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

Sponsor:	University of Michigan Cancer Center
Information provided by:	University of Michigan Cancer Center
ClinicalTrials.gov Identifier:	NCT00810602

Purpose

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	Intervention	Phase
Hematologic Malignancies Graft vs Host Disease	Procedure: reduced intensity, matched related donor stem cell transplant Drug: tacrolimus (standard GVHD prophylaxis) Drug: mycophenolate (standard GVHD prophylaxis) Drug: vorinostat	Phase II

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Single Group Assignment, Safety/Efficacy 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

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Tacrolimus anhydrous Tacrolimus Mycophenolate mofetil hydrochloride Mycophenolate Mofetil Suberoylanilide hydroxamic acid

U.S. FDA Resources

Further study details as provided by University of Michigan Cancer Center:

Primary Outcome Measures:

To assess if the addition of vorinostat to a standard GVHD prophylaxis regimen, can reduce the rate of grades 2-4 acute GVHD from 42% to 25%, as compared to historical control patients. [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To establish safety & feasibility of vorinostat administration in the above clinical setting [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
To determine the rates of steroid-free survival and relapse at 1 year [ Time Frame: one year ] [ Designated as safety issue: Yes ]
To determine overall survival rates [ Time Frame: one year ] [ Designated as safety issue: Yes ]
To correlate plasma concentrations of inflammatory markers of acute GVHD (including cytokines) with GVHD [ Time Frame: 180 days ] [ Designated as safety issue: No ]
To assay protein acetylation in PBMC before and after administration of vorinostat [ Time Frame: 180 days ] [ Designated as safety issue: No ]
To assay levels of vorinostat and its metabolites before, during and after administration of the preparative regimen [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	50
Study Start Date:	January 2009
Estimated Study Completion Date:	June 2011
Estimated Primary Completion Date:	June 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Vorinostat,combined with standard GVHD prevention medications	Procedure: reduced intensity, matched 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 vorintostat 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.

Arms

Assigned Interventions

1: Experimental

Vorinostat,combined with standard GVHD prevention medications

Procedure: reduced intensity, matched 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 vorintostat 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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00810602

Contacts

Contact: Cancer Answer Line

1 (800) 865 -1125

canceranswerline@umich.edu

Locations

United States, Michigan
University of Michigan Cancer Center	Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Pavan Reddy, MD 734-615-6406 reddypr@med.umich.edu
Contact: John E Levine, MD 734-936 jelevine@med.umich.edu

Sponsors and Collaborators

University of Michigan Cancer Center

Investigators

Principal Investigator:

Pavan Reddy, MD

University of Michigan Cancer Center

More Information

No publications provided

Responsible Party:	University of Michigan Comprehensive Cancer Center ( Pavan Reddy, MD / Associate Professor, Department of Internal Medicine )
Study ID Numbers:	umcc 2008.095
Study First Received:	December 17, 2008
Last Updated:	January 11, 2010
ClinicalTrials.gov Identifier:	NCT00810602 History of Changes
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Anticarcinogenic Agents
Immunologic Factors
Hematologic Neoplasms
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Tacrolimus
Neoplasms by Site
Sensory System Agents
Therapeutic Uses
Mycophenolate mofetil
Anti-Inflammatory Agents, Non-Steroidal
Analgesics

Immune System Diseases
Hematologic Diseases
Vorinostat
Enzyme Inhibitors
Protective Agents
Immunosuppressive Agents
Pharmacologic Actions
Neoplasms
Analgesics, Non-Narcotic
Graft vs Host Disease
Peripheral Nervous System Agents
Antirheumatic Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on February 08, 2010