Trial Outcomes & Findings for Vorinostat to Prevent Graft Versus Host Disease Following Reduced Intensity, Related Donor Stem Cell Transplant (NCT NCT00810602)

Last Updated: 2014-04-11

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

61 participants

Primary outcome timeframe

100 days

Results posted on

2014-04-11

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.
Overall Study STARTED	27	34
Overall Study COMPLETED	19	31
Overall Study NOT COMPLETED	8	3

Reasons for withdrawal

Reasons for withdrawal
Measure	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.
Overall Study Withdrawal by Subject	8	3

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vorinostat Prophylaxis n=50 Participants 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.
Age, Continuous	59 years n=5 Participants
Sex: Female, Male Female	22 Participants n=5 Participants
Sex: Female, Male Male	28 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	46 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants
Diagnosis Acute myelogenous leukemia	19 participants n=5 Participants
Diagnosis Myelodysplastic syndrome	10 participants n=5 Participants
Diagnosis Non-Hodgkin's lymphoma	12 participants n=5 Participants
Diagnosis Chronic lymphocytic leukemia	4 participants n=5 Participants
Diagnosis Myeloproliferative disorder or myelofibrosis	4 participants n=5 Participants
Diagnosis Acute biphenotypic leukemia	1 participants n=5 Participants
Disease Status Low	25 participants n=5 Participants
Disease Status Intermediate	20 participants n=5 Participants
Disease Status High	5 participants n=5 Participants
Comorbidity index Low	8 participants n=5 Participants
Comorbidity index Intermediate	15 participants n=5 Participants
Comorbidity index High	27 participants n=5 Participants
Donor Type Matched related	46 participants n=5 Participants
Donor Type One-antigen mismatched related	4 participants n=5 Participants
CMV Status Recipient or Donor positive (detailed below)	30 participants n=5 Participants
CMV Status R+, D+	17 participants n=5 Participants
CMV Status R-, D+	6 participants n=5 Participants
CMV Status R+, D-	7 participants n=5 Participants
CMV Status Recipient and Donor negative	20 participants n=5 Participants
CD34+ Count (10^6 cells/kg)	5.0 Count (10^6 cells/kg) n=5 Participants
Engraftment Day Neutrophil	12 days n=5 Participants
Engraftment Day Platelet	12 days n=5 Participants

PRIMARY outcome

Timeframe: 100 days

Population: evaluable

Outcome measures

Outcome measures
Measure	Vorinostat Prophylaxis n=50 Participants 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.
100-day Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD)	22 percentage of participants

SECONDARY outcome

Timeframe: 100 days

Population: The number of patients who received at least one dose of vorinostat.

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.

Outcome measures

Outcome measures
Measure	Vorinostat Prophylaxis n=58 Participants 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.
Number of Serious Adverse Events	33 Number of Serious Adverse Events

SECONDARY outcome

Timeframe: two years

Population: evaluable subjects

Determine the cumulative incidence of relapse at 2 years.

Outcome measures

Outcome measures
Measure	Vorinostat Prophylaxis n=50 Participants 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.
Percent Cumulative Incidence of Relapse at 2 Years.	16 percentage of participants

SECONDARY outcome

Timeframe: two years

Population: evaluable subjects

To determine 2-year overall survival rate

Outcome measures

Outcome measures
Measure	Vorinostat Prophylaxis n=50 Participants 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.
Percent Survival at 2-years	73 percentage of subjects

Adverse Events

Vorinostat Prophylaxis

Serious events: 31 serious events

Other events: 51 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Vorinostat Prophylaxis n=58 participants at risk 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.
Gastrointestinal disorders Anorexia	1.7% 1/58 • Adverse event data was collected from March 2008 through April of 2013.
Gastrointestinal disorders Diarrhea	1.7% 1/58 • Adverse event data was collected from March 2008 through April of 2013.
General disorders Edema: Limb	1.7% 1/58 • Adverse event data was collected from March 2008 through April of 2013.
Gastrointestinal disorders Hemmorrhoids	1.7% 1/58 • Adverse event data was collected from March 2008 through April of 2013.
Infections and infestations Infection	20.7% 12/58 • Adverse event data was collected from March 2008 through April of 2013.
Respiratory, thoracic and mediastinal disorders Pulmonary Hypertension	1.7% 1/58 • Adverse event data was collected from March 2008 through April of 2013.
Skin and subcutaneous tissue disorders Rash	1.7% 1/58 • Adverse event data was collected from March 2008 through April of 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Relapse	10.3% 6/58 • Adverse event data was collected from March 2008 through April of 2013.
Immune system disorders Graft Versus Host Disease	8.6% 5/58 • Adverse event data was collected from March 2008 through April of 2013.
Vascular disorders Thrombosis/Thrombus/Embolism	3.4% 2/58 • Adverse event data was collected from March 2008 through April of 2013.

Other adverse events

Other adverse events
Measure	Vorinostat Prophylaxis n=58 participants at risk 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.
Investigations Alanine Aminotransferase Increased	5.2% 3/58 • Number of events 3 • Adverse event data was collected from March 2008 through April of 2013.
Blood and lymphatic system disorders Hemoglobin	50.0% 29/58 • Number of events 45 • Adverse event data was collected from March 2008 through April of 2013.
Metabolism and nutrition disorders Hyperglycemia	20.7% 12/58 • Number of events 12 • Adverse event data was collected from March 2008 through April of 2013.
Metabolism and nutrition disorders Hypocalcemia	5.2% 3/58 • Number of events 4 • Adverse event data was collected from March 2008 through April of 2013.
Metabolism and nutrition disorders Hyponatremia	6.9% 4/58 • Number of events 5 • Adverse event data was collected from March 2008 through April of 2013.
Metabolism and nutrition disorders Hypophosphatemia	6.9% 4/58 • Number of events 4 • Adverse event data was collected from March 2008 through April of 2013.
Infections and infestations Infection	13.8% 8/58 • Number of events 8 • Adverse event data was collected from March 2008 through April of 2013.
Investigations Leukocytes (White Blood Cells Decreased)	87.9% 51/58 • Number of events 84 • Adverse event data was collected from March 2008 through April of 2013.
Investigations Lymphopenia	86.2% 50/58 • Number of events 109 • Adverse event data was collected from March 2008 through April of 2013.
Investigations Neutrophils Decreased	86.2% 50/58 • Number of events 100 • Adverse event data was collected from March 2008 through April of 2013.
Investigations Platelets Decreased	86.2% 50/58 • Number of events 184 • Adverse event data was collected from March 2008 through April of 2013.

Additional Information

Dr. Sung Choi

University of Michigan Comprehensive Cancer Center

Phone: 734-764-8630

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place