Itacitinib + Standard Therapy for Graft-versus-Host Disease
Recruiting in Palo Alto (17 mi)
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: City of Hope Medical Center
Must not be taking: Investigational drugs
Disqualifiers: Prior allogeneic HCT, Uncontrolled illness, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This clinical trial evaluates the safety and effectiveness of adding itacitinib to cyclophosphamide and tacrolimus for the prevention of graft versus host disease (GVHD) in patients undergoing hematopoietic stem cell transplant. Itacitinib is an enzyme inhibitor that may regulate the development, proliferation, and activation of immune cells important for GVHD development. Cyclophosphamide and tacrolimus are immunosuppressive agents that may prevent GVHD in patients who receive stem cell transplants. Giving itacitinib in addition to cyclophosphamide and tacrolimus may be more effective at preventing GVHD in patients receiving hematopoietic stem cell transplants.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, you cannot have had chemotherapy, radiation, biological, or immunotherapy within 21 days before starting the trial, unless it's part of a conditioning regimen or maintenance chemotherapy.
What data supports the effectiveness of the drug Itacitinib + Standard Therapy for Graft-versus-Host Disease?
Research shows that using cyclophosphamide and tacrolimus together can effectively prevent graft-versus-host disease (GVHD) after stem cell transplants, with low rates of severe GVHD and good survival outcomes. Additionally, tacrolimus has been successful in treating severe GVHD when combined with other therapies.12345
Is the combination of Itacitinib and standard therapy safe for treating graft-versus-host disease?
Tacrolimus, one of the drugs in the combination, has been shown to be generally safe for preventing graft-versus-host disease, with a toxicity profile similar to cyclosporin, except for less frequent hair growth and high blood pressure. However, it can cause kidney problems if blood levels are too high. Cyclophosphamide, another drug in the combination, is also used in post-transplantation regimens and has been studied for its safety in this context.678910
What makes the drug Itacitinib unique for treating graft-versus-host disease?
Eligibility Criteria
This trial is for patients up to 80 years old with certain blood cancers or disorders, like myelofibrosis and leukemia, who are eligible for a stem cell transplant. They must have good organ function and performance status, not be HIV positive or have active hepatitis B/C, agree to use birth control if applicable, and can't be pregnant or breastfeeding.Inclusion Criteria
I am 80 years old or younger.
Agreement to use effective birth control or abstain from heterosexual activity for at least 6 months after the last dose of protocol therapy
Documented informed consent of the participant and/or legally authorized representative
See 15 more
Exclusion Criteria
I do not have any untreated infections.
Prospective participants unable to comply with all study procedures
Any condition contraindicating patient's participation in the clinical study due to safety concerns with study procedures
See 8 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants undergo peripheral blood stem cell infusion and receive cyclophosphamide, itacitinib, and tacrolimus as GVHD prophylaxis
100 days
Multiple visits for drug administration and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessment of GVHD, survival, and microbiome diversity
1 year
Follow-up visits at day 180 and 1 year
Long-term follow-up
Participants are monitored for long-term outcomes such as overall survival and chronic GVHD
Up to 2 years
Treatment Details
Interventions
- Cyclophosphamide (Immunosuppressant)
- Itacitinib (Enzyme Inhibitor)
- Tacrolimus (Immunosuppressant)
Trial OverviewThe study tests adding Itacitinib to Cyclophosphamide and Tacrolimus in preventing Graft Versus Host Disease after a stem cell transplant. Itacitinib may help regulate immune cells that cause GVHD while the other drugs suppress the immune system to prevent it.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Prevention (PBSCs, cyclophosphamide, itacitinib, tacrolimus)Experimental Treatment5 Interventions
Patients undergo peripheral blood stem cell infusion on day 0. Patients receive cyclophosphamide IV QD on days 3 and 4, itacitinib PO QD on days 5-100, and tacrolimus IV or PO on days 6-65.
Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:
🇺🇸 Approved in United States as Cytoxan for:
- Breast cancer
- Ovarian cancer
- Multiple myeloma
- Leukemia
- Lymphoma
- Rheumatoid arthritis
🇪🇺 Approved in European Union as Endoxan for:
- Breast cancer
- Ovarian cancer
- Multiple myeloma
- Leukemia
- Lymphoma
- Rheumatoid arthritis
🇨🇦 Approved in Canada as Neosar for:
- Breast cancer
- Ovarian cancer
- Multiple myeloma
- Leukemia
- Lymphoma
- Rheumatoid arthritis
🇯🇵 Approved in Japan as Endoxan for:
- Breast cancer
- Ovarian cancer
- Multiple myeloma
- Leukemia
- Lymphoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
Loading ...
Who Is Running the Clinical Trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation. [2018]The outcome of hyperacute grade 3-4 steroid-refractory graft-versus-host-disease (SR-GVHD) remains dismal despite a plethora of agents being tried alone or in combination. Following T replete haploidentical transplantation with post-transplantation cyclophosphamide on 75 patients, 10 patients (13%) aged 2-20years, developed hyperacute SR-GVHD. We report on the outcome of two different regimens for treatment of SR-GVHD on the outcome of these patients. Five patients were treated in Regimen A consisting of anti-thymocyte globulin, Etanercept and Basiliximab. The next 5 patients were treated combining T cell costimulation blockade with Abatacept along with Etanercept and Basiliximab. The overall response at days 29 and 56 were 40% and 0% with Regimen A and100% and 40% with Regimen B. The major cause of treatment failure was progression of GVHD and opportunistic infections. Two of the patients achieving a complete remission on Regimen B are long term disease free survivors off immunosuppression. Our study demonstrates the dismal outcome of early onset SR-GVHD in children following T replete haploidentical transplantation. However, the combination of Abatacept with anticytokine agents seems to produce encouraging early response and might warrant further investigation.
Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease. [2015]Steroid refractory chronic graft-versus-host disease (cGVHD) is associated with a significant morbidity and mortality. Although first-line treatment of cGVHD is based on controlled trials, second-line treatment is almost solely based on phase II trials or retrospective analyses. The consensus conference on clinical practice in cGVHD held in Regensburg aimed to achieve a consensus on the current evidence of treatment options as well as to provide guidelines for daily clinical practice. Treatment modalities are the use of steroids and calcineurin inhibitors as well as immunomodulating modalities (photopheresis, mTOR-inhibitors, thalidomide, hydroxychloroquine, vitamin A analogs, clofazimine), and cytostatic agents (mycophenolate mofetil, methotrexate, cyclophosphamide, pentostatin). Recent reports showed some efficacy of rituximab, alemtuzumab, and etanercept in selected patients. Moreover, tyrosine kinase inihibitors such as imatinib came into the field because of their ability to interfere with the platelet-derived growth factor (PDGF-R) pathway involved in fibrosis. An other treatment option is low-dose thoracoabdominal irradiation. Although different treatment options are available, the "trial-and-error system" remains the only way to identify the drug effective in the individual patient, and valid biomarkers are eagerly needed to identify the likelihood of response to a drug in advance. Moreover, the sparse evidence for most treatment entities indicates the urgent need for systematic evaluation of second-line treatment options in cGVHD.
Successful therapy of refractory graft versus host disease with tacrolimus and Psoralen plus ultraviolet light. [2019]The authors report a patient who developed severe graft versus host disease (GVHD) after undergoing a matched, unrelated bone marrow transplant. Her symptoms worsened despite treatment with cyclosporine, high doses of methylprednisolone, and antithymocyte globulin. After treatment with tacrolimus (FK506) and Psoralen plus ultraviolet light (PUVA), there was complete resolution of all clinical and laboratory evidence of GVHD. This combination may be beneficial to other patients who develop severe GVHD that is resistant to conventional therapy.
Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors. [2018]Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571.
