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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Chronic Graft-versus-host-disease
• Intervention / Treatment: Drug: Low-dose ibrutinib

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.

• Study Type: Interventional
• Enrollment (Anticipated): 13
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Fernando De la Garza Salazar, MD; Phone Number: 52-81-8675-6718; Email: fernandodelagarza@gmail.com

Study Locations

• Mexico
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64630
      • Recruiting
      • Hospital Universitario Dr. José Eleuterio González
      • Contact: Dr Fernando De la Garza Salazar, MD; Phone Number: 8442322102; Email: fernandodelagarza@gmail.com
      • Contact: Fernando De la Garza Salazar, MD; Phone Number: 8442322102

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-dose ibrutinib; Patients will receive ibrutinib 140mg/day PO in combination with oral itraconazole (100mg/day) continuously for six months.	Drug: Low-dose ibrutinib; Daily ibrutinib (140mg QD) and itraconazole (100mg BID) for six months.; Other Names: INN-ibrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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.
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.
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
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
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
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
Proportion of therapy interruption	The proportion of patients that need ibrutinib interruption because of unacceptable toxicity (grade >=3).	Up to six months post enrollment

Collaborators and Investigators

• Sponsor: Hospital Universitario Dr. Jose E. Gonzalez
• Investigators: Principal Investigator: Fernando De la Garza Salazar, Hospital Universitario Dr. José Eleuterio González

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): August 1, 2023

Study Registration Dates

• First Submitted: April 13, 2022
• First Submitted That Met QC Criteria: April 21, 2022
• First Posted (Actual): April 27, 2022

Study Record Updates

• Last Update Posted (Actual): April 27, 2022
• Last Update Submitted That Met QC Criteria: April 21, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: refractory; ibrutinib; itraconazole; low-dose; azole
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: PI22-00027

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No