Steroid Refractory GVHDPhase 1GVHDNCT04070781
Itacitinib and Tocilizumab for Steroid Refractory Acute Graft Versus Host Disease
A Phase 1 study testing Itacitinib and Tocilizumab in people with Steroid Refractory GVHD and Graft Vs Host Disease, run by Columbia University at 2 sites in United States.
Trial summary
The study's primary objective is designed to assess the safety and tolerability, and determine the maximum tolerated dose (MTD) of both itacitinib and tocilizumab when given in combination to patients with steroid-refractory acute graft versus host disease (SR-aGVHD). Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Steroid Refractory GVHD, Graft Vs Host Disease
- What is being tested?
- Itacitinib and Tocilizumab
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 2 sitesUnited States
- Study dates
- 20 Jan 2020to 13 Dec 2021
- Phase
- Phase 1
- 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 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult men and women who are at least 18 years of age
- Recipients of their first allogeneic hematopoietic stem cell transplant from any donor source (including bone marrow, mobilized peripheral blood, cord blood) and human leukocyte antigen (HLA)-match (includes matched related, matched unrelated, mismatched unrelated, and haploidentical)
- Recipients of allogeneic stem cell transplant after any conditioning regimen intensity and those who have received any GVHD prophylaxis regimen, unless it included tocilizumab and/or itacitinib
- Steroid refractory acute GVHD (SR-aGVHD) that has been clinically diagnosed as per the MAGIC criteria and/or pathologically confirmed. Biopsies should be attempted whenever possible according to the investigator's discretion but it is not required as long as alternative diagnoses such as infection or medication side effects have been adequately ruled out. SR-aGVHD is defined as acute GVHD that has failed to exhibit a response after treatment for at least 7 days with a corticosteroid dose of 2 mg/kg of methylprednisolone or prednisone equivalent. SR-aGVHD is also defined as GVHD that flares when steroids are tapered prohibiting further taper.
- Adequate renal function determined by creatinine clearance ≥ 40 mL/min measured or calculated by Cockcroft-Gault equation.
- Absence of history of irreversible liver disease such as cirrhosis or veno-occlusive disease (VOD) that has not responded to therapy
Show all 10Show fewer
- Total bilirubin and/or transaminases (AST and/or ALT) that are ≤2.5 above institutional upper limit of normal that is not attributable to acute GVHD by biopsy
- Non-pregnant females or men and women willing to avoid pregnancy or fathering a child as evidenced by negative pregnancy test (females), non-childbearing potential (history of hysterectomy, oophorectomy, amenorrhea for 12 months) or agree to use barrier or chemical contraception for the duration of the study.
- Ability to swallow oral medication
- Able to give consent and comply with study visits and procedures
Who cannot join
- Primary disease not in complete remission, requiring active treatment, or having required treatment for relapsed disease
- Uncontrolled bacterial, viral, or fungal infections which is evidenced by hemodynamic instability, new radiological findings, new signs or symptoms, or persistently positive blood cultures as determined by the investigator.
- History of viral infection with HIV
- History of infection or exposure to hepatitis B or C with a risk of infection reactivation
- History of active or latent tuberculosis infection that has not been adequately treated
- Use of any JAK inhibitor or IL-6 antagonists for therapy or prophylaxis of acute GVHD. Continuation of calcineurin inhibitors intended for GVHD prophylaxis is allowed. Resumption of therapeutic dosing of calcineurin inhibitors that is being tapered is also allowed.
Show all 12Show fewer
- Severe organ dysfunction unrelated to GVHD that includes cholestatic disorders or unresolved VOD (defined as ongoing organ dysfunction and bilirubin elevation unrelated to GVHD > 2.5 the institutional upper limit of normal), clinically significant or uncontrolled cardiac disease (including unstable angina, acute myocardial infarction within 6 months of enrollment, New York Heart Association, Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia that requires therapy) or clinically significant respiratory disease that requires mechanical ventilation support or 50% or greater supplemental oxygen..
