Graft Vs Host Disease
Conditions
Keywords
ibrutinib, rituximab, cGVHD, chronic GVHD
Brief summary
This is a phase II trial evaluating the safety and efficacy of the combination of Ibrutinib and Rituximab as primary treatment of chronic GVHD. We plan to enroll 35 patients on this study. Patients will be formally monitored monthly for 12 months to evaluate for outcome and safety endpoints. All other assessments will be done at the physician's discretion or institutional standards. All patients, responders and treatment failures, will be followed for a period of one year from the time of initiation of therapy. The primary endpoint will be the proportion of patients that are alive and off all systemic IST at 12 months following initiation of treatment.
Interventions
DRUGRituximab
Rituximab is given IV weekly x 4 weeks (to be started on study day 7 ± 3 days), then IV q3months x 4 doses (months 4, 7, 10, 13).
DRUGIbrutinib
Ibrutinib is given orally every day (28-day cycles) for a total of 12 cycles.
Sponsors
Pharmacyclics LLC.
Northside Hospital, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* First episode of systemic immunosuppression-requiring cGVHD, defined as classic or overlap cGVHD by the NIH consensus criteria. * Previously untreated cGVHD, defined by having received \<10 days of corticosteroids or alternative systemic immunosuppressive agent started specifically for a new diagnosis of cGVHD. * KPS 70% or greater
Exclusion criteria
* Late persistent or recurrent acute GVHD * Active uncontrolled infection * History of HIV infection; active HBV or HCV infection * Inability to tolerate oral medications * Progressive or recurrent malignancy following allogeneic transplant * Exposure to BTK inhibitor following transplant * Received prior treatment with ECP for cGVHD
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Patients Who Remain Off Immunosuppressive Therapy at 12 Months After the Initiation of Treatment. | 12 months following initiation of treatment | The primary objective is to evaluate the efficacy of the combination of rituximab and ibrutinib versus the historical experience with rituximab alone in the upfront treatment of cGVHD. Patients will be followed for 12 months following the initiation of treatment to see if they remain off immunosuppressive therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| How Long it Takes for Patients to Discontinue Treatment Defined as the Date All Systemic Immunosuppressive Therapy is Discontinued After Resolution of GVHD. | Up to 32 months | To estimate time to discontinuation of systemic immunosuppression (defined as the date that all systemic IST has been discontinued after resolution of all reversible manifestations of cGVHD). |
| How Many Patients Are Still Alive Without the Requirement for Second-line cGVHD Therapy Measured by Overall Survival at 12 Months Following the Initiation of Treatment. | 12 months following initiation of treatment | To estimate failure-free survival (defined as being alive without the requirement for second-line cGVHD therapy). |
| How Many Patients Have Not Relapsed Measured by Progression-free Survival at 12 Months Following the Initiation of Treatment. | 12 months following initiation of treatment | To estimate non-relapse mortality |
| The Number of Patients Who Respond to Treatment Assessed by NIH Response Criteria Working Group Report. | 12 months following initiation of treatment | To estimate chronic GVHD response (CR + PR, both individual organ response and overall response, according to 2014 NIH Response Criteria Working Group Report \[CR - resolution of all manifestations in each organ or site; PR - improvement in at least 1 organ or site without progression in any other organ or site\]) |
| Number of Patients With Treatment-related Adverse Events Grade 3 or Greater as Assessed by CTCAE v.4.0. | 12 months following initiation of treatment | To estimate the incidence of grade 3 or greater adverse events, possibly or probably related to either ibrutinib and/or rituximab. |
| Number of Patients With Treatment-related Adverse Events Total as Assessed by CTCAE v.4.0. | 12 months following initiation of treatment | To evaluate the safety and tolerability of combination of rituximab and ibrutinib versus the historical experience with rituximab alone in the upfront treatment of cGVHD. |
| How Many Patients Have Not Died Measured by Overall Survival at 12 Months Following the Initiation of Treatment. | 12 months following initiation of treatment | To estimate overall survival |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab + Ibrutinib Eligible patients will be those with a first episode of symptomatic cGVHD, requiring systemic immunosuppression for control of symptoms. Following study entry, patients will be started on rituximab plus ibrutinib.
Rituximab: Rituximab is given IV weekly x 4 weeks (to be started on study day 7 ± 3 days), then IV q3months x 4 doses (months 4, 7, 10, 13).