Chronic graft-versus-host disease: Pathogenesis and clinical management. [2018]Chronic graft-versus-host disease (cGVHD) is the most common and severe complication among patients surviving >100 days after allogeneic transplantation. It starts with the expansion of donor T cells in response to alloantigens or autoantigens that are unchecked by normal thymic or peripheral mechanisms of deletion. The T cells induce damage to target organs either directly through cytolytic attack, inflammatory cytokines and fibrosis, or by promoting B cell activation and production of autoantibodies. HLA disparity, donor and patient age and sex, source of progenitor cells, graft composition and previous acute GVHD are the main factors that predict the risk of developing cGVHD. Once the diagnosis has been established, patients needing treatment (extensive cGVHD) must be identified. Poor prognostic factors such as extensive skin involvement, thrombocytopenia and progressive-type onset of cGVHD must be considered in order to define the immunosuppressive treatment requirements. Prednisone, together with a calcineurin inhibitor such as ciclosporin or tacrolimus, can be considered the standard regimen as primary treatment for cGVHD. Using that approach, among high-risk patients (identified as those with extensive cGVHD plus thrombocytopenia) 3-year survival reached 52%. Concerning salvage regimens, to date there is no clear standard regimen for cGVHD treatment, the best choice being to enter the patient into a clinical trial. Immunosuppressive drugs that inhibit T cell activation, proliferation or survival, such as mycophenolate mofetil, the anti-interleukin-2 alpha receptor antagonist daclizumab, sirolimus (rapamycin), extracorporeal photopheresis and pentostatin (deoxycoformycin), among other agents, have been used with a very wide range of complete responses ranging from 5% to 50%. In addition, anti-cytokine or B cell inhibitors such as etanercept or rituximab have also been evaluated. The severe immunosuppression induced by those drugs increases the risk of infectious complications and may have a deleterious effect on the graft versus tumour effect after transplant so that newer strategies based on the selective depletion of alloreactive T cells and induction of more specific immunotolerance against host tissues are required.
Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. [2021]Steroid-refractory chronic graft-versus-host disease (SR-cGVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. Innovative immunotherapeutic strategies are urgently needed for the treatment of SR-cGVHD. We conducted a phase 1 clinical trial to evaluate the safety, efficacy, and immune effects of abatacept, a novel immunomodulatory drug that acts as an inhibitor of T-cell activation via costimulatory blockade, in the treatment of SR-cGVHD. The study followed a 3+3 design with 2 escalating abatacept doses: 3 mg/kg and 10 mg/kg, with an expansion cohort treated at 10 mg/kg. Abatacept was well-tolerated with no dose-limiting toxicities. Of the 16 evaluable patients, 44% achieved a clinical partial response per 2005 National Institutes of Health Consensus Criteria. Importantly, abatacept resulted in a 51.3% reduction in prednisone usage in clinical responders (mean baseline, 27 vs 14 mg; P = .01). Increased PD-1 expression on circulating CD4 (P = .009) and CD8 (P = .007) T cells was observed in clinical responders. In summary, abatacept was safe and led to a marked improvement in National Institutes of Health cGVHD scores and a significant reduction in prednisone use. In this cohort of heavily pretreated patients, the results suggest abatacept may be a promising therapeutic agent for SR-cGVHD, and a phase 2 trial has been initiated. This trial was registered at www.clinicaltrials.gov as #NCT01954979.
Lack of a significant pharmacokinetic interaction between maraviroc and tacrolimus in allogeneic HSCT recipients. [2023]Emerging data suggest that the combination of tacrolimus and the CCR5 antagonist maraviroc, both cytochrome P450-3A4 substrates, may be effective in preventing graft-versus-host disease in patients undergoing allogeneic HSCT. This study evaluated whether a pharmacokinetic interaction exists between these agents.