- Receipt of live attenuated vaccine or the need for such a vaccine during the duration of the study
- Treatment with any other investigational agent within 7 days of enrollment (or 5 half-lives, whichever is greater)
- Treatment with any JAK inhibitor or IL-6 antagonist after stem cell transplant. Treatment with a JAK inhibitor before transplant is allowed. Treatment with IL-6 antagonist before transplant is allowed only if last dose was at least 4 weeks prior to transplant.
- Known allergies or sensitivities to itacitinib or tocilizumab
- Pregnant, breast-feeding, or unwilling or unable to avoid pregnancy or fathering a child. Pregnant women are excluded from this study as animal studies have shown that tocilizumab crosses the placenta and can interfere with fetal development in animal studies. Furthermore, itacitinib has been associated with embryo-fetal toxicity in animal studies
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Columbia University Irving Medical Center
New York, New York, 10032
Weill Cornell Medical College - New York Presbyterian Hospital
New York, New York, 10065
About this study
Official title: Phase I Study of Itacitinib in Combination With Tocilizumab for the Treatment of Steroid Refractory Acute Graft Versus Host Disease
The study's primary objective is designed to assess the safety and tolerability, and determine the maximum tolerated dose (MTD) of both itacitinib and tocilizumab when given in combination to patients with steroid-refractory acute graft versus host disease (SR-aGVHD).
The study's secondary objectives are to:
- Estimate the day 28 response rate (ORR) [complete response (CR), very good partial response (VGPR), and partial response (PR)] of the combination of itacitinib and tocilizumab for the treatment of SR-aGVHD
- Estimate the time to response and duration of response
- Estimate the incidence of primary disease relapse while on study treatment
- Estimate the incidence of infections including viral reactivation, bacterial infections and fungal infections while on study treatment
- Estimate the progression-free survival (PFS), overall survival (OS), non-relapse mortality, GVHD-related mortality of study subjects
- Estimate the proportion of patients who successfully discontinue steroids by 6 months and 12 months after therapy initiation
Read the detailed description
The treatment of acute and chronic GVHD consists mostly of steroids which has changed very little over the past 40 years. Response to current therapy for GVHD is far from perfect; only about 50% of patients respond to therapy and many of those responses are not durable.
The current study is a phase I study dose de-escalation study where up to 6 patients will be enrolled into each dose level (2 levels), followed by an expansion cohort at the MTD. The goal of the study is to determine the maximum tolerated dose of the combination of itacitinib and tocilizumab. Once the MTD is determined, the investigator will enroll 10 additional patients as an expansion cohort to further define the safety profile of the combination and estimate its response rate.
- Conditions
- Steroid Refractory GVHD, Graft Vs Host Disease
- Being tested
- Itacitinib, Tocilizumab
- Keywords
- Steroid Refractory GVHD
- Medical subject headings
- Graft vs Host Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ItacitinibDrug
Also called Itacitinib adipate
Itacitinib is a novel, potent, and selective inhibitor of the Janus Kinase (JAK) family of protein tyrosine kinases (TYKs) with selectivity for Janus Kinase 1 (JAK1). Itacitinib is an investigational product.
Itacitinib 200 mg daily in 28-day long cycles
TocilizumabDrug
Also called Actemra
Tocilizumab is a biologic medication currently approved to treat adults with moderately to severely active rheumatoid arthritis (RA), adults with giant cell arteritis (GCA), and children ages two and above with Polyarticular Juvenile Idiopathic Arthritis (PJIA) or Systemic Juvenile Idiopathic Arthritis (SJIA). Tocilizumab blocks the inflammatory protein interleukin 6 (IL-6). This improves joint pain and swelling from arthritis and other symptoms caused by inflammation.
