara I, Sun Y, Paczesny S, Mapara MY, Dinarello CA, DiPersio JF, Reddy P. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol. 2014 Jan;15(1):87-95. doi: 10.1016/S1470-2045(13)70512-6. Epub 2013 Nov 30.
PubMed 24295572
Study at a glance
From the registry record, last updated by the sponsor on 11 Apr 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Trial of Vorinostat Plus Tacrolimus & Mycophenolate to Prevent Graft Versus Host Disease Following Reduced Intensity Conditioning Related Donor Allogeneic Transplant
- ClinicalTrials.gov ID
- NCT00810602
- Acronym / sponsor ID
- UMCC 2008.095
- Conditions
- Hematologic Malignancies, Graft vs Host Disease
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 61 participants (actual)
- Lead sponsor
- Pavan Reddy, MDUniversity, hospital or other
- Study start
- Jan 2009
- Primary completion
- Apr 2013 (actual)
- Study completion
- Jul 2013 (actual)
- First posted
- 18 Dec 2008 (estimated)
- Results
- Posted 11 Apr 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The proposed research study is to test the drug vorinostat, in a new use as an additional medication, with other standard treatments for the prevention of severe acute graft versus host disease (GVHD).
If this treatment is safe and effective, when combined with a reduced intensity transplant, the research may achieve a more effective therapy for patients with high-risk, blood cell related cancers.
All subjects will receive an identical, known treatment to test if the treatment is safe and effective (a phase II trial). For patients to take part they must have a high-risk, blood cell cancer, be suitable candidates to receive a reduced intensity transplant and have a matched, related donor.
Adult subjects (age 18 years and older) will be considered as subjects provided, as detailed in the protocol, they meet additional criteria and are not excluded from participating. About fifty (50) subjects will be enrolled in this study at the University of Michigan.
Patients who receive blood stem cell transplants (HSCT), also called bone marrow transplants, to treat their cancer are at risk for serious complications, which may sometimes be fatal. The more common, serious ones are relapse (return of their disease), body organ injury from the intensity of the chemotherapy given prior to their transplant, and a serious complication called graft versus host disease (GVHD). GVHD is a form of rejection, where the transplanted cells of the donor attack the recipient's body as foreign, and do damage to organs and tissues.
To decrease the side effects of the chemotherapy given before a transplant, reduced intensity treatment plans(regimens)have recently been developed at a number of transplant centers. A decrease in the side effects of chemotherapy (called toxicities) has been achieved; however, this success with "less intensive" treatments has been partially offset by less successful results in controlling the patient's cancer.
As mentioned above, GVHD is a form of transplant rejection. GVHD can affect the digestive system, skin, liver and other body systems. GVHD can increase the risk of infection. After a matched, related donor stem cell transplant, GVHD when severe, is a major cause of discomfort, organ damage, and even death. When a graft vs host reaction develops, but is kept under control, studies show there may be a beneficial graft versus tumor effect, helping to destroy tumor cells in the patient, and thus providing a more effective control of their cancer.
The goal of this study is to try to maximize the potential benefits, of giving patients less intense chemotherapy to reduce the toxic effects, letting the graft vs host effect help in destroying tumor cells, but preventing acute severe GVHD by using the drug vorinostat, combined with standard medicines, to reduce the chance of serious GVHD-related complications.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Vorinostat prophylaxis | Experimental | Procedure: reduced intensity, related donor stem cell transplant, Drug: tacrolimus (standard GVHD prophylaxis), Drug: mycophenolate (standard GVHD prophylaxis), Drug: vorinostatVorinostat,combined with standard GVHD prevention medications(tacrolimus, mycophenolate) for adults who received a reduced intensity, related donor stem cell transplant |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Have a 7/8 or 8/8 HLA A, B, C and DR, HLA-matched related donor willing and able to donate allogeneic stem cells.
- For patients with multiple myeloma, CLL, and lymphoma: must be in CR, PR, or stable disease.
- For MDS, acute leukemia or CML: must have <20% blasts on marrow exam.
- For all other diseases: must have non-refractory disease.
- Any patient ≥ 18 years of age with a hematological malignancy and not considered a candidate for allogeneic myeloablative transplant due to illness and/or age (≥55 years).
