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

April 21, 2022 updated by: Cesar Homero Gutierrez-Aguirre, Hospital Universitario Dr. Jose E. Gonzalez

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

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
13

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Mexico
    • Nuevo Leon
      • Monterrey, Nuevo Leon, Mexico, 64630
        • Recruiting
        • Hospital Universitario Dr. Jose Eleuterio Gonzalez
        • Contact:
        • Contact:
          • Fernando De la Garza Salazar, MD
          • Phone Number: 8442322102

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Treatment safety
Time Frame: Up to six months of enrollment
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
Time Frame: Up to six months of enrollment
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Overall treatment-free survival
Time Frame: Up to six months post enrollment
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
Time Frame: Up to six months post enrollment
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
Time Frame: Up to six months post enrollment
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
Time Frame: Up to six months post enrollment
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
Time Frame: Up to six months post enrollment
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 Frame: From date of inclusion until the date of first documented response (partial or complete), assessed up to six months.
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 Frame: From date of inclusion until the date of first documented progression, assessed up to 6 months.
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
Time Frame: Up to six months post enrollment
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
Time Frame: Up to six months post enrollment
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
Time Frame: Up to six months post enrollment
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
Time Frame: Up to six months post enrollment
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
Time Frame: Up to six months post enrollment
The proportion of patients that need ibrutinib interruption because of unacceptable toxicity (grade >=3).
Up to six months post enrollment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Hospital Universitario Dr. Jose E. Gonzalez

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Fernando De la Garza Salazar, Hospital Universitario Dr. Jose Eleuterio Gonzalez

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2022

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 1, 2023

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 1, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 13, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 21, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 27, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 27, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 21, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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