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

NCT05348096 | Unknown Phase 2 DMC

• 1 other identifier: PI22-00027
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Graft-versus-host-disease

Keywords

ibrutinib; low-dose; azole; itraconazole; refractory

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (12)

• Overall treatment-free survival

  Up to six months post enrollment

• Steroid-free cumulative incidence

  Up to six months post enrollment

• Low-dose steroid cumulative incidence

  Up to six months post enrollment

• Immunosuppressive-free cumulative incidence

  Up to six months post enrollment

• Overall survival

  Up to six months post enrollment

Study Arms (1)

Low-dose ibrutinib

EXPERIMENTAL

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

Drug: Low-dose ibrutinib

Interventions

Low-dose ibrutinib DRUG

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

Also known as: INN-ibrutinib

Low-dose ibrutinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• \. Eastern Cooperative Oncology Group (ECOG) \<= 2

You may not qualify if:

• 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

Sponsors & Collaborators

• Hospital Universitario Dr. Jose E. Gonzalez: lead

Study Sites (1)

Hospital Universitario Dr. José Eleuterio González

Monterrey, Nuevo León, 64630, Mexico

RECRUITING

Related Publications (3)

• 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.

  PMID: 34218265 BACKGROUND

• 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.

  PMID: 31260802 RESULT

• 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.

  PMID: 31664782 RESULT

MeSH Terms

Conditions

Bronchiolitis Obliterans Syndrome

Interventions

ibrutinib

Condition Hierarchy (Ancestors)

Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Study Officials

• Fernando De la Garza Salazar

  Hospital Universitario Dr. José Eleuterio González

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Fernando De la Garza Salazar, MD

CONTACT

52-81-8675-6718; fernandodelagarza@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Professor

Model Details: Patients will receive oral ibrutinib (140mg QD) combined with a CYP3A4 inhibitor (oral itraconazole, 100mg BID) for six months.

Study Record Dates

• First Submitted: April 13, 2022
• First Posted: April 27, 2022
• Study Start: April 1, 2022
• Primary Completion: April 1, 2023
• Study Completion: August 1, 2023
• Last Updated: April 27, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)