Tocilizumab 4 or 8mg/kg cycle 1 day 1 every 4 weeks in 28-day cycles
| Study group | Role | What they receive |
|---|---|---|
| Itacitinib + Tocilizumab | Experimental | A dose de-escalation design will be used to identify the MTD of both itacitinib and tocilizumab when given in combination. The following two levels will be tested with at least 6 patients per dose:
* Dose level 1: Itacitinib 200 mg daily + tocilizumab 8mg/kg on cycle 1, day 1 (can repeat cycle 2 day 1 if Partial Response (PR) - Starting dose level
* Dose level -1: Itacitinib 200 mg daily + tocilizumab 4mg/kg on cycle 1, day 1 (can repeat cycle 2 day 1 if Partial Response (PR) - Dose De-escalation level
Itacitinib will be given daily in 28-day long cycles, tocilizumab will be given every 4 weeks in 28-day cycles. Receives: Drug: Itacitinib; Drug: Tocilizumab |
| Dose Expansion | Experimental | Once the MTD is determined, an additional 10 patients as an expansion cohort to further define the safety profile of the combination and estimate its response rate. Receives: Drug: Itacitinib; Drug: Tocilizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
MTD of Tocilizumab IV infusion when given with Itacitinib
Maximum Tolerated Dose (MTD) is the highest dose of a drug or treatment that does not cause unacceptable side effects.
Measured: 28 - 35 days after the End of Treatment (EOT) or the date of the last dose of the study drug
Access Safety and Tolerability
The safety and tolerability of study treatment is measured by the frequency and severity of adverse events and serious adverse events.
Measured: End of Cycle 1 (approximately 28 days)
Secondary outcomes (8)
Objective Response Rate (ORR)
The percentage of patients whose cancer shrinks or disappears after treatment (combination of itacitinib and tocilizumab for the treatment of SR-aGVHD), this will include patients with complete response (CR), very good partial response (VGPR) and partial response (PR). This rate will estimated after 28 days on treatment.
Measured: End of Cycle 1 (approximately 28 days)
Time to Response
Time to response as defined in the May 2009 CIBMTR Acute Graft-versus-Host Disease (GVHD) Workshop as the time needed for resolution of GVHD symptoms. Response evaluation will be relative to the assessment on Day 1.
Measured: Up to 36 months
Duration of Response
Duration of response is defined as the interval from day 28 to progression as outlined in the May 2009 Center for International Blood and Marrow Transplant Research (CIBMTR) Acute Graft-versus-Host Disease (GVHD) Workshop
Measured: Up to 36 months
Incidence of Disease Relapse
The occurrence of the return of a disease.
Measured: Up to 36 months
Incidence of Infections
The occurrence of infections including viral reactivation, bacterial infections and fungal infections while on study treatment
Measured: Up to 36 months
Progression-Free Survival (PFS)
Progression-free survival (PFS) (time alive without GVHD) probabilities will be estimated using Kaplan-Meier method, and, if exists, median with 95% confidence interval (CI) will also be reported
Measured: Up to 36 months
Overall Survival (OS)
The length of time from the start of treatment that subjects with the disease are still alive.
Measured: Up to 36 months
Proportion of Patients Discontinuing Steroids
The proportion of patients who successfully discontinue steroids by 6 months and 12 months after therapy initiation
Measured: 6-12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Aug 2019
- Study start20 Jan 2020
- Primary completion13 Dec 2021
- Study completion13 Dec 2021
Why it stopped: The primary reason for study closure is slow enrollment.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Steroid Refractory GVHDStudies of the same condition, open and under way.
- More trials run by Columbia UniversityThe sponsor's other registered studies.
- 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 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- Columbia University
- Sponsor type
- University, hospital or other
- Collaborators
- Incyte Corporation
- Responsible party
- Sponsor
- Investigators
- Markus Mapara, MD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04070781
- Sponsor's protocol ID
- AAAR8757
- Acronym
- GVHD
- Status last verified
- May 2024
- First submitted
- 26 Aug 2019
- Last updated
- 4 Jun 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 4 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of Itacitinib in Combination With Tocilizumab for the Treatment of Steroid Refractory Acute Graft Versus Host Disease
- ClinicalTrials.gov ID
- NCT04070781
- Acronym / sponsor ID
- GVHD / AAAR8757
- Conditions
- Steroid Refractory GVHD, Graft Vs Host Disease
- Keywords
- Steroid Refractory GVHD
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The primary reason for study closure is slow enrollment.
- Enrolment
- 1 participants (actual)
- Lead sponsor
- Columbia UniversityUniversity, hospital or other
- Collaborators
- Incyte Corporation
- Study start
- 20 Jan 2020 (actual)
- Primary completion
- 13 Dec 2021 (actual)
- Study completion
- 13 Dec 2021 (actual)
- First posted
- 28 Aug 2019 (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.
