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

• Sponsor: Pavan Reddy, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00810602
• Collaborator: (none)
• Enrollment: 61
• Locations: 2
• Arm: 1
• Duration (Months): 53.9
• Patients Per Site: 30.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief 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).

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.

Condition or Disease	Intervention/Treatment	Phase
Hematologic Malignancies; Graft vs Host Disease	Procedure: reduced intensity, related donor stem cell transplant; Drug: tacrolimus (standard GVHD prophylaxis); Drug: mycophenolate (standard GVHD prophylaxis); Drug: vorinostat	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Vorinostat Plus Tacrolimus & Mycophenolate to Prevent Graft Versus Host Disease Following Reduced Intensity Conditioning Related Donor Allogeneic Transplant
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

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

Procedure: reduced intensity, related donor stem cell transplant; 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.; Drug: 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: 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; 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.; Other Names: ZOLINZA

Outcome Measures

Primary Outcome Measures

1. 100-day Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD) [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.

Secondary Outcome Measures

1. Number of Serious Adverse Events [100 days]

   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.

2. Percent Cumulative Incidence of Relapse at 2 Years. [two years]

   Determine the cumulative incidence of relapse at 2 years.

3. Percent Survival at 2-years [two years]

   To determine 2-year overall survival rate

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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).

Exclusion Criteria:

• 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

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Cancer Center	Ann Arbor	Michigan	United States	48109
2	Washington University School of Medicine	St. Louis	Missouri	United States	63110

Sponsors and Collaborators

• Pavan Reddy, MD

Investigators

• Principal Investigator: Pavan Reddy, MD, University of Michigan Rogel Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pavan Reddy, MD, Professor, University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT00810602
• Other Study ID Numbers: UMCC 2008.095
• First Posted: Dec 18, 2008
• Last Update Posted: Apr 11, 2014
• Last Verified: Mar 1, 2014

• Additional relevant MeSH terms: Hematologic Neoplasms; Graft vs Host Disease; Vorinostat; Tacrolimus

Study Results

Participant Flow

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 Detail	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
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

Baseline Characteristics

Arm/Group Title	Vorinostat Prophylaxis
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 Participants	50
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59
Sex: Female, Male (Count of Participants)
Female	22 44%
Male	28 56%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 4%
Not Hispanic or Latino	46 92%
Unknown or Not Reported	2 4%
Diagnosis (participants) [Number]
Acute myelogenous leukemia	19 38%
Myelodysplastic syndrome	10 20%
Non-Hodgkin's lymphoma	12 24%
Chronic lymphocytic leukemia	4 8%
Myeloproliferative disorder or myelofibrosis	4 8%
Acute biphenotypic leukemia	1 2%
Disease Status (participants) [Number]
Low	25 50%
Intermediate	20 40%
High	5 10%
Comorbidity index (participants) [Number]
Low	8 16%
Intermediate	15 30%
High	27 54%
Donor Type (participants) [Number]
Matched related	46 92%
One-antigen mismatched related	4 8%
CMV Status (participants) [Number]
Recipient or Donor positive (detailed below)	30 60%
R+, D+	17 34%
R-, D+	6 12%
R+, D-	7 14%
Recipient and Donor negative	20 40%
CD34+ Count (10^6 cells/kg) (Count (10^6 cells/kg)) [Median (Full Range) ]
Median (Full Range) [Count (10^6 cells/kg)]	5.0
Engraftment Day (days) [Median (Full Range) ]
Neutrophil	12
Platelet	12

Outcome Measures

1. Primary Outcome

Title	100-day Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD)
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

Outcome Measure Data

Analysis Population Description

evaluable

Arm/Group Title	Vorinostat Prophylaxis
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.
Measure Participants	50
Number [percentage of participants]	22 44%

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
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent Cumulative Incidence of GVHD
	Estimated Value	22
	Confidence Interval	(2-Sided) 95%; 13 to 36
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Serious Adverse Events
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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Vorinostat Prophylaxis
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.
Measure Participants	58
Number [Number of Serious Adverse Events]	33

3. Secondary Outcome

Title	Percent Cumulative Incidence of Relapse at 2 Years.
Description	Determine the cumulative incidence of relapse at 2 years.
Time Frame	two years

Outcome Measure Data

Analysis Population Description

evaluable subjects

Arm/Group Title	Vorinostat Prophylaxis
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.
Measure Participants	50
Number [percentage of participants]	16 32%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vorinostat Prophylaxis
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent Cumulative Incidence of GVHD
	Estimated Value	16
	Confidence Interval	(2-Sided) 95%; 8 to 30
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percent Survival at 2-years
Description	To determine 2-year overall survival rate
Time Frame	two years

Outcome Measure Data

Analysis Population Description

evaluable subjects

Arm/Group Title	Vorinostat Prophylaxis
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.
Measure Participants	50
Number [percentage of subjects]	73

Adverse Events

Time Frame	Adverse event data was collected from March 2008 through April of 2013.
Arm/Group Title	Vorinostat Prophylaxis
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 (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Vorinostat Prophylaxis
	Affected / at Risk (%)	# Events
Total	31/58 (53.4%)
Gastrointestinal disorders
Anorexia	1/58 (1.7%)
Diarrhea	1/58 (1.7%)
Hemmorrhoids	1/58 (1.7%)
General disorders
Edema: Limb	1/58 (1.7%)
Immune system disorders
Graft Versus Host Disease	5/58 (8.6%)
Infections and infestations
Infection	12/58 (20.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Relapse	6/58 (10.3%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Hypertension	1/58 (1.7%)
Skin and subcutaneous tissue disorders
Rash	1/58 (1.7%)
Vascular disorders
Thrombosis/Thrombus/Embolism	2/58 (3.4%)
Other (Not Including Serious) Adverse Events
	Vorinostat Prophylaxis
	Affected / at Risk (%)	# Events
Total	51/58 (87.9%)
Blood and lymphatic system disorders
Hemoglobin	29/58 (50%)	45
Infections and infestations
Infection	8/58 (13.8%)	8
Investigations
Alanine Aminotransferase Increased	3/58 (5.2%)	3
Leukocytes (White Blood Cells Decreased)	51/58 (87.9%)	84
Lymphopenia	50/58 (86.2%)	109
Neutrophils Decreased	50/58 (86.2%)	100
Platelets Decreased	50/58 (86.2%)	184
Metabolism and nutrition disorders
Hyperglycemia	12/58 (20.7%)	12
Hypocalcemia	3/58 (5.2%)	4
Hyponatremia	4/58 (6.9%)	5
Hypophosphatemia	4/58 (6.9%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.