Key exclusion criteria (13 listed)
- Less than 18 years of age.
- Currently taking any HDAC inhibitors, or have taken an HDAC inhibitor within 30 days of the trial.
- Positive serum tests for HIV, HTLV1 / HTLV2.
- Detectable hepatitis B virus (HBV), hepatitis C (HCV) or Epstein-Barr (EBV).
- Pregnancy.
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 |
|---|---|---|
| reduced intensity, related donor stem cell transplantFludarabine /Busulfan(FluBu2)regimen Fludarabine: 40 mg/m2/day in 0.9 NS, administered IV on days -5 to day -2 pre-transplant for a total of 4 doses. Busulfan: 3.2 mg/kg in 0.9 NS administered IV on days -5 and -4 for a total of 2 doses. Total body irradiation 200 cGy delivered in a single fraction will be given on day 0 for patients receiving an HLA-mismatched transplant. | Procedure or surgery | Vorinostat prophylaxis |
| tacrolimus (standard GVHD prophylaxis)Tacrolimus will begin on day -3, IV or oral. Target trough level for tacrolimus is 8-12 ng/ml. In the absence of GVHD, tacrolimus tapering will begin on day +56 post transplant | Drug | Vorinostat prophylaxis |
| mycophenolate (standard GVHD prophylaxis)Mycophenolate will begin on day 0 at 10 mg/kg/dose (up to 1 gram per dose) every 8 hours orally or intravenously and will continue until day 28. | Drug | Vorinostat prophylaxis |
| vorinostatAlso: ZOLINZAVorinostat given at a dose 100 mg PO BID starting day -10. If tolerated, vorinostat will be continued until day 100 post-transplant,whether or not acute GVHD develops. Dose escalation/ de-escalation Ten subjects treated at a dose of 100 mg PO BID. If dosing modifications are not required, during the pre-engraftment period in more than 4 patients, AND no more than two observed drug related toxicities CTC grade 4 or higher [probably or definitely related to the drug] then vorinostat dose will be escalated to 200 mg PO BID. If dose escalation does not occur due to failure to meet the above criteria,then the study will enroll at the 100 mg PO BID dosing, subject to the protocol stopping rules. If dose escalation occurs, subjects will be treated at 200 mg PO BID dosing level. If the probability of unacceptable toxicity exceeds the rules in protocol, then the dose of vorinostat will be de-escalated to 100 mg PO BID for the remainder of study. | Drug | Vorinostat prophylaxis |
Primary outcome
100-day Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD)
Time frame: 100 days
Assess if the addition of Vorinostat to standard GVHD prophylaxis regimen can reduce the rate of grades 2-4 acute GVHD when compared to 48% in a cohort of identically treated RIC HSCT patients without vorinostat. A reduction of incidence to less than 25% will be considered successful.
3 secondary outcomes
Number of Serious Adverse Events
Time frame: 100 days
Percent Cumulative Incidence of Relapse at 2 Years.
Time frame: two years
Percent Survival at 2-years
Time frame: two years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Apr 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 24295572Choi SW, Braun T, Chang L, Ferrara JL, Pawarode A, Magenau JM, Hou G, Beumer JH, Levine JE, Goldstein S, Couriel DR, Stockerl-Goldstein K, Krijanovski OI, Kitko C, Yanik GA, Lehmann MH, Tawara I, Sun Y, Paczesny S, Mapara MY, Dinarello CA, DiPersio JF, Reddy P. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol. 2014 Jan;15(1):87-95. doi: 10.1016/S1470-2045(13)70512-6. Epub 2013 Nov 30.
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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.
Pavan Reddy, MD principal investigator
University of Michigan Rogel Cancer Center
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 reduced intensity, related donor stem cell transplant, tacrolimus (standard GVHD prophylaxis) and mycophenolate (standard GVHD prophylaxis) in people with Hematologic Malignancies and Graft vs Host Disease, run by Pavan Reddy, MD 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 13 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 11 Apr 2014. 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?
Yes. Results are posted in the registry (first posted 11 Apr 2014). 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?
100-day Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD) (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 NCT00810602, 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 11 Apr 2014.