Graft vs Host Disease, Hematologic Neoplasms, Non-Neoplastic Hematologic and Lymphocytic Disorder
Conditions
Brief summary
This protocol, UMCC 2012.047, was a pilot study initially intended for 12 subjects. After completing enrollment of the planned 12 subjects, we are extending the study to an additional 25 subjects. The trial will examine the safety and efficacy of the addition of vorinostat, the study drug, to standard medications to try to prevent or lower the risk of graft versus-host disease (GVHD) for recipients of unrelated (matched) donor, blood or marrow stem cell transplants. The transplant regimens, chosen according to current institutional policy, will depend upon the recipients underlying disease (their blood cancer or other blood disorder), previous therapy, and current health issues. GVHD prophylaxis (preventive drug intervention) will be the local institutional standard for post-transplant immunosuppression, including tacrolimus and methotrexate, plus vorinostat. Vorinostat will be given twice daily orally beginning 10 days prior to the recipient's transplant and continue for up to 100 days after transplant.
Detailed description
This trial is investigating the use of vorinostat (Merck) for standard graft versus-host disease (GVHD) prophylaxis after unrelated donor allogeneic hematopoietic cell transplantation (HCT). A major limitation of the increased utilization of allogeneic HCT (Hematopoietic Cell Transplantation) is the inferior outcomes when donors other than HLA (HumanLeukocyte Antigen)-matched siblings are used. Compared to matched related donors, recipients of matched unrelated donor transplants are at a significantly increased risk of death and transplant-related mortality (TRM). Acute GVHD remains a significant contributor to TRM, which develops in approximately 50-70% of recipients receiving these type of grafts despite standard immunosuppressive prophylaxis. Thus, novel GVHD prophylaxis strategies which successfully attenuate acute GVHD-related complications without increasing other causes of TRM or relapse are needed. The historical experience of day 100 grade 2-4 acute GVHD in 154 comparable patients treated at the University of Michigan (2005 - 2011) receiving standard GVHD prophylaxis after unrelated donor allogeneic transplant is 48%. At Washington University, the cumulative incidence of acute grade 2-4 GVHD in patients following unrelated donor transplant is 62%. Research data collectively suggests, that reducing lethal acute GVHD should improve long-term survival for patients undergoing unrelated donor transplant.
Interventions
DRUGVorinostat
administered at a dose of 100 mg orally, twice daily starting on day -10 in order to achieve steady-state prior to beginning the conditioning chemotherapy, and continued after transplant (day 0) until day +100.
DRUGTacrolimus
DRUGMethotrexate
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A prospective patient for allogeneic HSCT for hematologic conditions, both malignant and non-malignant. Donor can be unrelated marrow or peripheral blood cells. A patient with history of CNS involvement is eligible if CNS disease is in remission at time of study consideration. * Age between 18-75 years * The donor and recipient must have an HLA-8/8 allelic match at the HLA-A, -B, -C, and -DRB1. * Diagnosis of following diseases (subject to additional complex screening criteria) * Acute Myelogenous Leukemia: * First remission (cytogenetic intermediate or high risk) * Second or subsequent remission * Chronic Myelogenous Leukemia: * First, subsequent chronic phases, or atypical * Accelerated Phase * Myelodysplastic syndromes * Chronic Lymphocytic Leukemia * Primary Myelofibrosis * Mature B Cell Malignancies (including Mantle Cell Lymphoma, Follicular Lymphoma. Diffuse Large B Cell Lymphoma, Non-Hodgkin Lymphoma not otherwise specified) * Karnofsky (Attempt to classify a cancer patients' activities of daily life that runs from 0 to 100 where 100 represents perfect health and 0 represents death) \>70% * Life expectancy of greater than 6 months. * Organ and marrow function as defined by the institutional BMT (Bone Marrow Transplant) program clinical practice guidelines * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. * Able to swallow capsules/tablets
Exclusion criteria
