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

Primary Purpose

Chronic Graft-versus-host-disease

Status
Recruiting
Phase
Phase 2
Locations
Mexico
Study Type
Interventional
Intervention
Low-dose ibrutinib
Sponsored by
Hospital Universitario Dr. Jose E. Gonzalez
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Graft-versus-host-disease focused on measuring ibrutinib, low-dose, azole, itraconazole, refractory

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hospital Universitario Dr. José Eleuterio GonzálezRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Low-dose ibrutinib

Arm Description

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

Outcomes

Primary Outcome Measures

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.
Overall response rate
The proportion of patients with partial and/or complete response at six months of follow-up.

Secondary Outcome Measures

Overall treatment-free survival
The proportion of patients with any other treatment rather than ibrutinib at six months of follow-up.
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.
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.
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.
Overall survival
Overall survival is defined as the length of time from the start of ibrutinib to the time of death.
Time to any response
Time length from the first day of ibrutinib to any response (partial response or complete response)
Time to progression
Time length from the first day of ibrutinib to progression.
Complete response rate
The complete response rate was defined as the proportion of patients that achieve complete responses within the study's time frame.
Partial response rate
The partial response rate was defined as the proportion of patients that achieve partial responses within the study's time frame.
Progression rate
The progression rate was defined as the proportion of patients that progresses within the study's time frame.
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.
Proportion of therapy interruption
The proportion of patients that need ibrutinib interruption because of unacceptable toxicity (grade >=3).

Full Information

First Posted
April 13, 2022
Last Updated
April 21, 2022
Sponsor
Hospital Universitario Dr. Jose E. Gonzalez
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1. Study Identification

Unique Protocol Identification Number
NCT05348096
Brief Title
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

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
April 1, 2022 (Actual)
Primary Completion Date
April 1, 2023 (Anticipated)
Study Completion Date
August 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Hospital Universitario Dr. Jose E. Gonzalez

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Graft-versus-host-disease
Keywords
ibrutinib, low-dose, azole, itraconazole, refractory

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Patients will receive oral ibrutinib (140mg QD) combined with a CYP3A4 inhibitor (oral itraconazole, 100mg BID) for six months.
Masking
None (Open Label)
Allocation
N/A
Enrollment
13 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Low-dose ibrutinib
Arm Type
Experimental
Arm Description
Patients will receive ibrutinib 140mg/day PO in combination with oral itraconazole (100mg/day) continuously for six months.
Intervention Type
Drug
Intervention Name(s)
Low-dose ibrutinib
Other Intervention Name(s)
INN-ibrutinib
Intervention Description
Daily ibrutinib (140mg QD) and itraconazole (100mg BID) for six months.
Primary Outcome Measure Information:
Title
Treatment safety
Description
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.
Time Frame
Up to six months of enrollment
Title
Overall response rate
Description
The proportion of patients with partial and/or complete response at six months of follow-up.
Time Frame
Up to six months of enrollment
Secondary Outcome Measure Information:
Title
Overall treatment-free survival
Description
The proportion of patients with any other treatment rather than ibrutinib at six months of follow-up.
Time Frame
Up to six months post enrollment
Title
Steroid-free cumulative incidence
Description
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.
Time Frame
Up to six months post enrollment
Title
Low-dose steroid cumulative incidence
Description
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.
Time Frame
Up to six months post enrollment
Title
Immunosuppressive-free cumulative incidence
Description
The number of patients without any immunosuppressor divided by the total number of patients at the time interval of the study.
Time Frame
Up to six months post enrollment
Title
Overall survival
Description
Overall survival is defined as the length of time from the start of ibrutinib to the time of death.
Time Frame
Up to six months post enrollment
Title
Time to any response
Description
Time length from the first day of ibrutinib to any response (partial response or complete response)
Time Frame
From date of inclusion until the date of first documented response (partial or complete), assessed up to six months.
Title
Time to progression
Description
Time length from the first day of ibrutinib to progression.
Time Frame
From date of inclusion until the date of first documented progression, assessed up to 6 months.
Title
Complete response rate
Description
The complete response rate was defined as the proportion of patients that achieve complete responses within the study's time frame.
Time Frame
Up to six months post enrollment
Title
Partial response rate
Description
The partial response rate was defined as the proportion of patients that achieve partial responses within the study's time frame.
Time Frame
Up to six months post enrollment
Title
Progression rate
Description
The progression rate was defined as the proportion of patients that progresses within the study's time frame.
Time Frame
Up to six months post enrollment
Title
Any adverse events rate
Description
The any adverse event rate was defined as the proportion of patients with any grade adverse events within the study's time frame.
Time Frame
Up to six months post enrollment
Title
Proportion of therapy interruption
Description
The proportion of patients that need ibrutinib interruption because of unacceptable toxicity (grade >=3).
Time Frame
Up to six months post enrollment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Fernando De la Garza Salazar, MD
Phone
52-81-8675-6718
Email
fernandodelagarza@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fernando De la Garza Salazar
Organizational Affiliation
Hospital Universitario Dr. José Eleuterio González
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Universitario Dr. José Eleuterio González
City
Monterrey
State/Province
Nuevo Leon
ZIP/Postal Code
64630
Country
Mexico
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dr Fernando De la Garza Salazar, MD
Phone
8442322102
Email
fernandodelagarza@gmail.com
First Name & Middle Initial & Last Name & Degree
Fernando De la Garza Salazar, MD
Phone
8442322102

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34218265
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.
Results Reference
background
PubMed Identifier
31260802
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.
Results Reference
result
PubMed Identifier
31664782
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.
Results Reference
result

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

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