Chronic Graft-versus-host-disease
Conditions
Keywords
ibrutinib, low-dose, azole, itraconazole, refractory
Brief summary
Chronic graft-versus-host disease (cGVHD) affects 30 to 70% of Allogeneic Hematopoietic Cell Transplantation, decreases the quality of life, and increases mortality. First-line treatments for cGVHD are steroids, however, up to 50% of patients do not respond to treatment. There is no well-defined second-line treatment for cGVHD, but ibrutinib, a Bruton tyrosine kinase inhibitor, has been successfully used in phase 2 clinical trials for moderate to severe steroid-refractory cGVHD and has been shown to be safe, showing rates of response of 69% at a median follow-up of 26 months. Therefore, ibrutinib was approved by the FDA for the treatment of steroid-refractory cGVHD. Also, it is known that ibrutinib is metabolized by cytochrome isoenzyme 3A4 and that itraconazole is a potent inhibitor of this hepatic isoenzyme. Therefore, the investigators hypothesized that in subjects with newly diagnosed cGVHD and in patients with steroid-refractory cGVHD, low-dose ibrutinib in combination with itraconazole might be effective and safe.
Detailed description
In this phase 2 clinical trial, patients with newly diagnosed cGVHD and refractory cGVHD will receive low-dose ibrutinib (140mg/day) combined with a cytochrome 3A4 inhibitor (itraconazole, 100mg BID) for six months. The follow-up consists of weekly visits for the first months and then monthly for six months. The investigators will address clinical and biochemical parameters in each visit and grade severity using the NIH (2014) scale. Also, patients will answer the modified Lee symptom scale, and grade response to treatment using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). The investigators will grade adverse events with the Common Terminology Criteria for Adverse Events \[v5.0\]. The investigators will report proportion and time to any response, complete response, partial response, stable disease, and progression. Also, the investigators will report the proportion of patients that interrupted steroids for at least one month, the proportion of patients that interrupted every immunosuppressive therapy for at least one month, and the proportion of patients that interrupted ibrutinib specifying the cause of the interruption.
Interventions
DRUGLow-dose ibrutinib
Daily ibrutinib (140mg QD) and itraconazole (100mg BID) for six months.
Sponsors
Hospital Universitario Dr. Jose E. Gonzalez
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients will receive oral ibrutinib (140mg QD) combined with a CYP3A4 inhibitor (oral itraconazole, 100mg BID) for six months.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age (\>18 years) * Any type of peripheral blood stem cell transplant (matched-related, match non-related, and haplo) * Any conditioning regimen * Newly diagnosed moderate to severe chronic graft versus host disease * Steroid refractory moderate to severe chronic graft versus host disease defined as progression with prednisone 1mg/kg/day, or stable disease after four to six weeks of prednisone \>0.5 mg/kg/day, or disease progression when reducing prednisone below \<0.5 mg/kg/día. 5\. Eastern Cooperative Oncology Group (ECOG) \<= 2
Exclusion criteria
* Disease relapse (excluding positive minimal residual disease) * Secondary malignancies * Disease progression * Use of B lymphocyte cytotoxics in the last month (i.e., rituximab, bortezomib) * Advance stages of heart failure (NYHA III o IV) * Ventricular arrhythmias * Uncontrolled hypertension * Ischemic heart diseases such as unstable angina or stable angina in the last six months * Hepatitis B or C * Hypersensitivity to ibrutinib * Active bleeding * Uncontrolled acute infection * Hepatopathy Child-Pugh C * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment safety | Up to six months of enrollment | Treatment safety will be addressed by obtaining the proportion of patients with grade \>=3 adverse events as defined by the Common Terminology Criteria for Adverse Events \[v5.0\]. If the proportion of \>=3 adverse events is less than 20% then the treatment will be defined as safe. |
| Overall response rate | Up to six months of enrollment | The proportion of patients with partial and/or complete response at six months of follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Low-dose steroid cumulative incidence | Up to six months post enrollment | The number of patients using less than 0.15 mg/kg/day of prednisone 0 for at least one month divided by the total number of patients at the time interval of the study. |
| Immunosuppressive-free cumulative incidence | Up to six months post enrollment | The number of patients without any immunosuppressor divided by the total number of patients at the time interval of the study. |
| Overall survival | Up to six months post enrollment | Overall survival is defined as the length of time from the start of ibrutinib to the time of death. |
| Time to any response | From date of inclusion until the date of first documented response (partial or complete), assessed up to six months. | Time length from the first day of ibrutinib to any response (partial response or complete response) |
| Time to progression | From date of inclusion until the date of first documented progression, assessed up to 6 months. | Time length from the first day of ibrutinib to progression. |
| Overall treatment-free survival | Up to six months post enrollment | The proportion of patients with any other treatment rather than ibrutinib at six months of follow-up. |
| Partial response rate | Up to six months post enrollment | The partial response rate was defined as the proportion of patients that achieve partial responses within the study's time frame. |
| Progression rate | Up to six months post enrollment | The progression rate was defined as the proportion of patients that progresses within the study's time frame. |
| Any adverse events rate | Up to six months post enrollment | The any adverse event rate was defined as the proportion of patients with any grade adverse events within the study's time frame. |
| Proportion of therapy interruption | Up to six months post enrollment | The proportion of patients that need ibrutinib interruption because of unacceptable toxicity (grade \>=3). |
| Complete response rate | Up to six months post enrollment | The complete response rate was defined as the proportion of patients that achieve complete responses within the study's time frame. |
| Steroid-free cumulative incidence | Up to six months post enrollment | The number of patients using 0mg of prednisone for at least one month divided by the total number of patients at the time interval of the study. |
Countries
Mexico
Contacts
Primary ContactFernando De la Garza Salazar, MD
Outcome results
None listed