Clinical trial NCT05348096: Efficacy and Safety of Low-dose Ibrutinib and Itraconazole in Chronic Graft Versus Host Disease
Official title: Efficacy and Safety of the Combination of Low-dose Ibrutinib and Itraconazole in Moderate to Severe Chronic Graft Versus Host Disease: a Phase 2 Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Chronic Graft-versus-host-disease
Keywords: ibrutinib
low-dose
azole
itraconazole
refractory
Lead sponsor: Hospital Universitario Dr. Jose E. Gonzalez
Sponsor class: OTHER
First posted: 2022-04-27
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Patients will receive oral ibrutinib (140mg QD) combined with a CYP3A4 inhibitor (oral itraconazole, 100mg BID) for six months.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Treatment safety
timeFrame: Up to six months of enrollment
measure: Overall response rate
timeFrame: Up to six months of enrollment
Secondary outcomes:
measure: Overall treatment-free survival
timeFrame: Up to six months post enrollment
measure: Steroid-free cumulative incidence
timeFrame: Up to six months post enrollment
measure: Low-dose steroid cumulative incidence
timeFrame: Up to six months post enrollment
measure: Immunosuppressive-free cumulative incidence
timeFrame: Up to six months post enrollment
measure: Overall survival
timeFrame: Up to six months post enrollment
measure: Time to any response
timeFrame: From date of inclusion until the date of first documented response (partial or complete), assessed up to six months.
measure: Time to progression
timeFrame: From date of inclusion until the date of first documented progression, assessed up to 6 months.
measure: Complete response rate
timeFrame: Up to six months post enrollment
measure: Partial response rate
timeFrame: Up to six months post enrollment
measure: Progression rate
timeFrame: Up to six months post enrollment
measure: Any adverse events rate
timeFrame: Up to six months post enrollment
measure: Proportion of therapy interruption
timeFrame: Up to six months post enrollment
Other outcomes:
Locations:
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr. José Eleuterio González
state: Nuevo Leon
Study officials:
affiliation: Hospital Universitario Dr. José Eleuterio González
name: Fernando De la Garza Salazar
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wolff D, Fatobene G, Rocha V, Kroger N, Flowers ME. Steroid-refractory chronic graft-versus-host disease: treatment options and patient management. Bone Marrow Transplant. 2021 Sep;56(9):2079-2087. doi: 10.1038/s41409-021-01389-5. Epub 2021 Jul 3.
citation: Waller EK, Miklos D, Cutler C, Arora M, Jagasia MH, Pusic I, Flowers MED, Logan AC, Nakamura R, Chang S, Clow F, Lal ID, Styles L, Jaglowski S. Ibrutinib for Chronic Graft-versus-Host Disease After Failure of Prior Therapy: 1-Year Update of a Phase 1b/2 Study. Biol Blood Marrow Transplant. 2019 Oct;25(10):2002-2007. doi: 10.1016/j.bbmt.2019.06.023. Epub 2019 Jun 28.
citation: Tapaninen T, Olkkola AM, Tornio A, Neuvonen M, Elonen E, Neuvonen PJ, Niemi M, Backman JT. Itraconazole Increases Ibrutinib Exposure 10-Fold and Reduces Interindividual Variation-A Potentially Beneficial Drug-Drug Interaction. Clin Transl Sci. 2020 Mar;13(2):345-351. doi: 10.1111/cts.12716. Epub 2019 Nov 29.