Optimum use of tacrolimus in the prophylaxis of graft versus host disease. [2018]Transplantation of haemopoietic stem cells containing immunocompetent cells invariably leads to the development of graft versus host disease (GVHD) in the recipients unless immunosuppressive prophylaxis is administered for approximately 6 months. Despite the availability of immunosuppressive drugs such as cyclosporin, GVHD remains the most important cause of morbidity and mortality in haemopoietic stem recipients. Tacrolimus (FK506), a macrolide lactone isolated from the fermentation broth of Streptomyces tsukubiensis, has been introduced as an agent with greater activity than cyclosporin for GVHD prophylaxis. Several pilot studies using tacrolimus for prophylaxis of acute GVHD have shown promising results leading to 3 major pivotal trials. These studies were nonblinded randomised trials comparing the combination of tacrolimus and methotrexate with cyclosporin and methotrexate in both matched sibling and unrelated donor transplants for the prevention of acute GVHD. All 3 trials showed a significantly lower incidence of acute GVHD in the tacrolimus arm when compared to the cyclosporin arm. The overall and disease-free survival of patients with non-advanced malignancies was similar between the 2 groups. In one matched sibling study, the overall and disease-free survival in high-risk advanced disease patients who received tacrolimus was poorer than in the cyclosporin recipients. However, a recent matched case controlled study using the International Bone Marrow Transplant Registry database confirmed that the poorer survival outcome of the tacrolimus recipients was due to adverse influence of baseline prognostic factors in the tacrolimus group. The toxicity profile of tacrolimus is similar to that of cyclosporin with the exception that the incidence of hirsutism and hypertension is less frequent in tacrolimus recipients. The nephrotoxicity associated with tacrolimus is dose related. Logistic regression analysis indicated that whole blood tacrolimus concentrations greater than 20 ng/ml were associated with significant nephrotoxicity. The current recommended therapeutic concentration range in whole blood is 10 to 20 ng/ml. Some studies found equal efficacy with a therapeutic range of 5 to 15 ng/ml. This review addresses many details on the practical management of adverse effects, dosage and drug interactions.
Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. [2023]In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Prophylaxis regimens for GVHD: systematic review and meta-analysis. [2018]Opinions are divided regarding the best prophylactic regimen for GVHD. The aim of this study was to evaluate potential survival benefit of different prophylactic regimens for acute GVHD (aGVHD). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) including patients undergoing Allo-SCT. We included trials that assessed the addition of MTX, compared CsA and tacrolimus and evaluated the addition of steroids. Outcomes assessed were all-cause mortality (ACM) at the longest follow-up, aGVHD, chronic GVHD, TRM, relapse rate and regimen-specific adverse events. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. The regimen of MTX-CsA vs CsA alone (four trials) yielded no statistically significant difference in ACM (RR=0.84 (0.61-1.14)), but a significant decrease in aGVHD (RR=0.52 (0.39-0.7)). There was no difference in ACM for the comparison of MTX-CsA and MTX-tacrolimus (three trials); however, MTX-tacrolimus was superior to MTX-CsA in the reduction of aGVHD (RR=0.62 (0.52-0.75)) and severe aGVHD (RR=0.67 (0.47-0.95)). The addition of steroids did not affect the outcomes (four trials). We conclude that MTX-CsA and MTX-tacrolimus are both acceptable alternatives for GVHD prophylaxis, although MTX-tacrolimus may be superior in terms of aGVHD reduction.
Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice. [2021]Bruton's Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.
New Indication for Ruxolitinib. [2023]The kinase inhibitor ruxolitinib (Jakafi) is now approved to treat chronic graft-vs-host disease.
Efficacy and safety of itacitinib versus placebo in combination with corticosteroids for initial treatment of acute graft-versus-host disease (GRAVITAS-301): a randomised, multicentre, double-blind, phase 3 trial. [2022]Acute graft-versus-host disease (GVHD) is a common and life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT); there is an urgent unmet need for effective therapies. We aimed to evaluate the Janus kinase 1 inhibitor itacitinib versus placebo, both in combination with corticosteroids, for initial treatment of acute GVHD.
The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects. [2019]The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.
The Effectiveness of Ruxolitinib for Acute/Chronic Graft-versus-Host Disease in Children: A Retrospective Study. [2022]This study aimed to evaluate the effectiveness of Ruxolitinib for acute/chronic graft-versus-host disease in children.