Graft-versus-host-disease, GVHD, Low Risk Acute Graft-versus-host Disease
Conditions
Keywords
Graft-versus-host disease, Itacitinib
Brief summary
Graft-versus-host disease (GVHD) is treated with high doses of systemic steroids which can lead to serious complications. A new blood test can identify patients whose GVHD is most likely to respond to well to treatment (low risk GVHD). This study will test whether patients with low risk GVHD can be successfully treated without steroids. Patients who participate with this study will be treated with itacitinib instead of steroids. Itacitinib is an experimental drug with an excellent safety record and appears to have activity as a GVHD treatment.
Detailed description
Patients with newly diagnosed low risk acute GVHD defined as Minnesota standard risk based on symptoms and Ann Arbor 1 GVHD based on biomarkers were eligible if they met all other eligible criteria (see eligibility criteria below). Enrolled patients were required to start treatment within 4 days of confirmation of Ann Arbor 1 status. Treatment consisted of itacitinib 200 mg daily for 28 days. Patients with a clinical response on day 28 were eligible for a second 28 day cycle of itacitinib 200 mg daily. Missed doses could be made up by extending the treatment duration for up to 2 additional weeks. Medications given for GVHD prophylaxis and topical treatments for GVHD were allowed. Supportive care was provided according to institutional standards. Itacitinib was permanently discontinued after any of the following: administration of 56 doses of itacitinib or initiation of systemic corticosteroids or any other systemic treatment for GVHD or patient withdrawal from the study or general or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator OR ten weeks elapsed since the first dose of itacitinib.
Interventions
DRUGItacitinib
for up to 56 days
Sponsors
John Levine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open label, single arm, non-inferiority study
Eligibility
Sex/Gender
ALL
Age
12 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Newly diagnosed GVHD that meets criteria for Minnesota standard risk * Ann Arbor 1 GVHD by biomarkers * GVHD not previously treated systemically (topical therapies and non-absorbed steroids are allowed) * Any donor type, HLA-match, conditioning regimen is acceptable * Age 12 - 75 years (children \<18 years must also weigh 50 kg or more) * Patients must be engrafted post-transplant (ANC \>500/μL and platelet count \>20,000). Use of growth factor supplementation to maintain neutrophil count is allowed. * Direct bilirubin must be \<2 mg/dL unless the elevation is known to be due to Gilbert syndrome within 3 days prior to enrollment. * ALT/SGPT and AST/SGOT must be \<5x the upper limit of the normal range within 3 days prior to enrollment. * Signed and dated written informed consent obtained from patient or legal representative.
Exclusion criteria
* Patients currently being treated with any JAK inhibitor including ruxolitinib * Relapsed, progressing, or persistent malignancy requiring withdrawal of systemic immune suppression * Patients with uncontrolled infection (i.e., progressive symptoms related to infection despite treatment or persistently positive microbiological cultures despite treatment or any other evidence of severe sepsis) * Severe organ dysfunction including requirement for dialysis, mechanical ventilation or oxygen supplementation exceeding 40% FiO2 within 7 days of enrollment. * Creatinine clearance or estimated glomerular filtration rate \<30 ml/min as calculated by institutional practice (e.g., Cockcroft-Gault equation, CKD-EPI equation, etc) * A clinical presentation resembling de novo chronic GVHD or overlap syndrome developing before or present at the time of enrollment * Patients receiving corticosteroids \>10 mg/day prednisone (or other steroid equivalent) for any indication within 7 days before the onset of acute GVHD except for adrenal insufficiency or premedication for transfusions/IV meds * Patients who are pregnant * Patients receiving investigational agents within 30 days of enrollment. However, the Principal Investigator (PI) may approve prior use of an investigational agent if the agent is not expected to interfere with the safety or the efficacy of itacitinib * History of allergic reaction to itacitinib or any JAK inhibitor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Achieve CR or PR by Day 28 of Treatment | Day 28 | Number of patients who achieve CR or PR by day 28 of treatment with itacitinib without the addition of any other systemic GVHD treatment including steroids. Complete Response (CR): All evaluable organs (skin, liver, GI tract) stage 0. For a response to be scored as CR on day 28, the patient must be in CR on that day and have had no intervening additional GVHD therapy. Partial Response (PR): An improvement in one or more organ involved with GVHD symptoms without worsening in others. For a response to be scored as PR on day 28, the patient must be in PR on that day and have had no intervening additional GVHD therapy. |
| Number of Participants Who Developed Steroid Refractory GVHD | Day 28 | Number of participants who developed steroid refractory GVHD within 28 days of starting steroids. Steroid-refractory GVHD (defined as GVHD that worsens (increase by one or more grade) after 3 days, or fails to respond to treatment within 7 days (for GVHD grade III) or 14 days (for GVHD grade II) or 2nd line therapy beyond systemic steroid treatment is begun within 28 days of starting steroids. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Non-relapse Mortality (NRM) | 6 months and 1 year | Number of participants with non-relapse mortality (NRM) at 6 months and 1 year |
| Number of Participants Who Relapsed | 6 months and 1 year | Number of participants who relapsed by 6 months and by 1 year |
| Number of Participants With Serious Infectious | Day 90 | Number of participants who developed serious infections by day 90. Serious infectious complications is defined as any viral and bacterial infections requiring treatment and proven fungal infections. |