The study's primary objective is designed to assess the safety and tolerability, and determine the maximum tolerated dose (MTD) of both itacitinib and tocilizumab when given in combination to patients with steroid-refractory acute graft versus host disease (SR-aGVHD).
The study's secondary objectives are to:
- Estimate the day 28 response rate (ORR) [complete response (CR), very good partial response (VGPR), and partial response (PR)] of the combination of itacitinib and tocilizumab for the treatment of SR-aGVHD
- Estimate the time to response and duration of response
- Estimate the incidence of primary disease relapse while on study treatment
- Estimate the incidence of infections including viral reactivation, bacterial infections and fungal infections while on study treatment
- Estimate the progression-free survival (PFS), overall survival (OS), non-relapse mortality, GVHD-related mortality of study subjects
- Estimate the proportion of patients who successfully discontinue steroids by 6 months and 12 months after therapy initiation
Detailed description
The treatment of acute and chronic GVHD consists mostly of steroids which has changed very little over the past 40 years. Response to current therapy for GVHD is far from perfect; only about 50% of patients respond to therapy and many of those responses are not durable.
The current study is a phase I study dose de-escalation study where up to 6 patients will be enrolled into each dose level (2 levels), followed by an expansion cohort at the MTD. The goal of the study is to determine the maximum tolerated dose of the combination of itacitinib and tocilizumab. Once the MTD is determined, the investigator will enroll 10 additional patients as an expansion cohort to further define the safety profile of the combination and estimate its response rate.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Itacitinib + Tocilizumab | Experimental | Drug: Itacitinib, Drug: TocilizumabA dose de-escalation design will be used to identify the MTD of both itacitinib and tocilizumab when given in combination. The following two levels will be tested with at least 6 patients per dose: * Dose level 1: Itacitinib 200 mg daily + tocilizumab 8mg/kg on cycle 1, day 1 (can repeat cycle 2 day 1 if Partial Response (PR) - Starting dose level * Dose level -1: Itacitinib 200 mg daily + tocilizumab 4mg/kg on cycle 1, day 1 (can repeat cycle 2 day 1 if Partial Response (PR) - Dose De-escalation level Itacitinib will be given daily in 28-day long cycles, tocilizumab will be given every 4 weeks in 28-day cycles. |
| Dose Expansion | Experimental | Drug: Itacitinib, Drug: TocilizumabOnce the MTD is determined, an additional 10 patients as an expansion cohort to further define the safety profile of the combination and estimate its response rate. |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Adult men and women who are at least 18 years of age
- Recipients of their first allogeneic hematopoietic stem cell transplant from any donor source (including bone marrow, mobilized peripheral blood, cord blood) and human leukocyte antigen (HLA)-match (includes matched related, matched unrelated, mismatched unrelated, and haploidentical)
- Recipients of allogeneic stem cell transplant after any conditioning regimen intensity and those who have received any GVHD prophylaxis regimen, unless it included tocilizumab and/or itacitinib
- Steroid refractory acute GVHD (SR-aGVHD) that has been clinically diagnosed as per the MAGIC criteria and/or pathologically confirmed. Biopsies should be attempted whenever possible according to the investigator's discretion but it is not required as long as alternative diagnoses such as infection or medication side effects have been adequately ruled out. SR-aGVHD is defined as acute GVHD that has failed to exhibit a response after treatment for at least 7 days with a corticosteroid dose of 2 mg/kg of methylprednisolone or prednisone equivalent. SR-aGVHD is also defined as GVHD that flares when steroids are tapered prohibiting further taper.
- Adequate renal function determined by creatinine clearance ≥ 40 mL/min measured or calculated by Cockcroft-Gault equation.
Key exclusion criteria (12 listed)
- Primary disease not in complete remission, requiring active treatment, or having required treatment for relapsed disease
- Uncontrolled bacterial, viral, or fungal infections which is evidenced by hemodynamic instability, new radiological findings, new signs or symptoms, or persistently positive blood cultures as determined by the investigator.
