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Graft vs Host Disease

Hematologic Diseases

Homologous Wasting Disease

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Anti-Infective Agents

Fludarabine

Fludarabine phosphate

Tin Fluorides

Mycophenolic Acid

Tacrolimus

Busulfan

Vorinostat

Immunosuppressive Agents

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Calcineurin Inhibitors

Enzyme Inhibitors

Histone Deacetylase Inhibitors

Vorinostat,combined with standard GVHD prevention medications(tacrolimus, mycophenolate) for adults who received a 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.

reduced intensity, related donor stem cell transplant

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

tacrolimus (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.

mycophenolate (standard GVHD prophylaxis)

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.

vorinostat

Pavan Reddy, MD

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.

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

Phase II Trial of Vorinostat Plus Tacrolimus & Mycophenolate to Prevent Graft Versus Host Disease Following Reduced Intensity Conditioning Related Donor Allogeneic Transplant

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.

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.

Determine the cumulative incidence of relapse at 2 years.

To determine 2-year overall survival rate

Professor

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.

Vorinostat Prophylaxis

Age, Continuous

(44%, 56% of evaluable subjects, respectively)

Sex: Female, Male

Ethnicity (NIH/OMB)

Acute myelogenous leukemia

Myelodysplastic syndrome

Non-Hodgkin's lymphoma

Chronic lymphocytic leukemia

Myeloproliferative disorder or myelofibrosis

Acute biphenotypic leukemia

Diagnosis

Intermediate

High

Disease Status

Hematopoietic Cell Transplant - Comorbidity Index: Low = 0, Intermediate = 1 or 2, High ≥ 3

Comorbidity index

Matched related

One-antigen mismatched related

Donor Type

Recipient or Donor positive (detailed below)

R+, D+

R-, D+

R+, D-

Recipient and Donor negative

Recipient(R),Donor (D), positive (+), negative(-)

CMV Status

CD34+ Count (10^6 cells/kg)

Neutrophil

Platelet

Median time to platelet and neutrophil engraftment.

Engraftment Day

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.

Dr. Sung Choi

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.

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)

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

Number of Serious Adverse Events

Percent Cumulative Incidence of Relapse at 2 Years.

Percent Survival at 2-years

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 1

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.

Spots Global Cancer Trial Database for reduced intensity, related donor stem cell transplant