| Cumulative Steroid Dose | Day 28 | Cumulative steroid dose (over 4 weeks) in patients who receive steroids as second line therapy |
| Number of Participants Who Developed Chronic GVHD | 1 year | Number of participants who developed chronic GVHD requiring systemic treatment at 1 year |
| Number of Participants Alive at 6 Months and 1 Year | 6 months and 1 year | Number of overall survival (OS), defined as the duration from the date of diagnosis to death or last follow-up, with no restriction on the cause of death. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Risk GVHD Patients Treated Itacitinib 200 mg administered orally daily for 28 days, with a second 28 day cycle allowed for responding patients. | 70 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 8 |
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Low Risk GVHD Patients Treated |
|---|---|
| Age, Continuous | 60 years |
| Anti-Thymocyte Globulin (ATG) No | 61 Participants |
| Anti-Thymocyte Globulin (ATG) Yes | 9 Participants |
| Conditioning Regimen Myeloablative | 33 Participants |
| Conditioning Regimen Reduced/Non-Myeloablative | 37 Participants |
| Diagnosis Acute Leukemia | 32 Participants |
| Diagnosis Lymphoma | 6 Participants |
| Diagnosis MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm (MDS/MPN) | 29 Participants |
| Diagnosis Non-Malignant | 3 Participants |
| Donor Matched related | 13 Participants |
| Donor Matched unrelated | 37 Participants |
| Donor Mismatched related | 15 Participants |
| Donor Mismatched unrelated | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| GVHD Prophylaxis CNI/MMF (+/- Other) | 7 Participants |
| GVHD Prophylaxis CNI/MTX (+/- Other) | 24 Participants |
| GVHD Prophylaxis CNI/sirolimus | 2 Participants |
| GVHD Prophylaxis Cyclophosphamide based | 35 Participants |
| GVHD Prophylaxis Other | 0 Participants |
| GVHD Prophylaxis T Cell Depletion | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 57 Participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 70 |
| other Total, other adverse events | 34 / 70 |
| serious Total, serious adverse events | 23 / 70 |
Outcome results
Primary
Number of Participants Who Developed Steroid Refractory GVHD
Number of participants who developed steroid refractory GVHD within 28 days of starting steroids. Steroid-refractory GVHD (defined as GVHD that worsens (increase by one or more grade) after 3 days, or fails to respond to treatment within 7 days (for GVHD grade III) or 14 days (for GVHD grade II) or 2nd line therapy beyond systemic steroid treatment is begun within 28 days of starting steroids.
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Risk GVHD Patients Treated | Number of Participants Who Developed Steroid Refractory GVHD | 1 Participants |
Primary
Number of Patients Who Achieve CR or PR by Day 28 of Treatment
Number of patients who achieve CR or PR by day 28 of treatment with itacitinib without the addition of any other systemic GVHD treatment including steroids. Complete Response (CR): All evaluable organs (skin, liver, GI tract) stage 0. For a response to be scored as CR on day 28, the patient must be in CR on that day and have had no intervening additional GVHD therapy. Partial Response (PR): An improvement in one or more organ involved with GVHD symptoms without worsening in others. For a response to be scored as PR on day 28, the patient must be in PR on that day and have had no intervening additional GVHD therapy.
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Risk GVHD Patients Treated | Number of Patients Who Achieve CR or PR by Day 28 of Treatment | 62 Participants |
Secondary
Cumulative Steroid Dose
Cumulative steroid dose (over 4 weeks) in patients who receive steroids as second line therapy
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Risk GVHD Patients Treated | Cumulative Steroid Dose | 1.9 mg/kg | Standard Error 0.6 |
Secondary
Number of Participants Alive at 6 Months and 1 Year
Number of overall survival (OS), defined as the duration from the date of diagnosis to death or last follow-up, with no restriction on the cause of death.
Time frame: 6 months and 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Risk GVHD Patients Treated | Number of Participants Alive at 6 Months and 1 Year | 6 months | 66 Participants |
| Low Risk GVHD Patients Treated | Number of Participants Alive at 6 Months and 1 Year | 1 year | 62 Participants |
Secondary
Number of Participants Who Developed Chronic GVHD
Number of participants who developed chronic GVHD requiring systemic treatment at 1 year
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Risk GVHD Patients Treated | Number of Participants Who Developed Chronic GVHD | 18 Participants |
Secondary
Number of Participants Who Relapsed
Number of participants who relapsed by 6 months and by 1 year
Time frame: 6 months and 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Risk GVHD Patients Treated | Number of Participants Who Relapsed | 6 months | 8 Participants |
| Low Risk GVHD Patients Treated | Number of Participants Who Relapsed | 1 year | 12 Participants |
Secondary
Number of Participants With Non-relapse Mortality (NRM)
Number of participants with non-relapse mortality (NRM) at 6 months and 1 year
Time frame: 6 months and 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Risk GVHD Patients Treated | Number of Participants With Non-relapse Mortality (NRM) | 6 months | 2 Participants |
| Low Risk GVHD Patients Treated | Number of Participants With Non-relapse Mortality (NRM) | 1 year | 3 Participants |
Secondary
Number of Participants With Serious Infectious
Number of participants who developed serious infections by day 90. Serious infectious complications is defined as any viral and bacterial infections requiring treatment and proven fungal infections.
Time frame: Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Risk GVHD Patients Treated | Number of Participants With Serious Infectious | 19 Participants |