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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
13
Daily ibrutinib (140mg QD) and itraconazole (100mg BID) for six months.
Hospital Universitario Dr. José Eleuterio González
Monterrey, Nuevo León, Mexico
RECRUITINGTreatment safety
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.
Time frame: Up to six months of enrollment
Overall response rate
The proportion of patients with partial and/or complete response at six months of follow-up.
Time frame: Up to six months of enrollment
Overall treatment-free survival
The proportion of patients with any other treatment rather than ibrutinib at six months of follow-up.
Time frame: Up to six months post enrollment
Steroid-free cumulative incidence
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.
Time frame: Up to six months post enrollment
Low-dose steroid cumulative incidence
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.
Time frame: Up to six months post enrollment
Immunosuppressive-free cumulative incidence
The number of patients without any immunosuppressor divided by the total number of patients at the time interval of the study.
Time frame: Up to six months post enrollment
Overall survival
Overall survival is defined as the length of time from the start of ibrutinib to the time of death.
Time frame: Up to six months post enrollment
Time to any response
Time length from the first day of ibrutinib to any response (partial response or complete response)
Time frame: From date of inclusion until the date of first documented response (partial or complete), assessed up to six months.
Time to progression
Time length from the first day of ibrutinib to progression.
Time frame: From date of inclusion until the date of first documented progression, assessed up to 6 months.
Complete response rate
The complete response rate was defined as the proportion of patients that achieve complete responses within the study's time frame.
Time frame: Up to six months post enrollment
Partial response rate
The partial response rate was defined as the proportion of patients that achieve partial responses within the study's time frame.
Time frame: Up to six months post enrollment
Progression rate
The progression rate was defined as the proportion of patients that progresses within the study's time frame.
Time frame: Up to six months post enrollment
Any adverse events rate
The any adverse event rate was defined as the proportion of patients with any grade adverse events within the study's time frame.
Time frame: Up to six months post enrollment
Proportion of therapy interruption
The proportion of patients that need ibrutinib interruption because of unacceptable toxicity (grade \>=3).
Time frame: Up to six months post enrollment
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.