- History of viral infection with HIV
- History of infection or exposure to hepatitis B or C with a risk of infection reactivation
- History of active or latent tuberculosis infection that has not been adequately treated
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 |
|---|---|---|
| ItacitinibAlso: Itacitinib adipateItacitinib is a novel, potent, and selective inhibitor of the Janus Kinase (JAK) family of protein tyrosine kinases (TYKs) with selectivity for Janus Kinase 1 (JAK1). Itacitinib is an investigational product. Itacitinib 200 mg daily in 28-day long cycles | Drug | Dose Expansion, Itacitinib + Tocilizumab |
| TocilizumabAlso: ActemraTocilizumab is a biologic medication currently approved to treat adults with moderately to severely active rheumatoid arthritis (RA), adults with giant cell arteritis (GCA), and children ages two and above with Polyarticular Juvenile Idiopathic Arthritis (PJIA) or Systemic Juvenile Idiopathic Arthritis (SJIA). Tocilizumab blocks the inflammatory protein interleukin 6 (IL-6). This improves joint pain and swelling from arthritis and other symptoms caused by inflammation. Tocilizumab 4 or 8mg/kg cycle 1 day 1 every 4 weeks in 28-day cycles | Drug | Dose Expansion, Itacitinib + Tocilizumab |
Primary outcome
MTD of Tocilizumab IV infusion when given with Itacitinib
Time frame: 28 - 35 days after the End of Treatment (EOT) or the date of the last dose of the study drug
Maximum Tolerated Dose (MTD) is the highest dose of a drug or treatment that does not cause unacceptable side effects.
Access Safety and Tolerability
Time frame: End of Cycle 1 (approximately 28 days)
The safety and tolerability of study treatment is measured by the frequency and severity of adverse events and serious adverse events.
8 secondary outcomes
Objective Response Rate (ORR)
Time frame: End of Cycle 1 (approximately 28 days)
Time to Response
Time frame: Up to 36 months
Duration of Response
Time frame: Up to 36 months
Incidence of Disease Relapse
Time frame: Up to 36 months
Incidence of Infections
Time frame: Up to 36 months
Progression-Free Survival (PFS)
Time frame: Up to 36 months
Overall Survival (OS)
Time frame: Up to 36 months
Proportion of Patients Discontinuing Steroids
Time frame: 6-12 months
Results and safety
The study was stopped early (reason given: The primary reason for study closure is slow enrollment.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Jun 2024.
- Columbia University Medical CenterLink provided by the sponsor.
Related trials for Steroid Refractory GVHD
RecruitingPhase 1
Ex Vivo-Expanded Regulatory T Cells Plus Low-Dose Interleukin-2 for Steroid-Refractory Chronic GVHD
Graft Versus Host Disease (cGvHD)
RecruitingPhase 1
A Study of LBP-MARCO and Ruxolitinib in People With Graft-Versus-Host Disease (GVHD)
Transplant Failure or Rejection of Bone Marrow (Graft vs Host Disease, GVHD)
RecruitingPhase 3
A Study of Tacrolimus/Methotrexate/Ruxolitinib Versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative/Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation (BMT CTN 2203)
Graft-versus-host Disease (GVHD)
Not yet recruitingPhase 1/2
CK0802 for Treatment of Steroid Refractory Graft vs. Host Disease (GVHD)
Steroid Refractory Graft Versus Host Disease
Not yet recruitingPhase 1/2
Jaktinib for Steroid-Refractory Acute Graft-Versus-Host Disease
Acute Graft vs Host Disease
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.
Markus Mapara, MD principal investigator
Columbia University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Itacitinib and Tocilizumab in people with Steroid Refractory GVHD and Graft Vs Host Disease, run by Columbia University at 2 sites in United States.
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 10 inclusion and 12 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: stopped early, as of the sponsor's last update on 4 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: The primary reason for study closure is slow enrollment.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
MTD of Tocilizumab IV infusion when given with Itacitinib (time frame: 28 - 35 days after the End of Treatment (EOT) or the date of the last dose of the study drug). 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?
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 4 Jun 2024.