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

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ClinicalTrials.gov Identifier: NCT00810602
Recruitment Status : Completed
First Posted : December 18, 2008
Results First Posted : April 11, 2014
Last Update Posted : April 11, 2014
Sponsor:
Information provided by (Responsible Party):
Pavan Reddy, MD, University of Michigan Rogel Cancer Center

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (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
Enrollment 61
Recruitment Details 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 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.
Arm/Group Title Phase 1 Phase 2
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 27 34
Completed 19 31
Not Completed 8 3
Reason Not Completed
Withdrawal by Subject             8             3
Arm/Group Title Vorinostat Prophylaxis
Hide Arm/Group Description

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.

Overall Number of Baseline Participants 50
Hide Baseline Analysis Population Description
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.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 50 participants
59
(43 to 69)
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants
Female
22
  44.0%
Male
28
  56.0%
[1]
Measure Description: (44%, 56% of evaluable subjects, respectively)
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants
Hispanic or Latino
2
   4.0%
Not Hispanic or Latino
46
  92.0%
Unknown or Not Reported
2
   4.0%
Diagnosis  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 50 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  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 50 participants
Low 25
Intermediate 20
High 5
Comorbidity index   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 50 participants
Low 8
Intermediate 15
High 27
[1]
Measure Description: Hematopoietic Cell Transplant – Comorbidity Index: Low = 0, Intermediate = 1 or 2, High ≥ 3
Donor Type  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 50 participants
Matched related 46
One-antigen mismatched related 4
CMV Status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 50 participants
Recipient or Donor positive (detailed below) 30
R+, D+ 17
R-, D+ 6
R+, D- 7
Recipient and Donor negative 20
[1]
Measure Description: Recipient(R),Donor (D), positive (+), negative(-)
CD34+ Count (10^6 cells/kg)  
Median (Full Range)
Unit of measure:  Count (10^6 cells/kg)
Number Analyzed 50 participants
5.0
(1.9 to 8)
Engraftment Day   [1] 
Median (Full Range)
Unit of measure:  Days
Number Analyzed 50 participants
Neutrophil
12
(8 to 19)
Platelet
12
(9 to 30)
[1]
Measure Description: Median time to platelet and neutrophil engraftment.
1.Primary Outcome
Title 100-day Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD)
Hide Description 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.
Time Frame 100 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
evaluable
Arm/Group Title Vorinostat Prophylaxis
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 50
Measure Type: Number
Unit of Measure: percentage of participants
22
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vorinostat Prophylaxis
Comments Hypothesis: The addition of vorinostat will reduce the incidence of grade 2-4 acute graft versus host disease (GVHD) to 25% or lower by day 100.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Percent Cumulative Incidence of GVHD
Estimated Value 22
Confidence Interval (2-Sided) 95%
13 to 36
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Serious Adverse Events
Hide Description 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.
Time Frame 100 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The number of patients who received at least one dose of vorinostat.
Arm/Group Title Vorinostat Prophylaxis
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 58
Measure Type: Number
Unit of Measure: Number of Serious Adverse Events
33
3.Secondary Outcome
Title Percent Cumulative Incidence of Relapse at 2 Years.
Hide Description Determine the cumulative incidence of relapse at 2 years.
Time Frame two years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
evaluable subjects
Arm/Group Title Vorinostat Prophylaxis
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 50
Measure Type: Number
Unit of Measure: percentage of participants
16
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vorinostat Prophylaxis
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Percent Cumulative Incidence of GVHD
Estimated Value 16
Confidence Interval (2-Sided) 95%
8 to 30
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percent Survival at 2-years
Hide Description To determine 2-year overall survival rate
Time Frame two years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
evaluable subjects
Arm/Group Title Vorinostat Prophylaxis
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 50
Measure Type: Number
Unit of Measure: percentage of subjects
73
Time Frame Adverse event data was collected from March 2008 through April of 2013.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Vorinostat Prophylaxis
Hide Arm/Group Description

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.

All-Cause Mortality
Vorinostat Prophylaxis
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Vorinostat Prophylaxis
Affected / at Risk (%) # Events
Total   31/58 (53.45%)    
Gastrointestinal disorders   
Anorexia  1/58 (1.72%) 
Diarrhea  1/58 (1.72%) 
Hemmorrhoids  1/58 (1.72%) 
General disorders   
Edema: Limb  1/58 (1.72%) 
Immune system disorders   
Graft Versus Host Disease  5/58 (8.62%) 
Infections and infestations   
Infection  12/58 (20.69%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Relapse  6/58 (10.34%) 
Respiratory, thoracic and mediastinal disorders   
Pulmonary Hypertension  1/58 (1.72%) 
Skin and subcutaneous tissue disorders   
Rash  1/58 (1.72%) 
Vascular disorders   
Thrombosis/Thrombus/Embolism  2/58 (3.45%) 
1
Term from vocabulary, CTCAE (3.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Vorinostat Prophylaxis
Affected / at Risk (%) # Events
Total   51/58 (87.93%)    
Blood and lymphatic system disorders   
Hemoglobin  29/58 (50.00%)  45
Infections and infestations   
Infection  8/58 (13.79%)  8
Investigations   
Alanine Aminotransferase Increased  3/58 (5.17%)  3
Leukocytes (White Blood Cells Decreased)  51/58 (87.93%)  84
Lymphopenia  50/58 (86.21%)  109
Neutrophils Decreased  50/58 (86.21%)  100
Platelets Decreased  50/58 (86.21%)  184
Metabolism and nutrition disorders   
Hyperglycemia  12/58 (20.69%)  12
Hypocalcemia  3/58 (5.17%)  4
Hyponatremia  4/58 (6.90%)  5
Hypophosphatemia  4/58 (6.90%)  4
1
Term from vocabulary, CTCAE (3.0)
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
Responsible Party: Pavan Reddy, MD, University of Michigan Rogel Cancer Center
ClinicalTrials.gov Identifier: NCT00810602     History of Changes
Other Study ID Numbers: UMCC 2008.095
First Submitted: December 17, 2008
First Posted: December 18, 2008
Results First Submitted: November 27, 2013
Results First Posted: April 11, 2014
Last Update Posted: April 11, 2014