Chronic Graft-versus-host-diseasePhase 2NCT05348096
Efficacy and Safety of Low-dose Ibrutinib and Itraconazole in Chronic Graft Versus Host Disease
A Phase 2 study testing Low-dose ibrutinib in people with Chronic Graft-versus-host-disease, run by Hospital Universitario Dr. Jose E. Gonzalez at 1 site in Mexico.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Graft-versus-host-disease
- What is being tested?
- Low-dose ibrutinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 1 siteMexico
- Study dates
- 1 Apr 2022to 1 Aug 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 14Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Mexico1 site, 1 recruiting
- Recruiting
Hospital Universitario Dr. José Eleuterio González
Monterrey, Nuevo León, 64630
Dr Fernando De la Garza Salazar, MD, 8442322102, fernandodelagarza@gmail.com
Fernando De la Garza Salazar, MD, 8442322102
About this study
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
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.
Read the 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
- Being tested
- Low-dose ibrutinib
- Keywords
- ibrutinib, low-dose, azole, itraconazole, refractory
- Medical subject headings
- Bronchiolitis Obliterans Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low-dose ibrutinibDrug
Also called INN-ibrutinib
Daily ibrutinib (140mg QD) and itraconazole (100mg BID) for six months.
| Study group | Role | What they receive |
|---|---|---|
| Low-dose ibrutinib | Experimental | Patients will receive ibrutinib 140mg/day PO in combination with oral itraconazole (100mg/day) continuously for six months. Receives: Drug: Low-dose ibrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Up to six months of enrollment
Secondary outcomes (12)
Overall treatment-free survival
The proportion of patients with any other treatment rather than ibrutinib at six months of follow-up.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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)
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Up to six months post enrollment
Proportion of therapy interruption
The proportion of patients that need ibrutinib interruption because of unacceptable toxicity (grade >=3).
Measured: Up to six months post enrollment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Apr 2022
- Study start1 Apr 2022
- Primary completion1 Apr 2023 (estimated)
- Study completion1 Aug 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Chronic Graft-versus-host-diseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- 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)
- Enrolment
- 13 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital Universitario Dr. Jose E. Gonzalez
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Cesar Homero Gutierrez-Aguirre, Hospital Universitario Dr. Jose E. Gonzalez
- Investigators
- Fernando De la Garza Salazar, Principal investigator, Hospital Universitario Dr. José Eleuterio González
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05348096
- Sponsor's protocol ID
- PI22-00027
- Status last verified
- Apr 2022
- First submitted
- 13 Apr 2022
- Last updated
- 27 Apr 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 34218265Waller 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.
PubMed 31260802Tapaninen 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.
PubMed 31664782
Study at a glance
From the registry record, last updated by the sponsor on 27 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT05348096
- Acronym / sponsor ID
- PI22-00027
- Conditions
- Chronic Graft-versus-host-disease
- Keywords
- ibrutinib, low-dose, azole, itraconazole, refractory
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 13 participants (estimated)
- Lead sponsor
- Hospital Universitario Dr. Jose E. GonzalezUniversity, hospital or other
- Study start
- 1 Apr 2022 (actual)
- Primary completion
- 1 Apr 2023 (estimated)
- Study completion
- 1 Aug 2023 (estimated)
- First posted
- 27 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Patients will receive oral ibrutinib (140mg QD) combined with a CYP3A4 inhibitor (oral itraconazole, 100mg BID) for six months.
| Arm | Type | Receives |
|---|---|---|
| Low-dose ibrutinib | Experimental | Drug: Low-dose ibrutinibPatients will receive ibrutinib 140mg/day PO in combination with oral itraconazole (100mg/day) continuously for six months. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (14 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Low-dose ibrutinibAlso: INN-ibrutinibDaily ibrutinib (140mg QD) and itraconazole (100mg BID) for six months. | Drug | Low-dose ibrutinib |
Primary outcome
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.
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.
12 secondary outcomes
Overall treatment-free survival
Time frame: Up to six months post enrollment
Steroid-free cumulative incidence
Time frame: Up to six months post enrollment
Low-dose steroid cumulative incidence
Time frame: Up to six months post enrollment
Immunosuppressive-free cumulative incidence
Time frame: Up to six months post enrollment
Overall survival
Time frame: 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 to progression
Time frame: 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
Partial response rate
Time frame: Up to six months post enrollment
Progression rate
Time frame: Up to six months post enrollment
Any adverse events rate
Time frame: Up to six months post enrollment
Proportion of therapy interruption
Time frame: Up to six months post enrollment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Apr 2022.
- Background: PubMed 34218265Wolff 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 publication: PubMed 31260802Waller 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 publication: PubMed 31664782Tapaninen 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Fernando De la Garza Salazar principal investigator
Hospital Universitario Dr. José Eleuterio González
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Low-dose ibrutinib in people with Chronic Graft-versus-host-disease, run by Hospital Universitario Dr. Jose E. Gonzalez at 1 site in Mexico.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 27 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Mexico. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Fernando De la Garza Salazar, MD (52-81-8675-6718, fernandodelagarza@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Treatment safety (time frame: Up to six months of enrollment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05348096, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Apr 2022.