* Not a candidate for an unrelated donor allogeneic transplant conditioning regimen based on the current institutional BMT program clinical practice guidelines. Organ function criteria will be utilized per the current institutional BMT program clinical practice guidelines. There will be no restriction to study entry based on hematological parameters. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat * Undergoing a total body irradiation (TBI)-based conditioning regimen (TBI 1200 cGy) * Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients still under therapy for presumed or proven infection are eligible provided there is clear evidence (radiographic findings and/or culture results) that the infection is well-controlled. Patients under treatment for infection will be enrolled only after clearance from the PI * Any medical or psychological comorbidities/conditions that would keep the patient from complying with the needs of the protocol and/or would markedly increase the risk of morbidity and mortality. * Pregnant women or nursing mothers. * Evidence of HIV seropositivity and/or positive PCR assay, HTLV1 / HTLV2 seropositivity. * Evidence of Hepatitis B or Hepatitis C PCR positivity. * Less than 18 years of age. * A history of prolonged QTc syndrome. * Taking or have had prior treatment with a drug like vorinostat within the last 30 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients That Experience Grade 2-4 GVHD Within 100 Days of Transplant | 100 Days | GVHD Staging: Grade 2: (Skin) Maculopapular rash 25-50% BSA, (Liver) bilirubin 3.1-6mg/dl, (Gut) 1000-1500 ml/day for adult and 20-30ml/kg/day for child. Grade 3: (Skin) Maculopapular rash \>50% BSA, (Liver) 6.1-15mg/dl, (Gut) \>1500mg/day for adult and \>30ml/kg/day for child. Grade 4: (Skin) Generalized erythroderma plus bullous formation and desquamation \>5% BSA, (Liver) \>15mg/dl, (Gut) Severe abdominal pain with or without ileus, or grossly bloody stool. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Alive at 1 Year | 1 Year | Overall survival at 1 Year. |
| Non-Relapse Mortality Incidence | 1 year | — |
Countries
United States
Participant flow
Pre-assignment details
12 patients were enrolled in the initial NCI funded portion of the Vorinostat trial (NCT1789255). 26 were enrolled to the expansion of that trial (NCT01790568). 1 pt removed prior to transplant so 25 were evaluable. All patients were treated identically. Although 26 patients were enrolled to this portion of the trial, ALL 37 are analyzed together.
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat Vorinostat, in combination with standard of care medications tacrolimus and methotrexate, for GVHD prophylaxis after unrelated donor stem cell transplant.
Vorinostat: administered at a dose of 100 mg orally, twice daily starting on day -10 in order to achieve steady-state prior to beginning the conditioning chemotherapy, and continued after transplant (day 0) until day +100. | 37 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Progression prior to transplant | 0 | 1 |
Baseline characteristics
| Characteristic | Vorinostat |
|---|---|
| Age, Continuous | 56 years |
| Race/Ethnicity, Customized Race/Ethnicity Asian | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Not reported | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White, Hispanic | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White, non-hispanic | 33 Participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 37 |
| other Total, other adverse events | 26 / 37 |
| serious Total, serious adverse events | 24 / 37 |
Outcome results
Primary
Percentage of Patients That Experience Grade 2-4 GVHD Within 100 Days of Transplant
GVHD Staging: Grade 2: (Skin) Maculopapular rash 25-50% BSA, (Liver) bilirubin 3.1-6mg/dl, (Gut) 1000-1500 ml/day for adult and 20-30ml/kg/day for child. Grade 3: (Skin) Maculopapular rash \>50% BSA, (Liver) 6.1-15mg/dl, (Gut) \>1500mg/day for adult and \>30ml/kg/day for child. Grade 4: (Skin) Generalized erythroderma plus bullous formation and desquamation \>5% BSA, (Liver) \>15mg/dl, (Gut) Severe abdominal pain with or without ileus, or grossly bloody stool.
Time frame: 100 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat | Percentage of Patients That Experience Grade 2-4 GVHD Within 100 Days of Transplant | 22 percentage of patients |
Secondary
Non-Relapse Mortality Incidence
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat | Non-Relapse Mortality Incidence | 16 percentage of patients |
Secondary
Percentage of Patients Alive at 1 Year
Overall survival at 1 Year.
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat | Percentage of Patients Alive at 1 Year | 76 percentage of patients |