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

NCT ID: NCT05348096

Last Updated: 2022-04-27

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-04-01
• Study Completion Date: 2023-08-01

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.

Conditions

Chronic Graft-versus-host-disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Low-dose ibrutinib

Patients will receive ibrutinib 140mg/day PO in combination with oral itraconazole (100mg/day) continuously for six months.

Group Type: EXPERIMENTAL

Low-dose ibrutinib

Intervention Type: DRUG

Daily ibrutinib (140mg QD) and itraconazole (100mg BID) for six months.

Interventions

Low-dose ibrutinib

Daily ibrutinib (140mg QD) and itraconazole (100mg BID) for six months.

Intervention Type: DRUG

Other Intervention Names

INN-ibrutinib

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospital Universitario Dr. Jose E. Gonzalez

OTHER

Sponsor Role: lead

Responsible Party

Cesar Homero Gutierrez-Aguirre

Clinical Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Fernando De la Garza Salazar

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario Dr. José Eleuterio González

Locations

Hospital Universitario Dr. José Eleuterio González

Monterrey, Nuevo León, Mexico

Site Status: RECRUITING

Countries

Mexico

Central Contacts

Fernando De la Garza Salazar, MD

Role: CONTACT

fernandodelagarza@gmail.com

52-81-8675-6718

Facility Contacts

Dr Fernando De la Garza Salazar, MD

Role: primary

fernandodelagarza@gmail.com

8442322102

Fernando De la Garza Salazar, MD

Role: backup

8442322102

References

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.

Reference Type: BACKGROUND

PMID: 34218265 (View on PubMed)

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.

Reference Type: RESULT

PMID: 31260802 (View on PubMed)

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.

Reference Type: RESULT

PMID: 31664782 (View on PubMed)

Other Identifiers

PI22-00027

Identifier Type: -

Identifier Source: org_study_id