Efficacy and Safety of Low-dose Ibrutinib and Itraconazole in Chronic Graft Versus Host Disease

Chronic Graft-versus-host-disease Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05348096
• Other study ID #: PI22-00027
• Status: Recruiting
• Phase: Phase 2
• Start date: April 1, 2022
• Est. completion date: August 1, 2023

Study information

• Verified date: April 2022
• Source: Hospital Universitario Dr. Jose E. Gonzalez
• Contact: Fernando De la Garza Salazar, MD
• Phone: 52-81-8675-6718
• Email: fernandodelagarza[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 13
• Est. completion date: August 1, 2023
• Est. primary completion date: April 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Graft-versus-host-disease
• Graft vs Host Disease

Intervention

Drug:
• Low-dose ibrutinib
Daily ibrutinib (140mg QD) and itraconazole (100mg BID) for six months.

Locations

Country	Name	City	State
Mexico	Hospital Universitario Dr. José Eleuterio González	Monterrey	Nuevo Leon

Sponsors (1)

Lead Sponsor	Collaborator
Hospital Universitario Dr. Jose E. Gonzalez

Country where clinical trial is conducted

Mexico, 

References & Publications (3)

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 — View 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 S — View Citation

Wolff D, Fatobene G, Rocha V, Kröger 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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treatment 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.	Up to six months of enrollment
Primary	Overall response rate	The proportion of patients with partial and/or complete response at six months of follow-up.	Up to six months of enrollment
Secondary	Overall treatment-free survival	The proportion of patients with any other treatment rather than ibrutinib at six months of follow-up.	Up to six months post enrollment
Secondary	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.	Up to six months post enrollment
Secondary	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.	Up to six months post enrollment
Secondary	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.	Up to six months post enrollment
Secondary	Overall survival	Overall survival is defined as the length of time from the start of ibrutinib to the time of death.	Up to six months post enrollment
Secondary	Time to any response	Time length from the first day of ibrutinib to any response (partial response or complete response)	From date of inclusion until the date of first documented response (partial or complete), assessed up to six months.
Secondary	Time to progression	Time length from the first day of ibrutinib to progression.	From date of inclusion until the date of first documented progression, assessed up to 6 months.
Secondary	Complete response rate	The complete response rate was defined as the proportion of patients that achieve complete responses within the study's time frame.	Up to six months post enrollment
Secondary	Partial response rate	The partial response rate was defined as the proportion of patients that achieve partial responses within the study's time frame.	Up to six months post enrollment
Secondary	Progression rate	The progression rate was defined as the proportion of patients that progresses within the study's time frame.	Up to six months post enrollment
Secondary	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.	Up to six months post enrollment
Secondary	Proportion of therapy interruption	The proportion of patients that need ibrutinib interruption because of unacceptable toxicity (grade >=3).	Up to six months post enrollment