Ibrutinib: Ibrutinib is given orally every day (28-day cycles) for a total of 12 cycles. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Rituximab + Ibrutinib | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 4 Participants | — |
| Age, Categorical Between 18 and 65 years | 11 Participants | — |
| Age, Continuous | 58 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 15 participants | — |
| Sex: Female, Male Female | 8 Participants | — |
| Sex: Female, Male Male | 7 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 4 / 15 |
Outcome results
Primary
The Number of Patients Who Remain Off Immunosuppressive Therapy at 12 Months After the Initiation of Treatment.
The primary objective is to evaluate the efficacy of the combination of rituximab and ibrutinib versus the historical experience with rituximab alone in the upfront treatment of cGVHD. Patients will be followed for 12 months following the initiation of treatment to see if they remain off immunosuppressive therapy.
Time frame: 12 months following initiation of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab + Ibrutinib | The Number of Patients Who Remain Off Immunosuppressive Therapy at 12 Months After the Initiation of Treatment. | 4 Participants |
Secondary
How Long it Takes for Patients to Discontinue Treatment Defined as the Date All Systemic Immunosuppressive Therapy is Discontinued After Resolution of GVHD.
To estimate time to discontinuation of systemic immunosuppression (defined as the date that all systemic IST has been discontinued after resolution of all reversible manifestations of cGVHD).
Time frame: Up to 32 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab + Ibrutinib | How Long it Takes for Patients to Discontinue Treatment Defined as the Date All Systemic Immunosuppressive Therapy is Discontinued After Resolution of GVHD. | 15 months |
Secondary
How Many Patients Are Still Alive Without the Requirement for Second-line cGVHD Therapy Measured by Overall Survival at 12 Months Following the Initiation of Treatment.
To estimate failure-free survival (defined as being alive without the requirement for second-line cGVHD therapy).
Time frame: 12 months following initiation of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab + Ibrutinib | How Many Patients Are Still Alive Without the Requirement for Second-line cGVHD Therapy Measured by Overall Survival at 12 Months Following the Initiation of Treatment. | 7 Participants |
Secondary
How Many Patients Have Not Died Measured by Overall Survival at 12 Months Following the Initiation of Treatment.
To estimate overall survival
Time frame: 12 months following initiation of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab + Ibrutinib | How Many Patients Have Not Died Measured by Overall Survival at 12 Months Following the Initiation of Treatment. | 13 Participants |
Secondary
How Many Patients Have Not Relapsed Measured by Progression-free Survival at 12 Months Following the Initiation of Treatment.
To estimate non-relapse mortality
Time frame: 12 months following initiation of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab + Ibrutinib | How Many Patients Have Not Relapsed Measured by Progression-free Survival at 12 Months Following the Initiation of Treatment. | 11 Participants |
Secondary
Number of Patients With Treatment-related Adverse Events Grade 3 or Greater as Assessed by CTCAE v.4.0.
To estimate the incidence of grade 3 or greater adverse events, possibly or probably related to either ibrutinib and/or rituximab.
Time frame: 12 months following initiation of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab + Ibrutinib | Number of Patients With Treatment-related Adverse Events Grade 3 or Greater as Assessed by CTCAE v.4.0. | 9 Participants |
Secondary
Number of Patients With Treatment-related Adverse Events Total as Assessed by CTCAE v.4.0.
To evaluate the safety and tolerability of combination of rituximab and ibrutinib versus the historical experience with rituximab alone in the upfront treatment of cGVHD.
Time frame: 12 months following initiation of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab + Ibrutinib | Number of Patients With Treatment-related Adverse Events Total as Assessed by CTCAE v.4.0. | 13 Participants |
Secondary
The Number of Patients Who Respond to Treatment Assessed by NIH Response Criteria Working Group Report.
To estimate chronic GVHD response (CR + PR, both individual organ response and overall response, according to 2014 NIH Response Criteria Working Group Report \[CR - resolution of all manifestations in each organ or site; PR - improvement in at least 1 organ or site without progression in any other organ or site\])
Time frame: 12 months following initiation of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab + Ibrutinib | The Number of Patients Who Respond to Treatment Assessed by NIH Response Criteria Working Group Report. | 11 Participants |