Vorinostat to Prevent Graft Versus Host Disease Following Reduced Intensity, Related Donor Stem Cell Transplant

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pavan Reddy, MD, University of Michigan Cancer Center
ClinicalTrials.gov Identifier:
NCT00810602
First received: December 17, 2008
Last updated: March 5, 2014
Last verified: March 2014
Results First Received: November 27, 2013  
Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: Hematologic Malignancies
Graft vs Host Disease
Interventions: Procedure: reduced intensity, related donor stem cell transplant
Drug: tacrolimus (standard GVHD prophylaxis)
Drug: mycophenolate (standard GVHD prophylaxis)
Drug: vorinostat

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
From March 2008 through February 2013, eligible patients with advanced hematological cancers were enrolled at the University of Michigan and Washington University in St. Louis.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
All patients received a preparative regimen of intravenous fludarabine (40 mg/m2 on day -5 through day -2) and busulfan (3.2 mg/kg on days -5 and -4) (FluBu2) followed by the infusion of peripheral blood stem cells (PBSC) on day 0. GVHD prophylaxis consisted of tacrolimus initiated on day -3 and mycophenolate mofetil (MMF) on day 0 through day 28.

Reporting Groups
  Description
Phase 1 In the Phase 1 portion of the study, participants were administered Vorinostat, either 100 mg or 200mg, twice daily, orally, starting ten days prior to the stem cell infusion and continuing through day 100 post-HSCT. If tolerated, vorinostat will be continued until day 100 post-transplant,whether or not acute GVHD develops.
Phase 2 100 mg was selected as the Phase 2 dose. Participants were administered Vorinostat, 100 mg, twice daily, orally, starting ten days prior to the stem cell infusion and continuing through day 100 post-HSCT. If tolerated, vorinostat will be continued until day 100 post-transplant,whether or not acute GVHD develops.

Participant Flow:   Overall Study
    Phase 1     Phase 2  
STARTED     27     34  
COMPLETED     19     31  
NOT COMPLETED     8     3  
Withdrawal by Subject                 8                 3  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Only participants that completed 21 days of vorinostat were considered evaluable for both toxicity and the primary outcome, therfore only 50 of the 61 patients initially enrolled are represented in baseline characteristics.

Reporting Groups
  Description
Vorinostat Prophylaxis

Vorinostat, combined with standard GVHD prevention medications(tacrolimus, mycophenolate) for adults who received a reduced intensity, related donor stem cell transplant.

Vorinostat was administered daily starting ten days prior to the stem cell infusion and continued through day 100 post-HSCT. If tolerated, vorinostat will be continued until day 100 post-transplant,whether or not acute GVHD develops.

The phase 1 portion of the study tested two doses of vorinostat, 100 mg BID and 200 mg BID.The first ten patients received vorinostat 100 mg BID, followed by nine patients who received the 200 mg BID dose.

Although no dose-limiting toxicities were reached at the 200 mg BID dose, there was an increased incidence of protocol-driven dose modifications, primarily due to non-symptomatic thrombocytopenia after engraftment. Consequently, the 100 mg BID dose was selected as the phase 2 dose for the remaining patients.


Baseline Measures
    Vorinostat Prophylaxis  
Number of Participants  
[units: participants]
  50  
Age  
[units: years]
Median ( Full Range )
  59  
  ( 43 to 69 )  
Gender [1]
[units: participants]
 
Female     22  
Male     28  
Ethnicity (NIH/OMB)  
[units: participants]
 
Hispanic or Latino     2  
Not Hispanic or Latino     46  
Unknown or Not Reported     2  
Diagnosis  
[units: participants]
 
Acute myelogenous leukemia     19  
Myelodysplastic syndrome     10  
Non-Hodgkin's lymphoma     12  
Chronic lymphocytic leukemia     4  
Myeloproliferative disorder or myelofibrosis     4  
Acute biphenotypic leukemia     1  
Disease Status  
[units: participants]
 
Low     25  
Intermediate     20  
High     5  
Comorbidity index [2]
[units: participants]
 
Low     8  
Intermediate     15  
High     27  
Donor Type  
[units: participants]
 
Matched related     46  
One-antigen mismatched related     4  
CMV Status [3]
[units: participants]
 
Recipient or Donor positive (detailed below)     30  
R+, D+     17  
R-, D+     6  
R+, D-     7  
Recipient and Donor negative     20  
CD34+ Count (10^6 cells/kg)  
[units: Count¬†(10^6¬†cells/kg)]
Median ( Full Range )
  5.0  
  ( 1.9 to 8 )  
Engraftment Day [4]
[units: days]
Median ( Full Range )
 
Neutrophil     12  
  ( 8 to 19 )  
Platelet     12  
  ( 9 to 30 )  
[1] (44%, 56% of evaluable subjects, respectively)
[2] Hematopoietic Cell Transplant – Comorbidity Index: Low = 0, Intermediate = 1 or 2, High ≥ 3
[3] Recipient(R),Donor (D), positive (+), negative(-)
[4] Median time to platelet and neutrophil engraftment.



  Outcome Measures
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1.  Primary:   100-day Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD)   [ Time Frame: 100 days ]

2.  Secondary:   Number of Serious Adverse Events   [ Time Frame: 100 days ]

3.  Secondary:   Percent Cumulative Incidence of Relapse at 2 Years.   [ Time Frame: two years ]

4.  Secondary:   Percent Survival at 2-years   [ Time Frame: two years ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
All Principal Investigators ARE employed by the organization sponsoring the study.


Results Point of Contact:  
Name/Title: Dr. Sung Choi
Organization: University of Michigan Comprehensive Cancer Center
phone: 734-764-8630
e-mail: sungchoi@med.umich.edu


Publications of Results:

Responsible Party: Pavan Reddy, MD, University of Michigan Cancer Center
ClinicalTrials.gov Identifier: NCT00810602     History of Changes
Other Study ID Numbers: UMCC 2008.095
Study First Received: December 17, 2008
Results First Received: November 27, 2013
Last Updated: March 5, 2014
Health Authority: United States: Food and Drug Administration