Itacitinib + Standard Therapy for Graft-versus-Host Disease

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Investigational drugs

Disqualifiers: Prior allogeneic HCT, Uncontrolled illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 180

Duration: 100 days

50 Participants Needed

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. ^{1 2 3 4 5}

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. ^{6 7 8 9 10}

What makes the drug Itacitinib unique for treating graft-versus-host disease?

Itacitinib is unique because it is a Janus kinase 1 inhibitor, which means it specifically targets and blocks certain pathways involved in the immune response, potentially reducing the severity of graft-versus-host disease when combined with standard corticosteroid therapy. ^{11 12 13 14 15}

Research Team

Monzr M. Al Malki

Principal Investigator

City of Hope Medical Center

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

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

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
• Itacitinib
• Tacrolimus

Trial Overview The 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

Group I: Prevention (PBSCs, cyclophosphamide, itacitinib, tacrolimus) Experimental Treatment 5 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

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 75 patients aged 2-20 years who underwent T replete haploidentical transplantation, 13% developed hyperacute steroid-refractory graft-versus-host disease (SR-GVHD), highlighting the serious challenges in treating this condition.

The treatment regimen combining Abatacept with anti-cytokine agents showed promising results, achieving a 100% response rate at day 29 and leading to long-term disease-free survival in two patients, suggesting this approach may be worth further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation. Jaiswal, SR., Zaman, S., Chakrabarti, A., et al.[2018]

Steroid refractory chronic graft-versus-host disease (cGVHD) has limited treatment options, primarily based on phase II trials and retrospective analyses, highlighting the need for more systematic evaluations of second-line therapies.

Current treatment modalities include a variety of agents such as steroids, calcineurin inhibitors, and newer options like tyrosine kinase inhibitors, but the effectiveness of these treatments often relies on a trial-and-error approach, emphasizing the need for valid biomarkers to predict patient responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease. Wolff, D., Schleuning, M., von Harsdorf, S., et al.[2015]

A patient with severe graft versus host disease (GVHD) after a bone marrow transplant showed no improvement with standard treatments like cyclosporine and high-dose steroids.

However, treatment with tacrolimus and Psoralen plus ultraviolet light (PUVA) led to complete resolution of GVHD symptoms, suggesting this combination could be effective for other patients with treatment-resistant GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful therapy of refractory graft versus host disease with tacrolimus and Psoralen plus ultraviolet light. Jubran, RF., Dinndorf, PA.[2019]

In a study of 35 patients undergoing allogeneic peripheral blood stem cell transplantation (alloPBSCT), a combination of post-transplant cyclophosphamide and standard immunosuppressants effectively reduced the incidence of acute and chronic graft-versus-host disease (GVHD) to 17% and 7%, respectively, with no severe grade IV GVHD cases reported.

The approach resulted in an impressive 2-year nonrelapse mortality rate of just 3% and maintained overall survival at 77%, demonstrating that this strategy not only controls GVHD but also preserves the beneficial graft-versus-tumor effect essential for combating hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors. Carnevale-Schianca, F., Caravelli, D., Gallo, S., et al.[2018]

Chronic graft-versus-host disease (cGVHD) is a serious complication after allogeneic transplantation, primarily driven by donor T cells attacking the recipient's tissues, with risk factors including HLA disparity and previous acute GVHD.

Standard treatment for extensive cGVHD involves prednisone and a calcineurin inhibitor, achieving a 52% three-year survival rate in high-risk patients, but there is no clear standard for salvage regimens, highlighting the need for new strategies to manage this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic graft-versus-host disease: Pathogenesis and clinical management. Pérez-Simón, JA., Sánchez-Abarca, I., Díez-Campelo, M., et al.[2018]

In a phase 1 clinical trial involving 16 patients with steroid-refractory chronic graft-versus-host disease (SR-cGVHD), the immunomodulatory drug abatacept was found to be safe and well-tolerated, with no dose-limiting toxicities reported.

Abatacept led to a 44% clinical partial response rate and a significant 51.3% reduction in prednisone usage among responders, indicating its potential as an effective treatment option for SR-cGVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. Nahas, MR., Soiffer, RJ., Kim, HT., et al.[2021]

In a study of 79 allogeneic HSCT recipients, the combination of maraviroc and tacrolimus did not significantly alter the metabolism of tacrolimus, indicating that maraviroc does not inhibit tacrolimus metabolism.

The results suggest that using maraviroc alongside tacrolimus is safe and does not affect tacrolimus concentrations, implying that maraviroc's protective effect against graft-versus-host disease is not due to increased tacrolimus levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of a significant pharmacokinetic interaction between maraviroc and tacrolimus in allogeneic HSCT recipients. Ganetsky, A., Miano, TA., Hughes, ME., et al.[2023]

Tacrolimus is more effective than cyclosporin in preventing acute graft versus host disease (GVHD) in patients receiving haemopoietic stem cell transplants, as shown in three major pivotal trials that reported a significantly lower incidence of GVHD with tacrolimus.

While tacrolimus has a similar toxicity profile to cyclosporin, it has a lower incidence of hirsutism and hypertension, although nephrotoxicity is dose-related, with recommended therapeutic blood concentrations between 10 to 20 ng/ml to minimize risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimum use of tacrolimus in the prophylaxis of graft versus host disease. Uberti, JP., Cronin, S., Ratanatharathorn, V.[2018]

In a phase 3 trial involving 431 adults undergoing allogeneic hematopoietic stem-cell transplantation, the combination of cyclophosphamide, tacrolimus, and mycophenolate mofetil significantly improved GVHD-free, relapse-free survival at 1 year compared to the standard regimen of tacrolimus and methotrexate, with a hazard ratio of 0.64.

Patients receiving the experimental prophylaxis experienced less severe acute and chronic GVHD and a higher rate of immunosuppression-free survival, indicating a potentially safer and more effective approach to preventing GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. Bolaños-Meade, J., Hamadani, M., Wu, J., et al.[2023]

In a systematic review of randomized controlled trials involving patients undergoing Allo-SCT, the combination of MTX and CsA did not significantly reduce all-cause mortality but led to a significant decrease in acute GVHD (aGVHD) compared to CsA alone.

The combination of MTX and tacrolimus was found to be superior to MTX and CsA in reducing both aGVHD and severe aGVHD, suggesting that MTX-tacrolimus may be the more effective prophylactic regimen for preventing GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylaxis regimens for GVHD: systematic review and meta-analysis. Ram, R., Gafter-Gvili, A., Yeshurun, M., et al.[2018]

Ibrutinib, an FDA-approved inhibitor of BTK and ITK, significantly reduced chronic graft-versus-host disease (cGVHD) in four different mouse models, leading to improved long-term survival and lower clinical scores.

The treatment with Ibrutinib resulted in decreased levels of serum autoantibodies and reduced B-cell proliferation, indicating its potential as a safe and effective prophylactic strategy against cGVHD in patients undergoing allogeneic hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice. Schutt, SD., Fu, J., Nguyen, H., et al.[2021]

Ruxolitinib (Jakafi) has received approval for the treatment of chronic graft-vs-host disease, indicating its efficacy in managing this condition.

The approval of ruxolitinib highlights its role as a kinase inhibitor, which works by targeting specific pathways involved in the immune response, potentially improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Indication for Ruxolitinib. Aschenbrenner, DS.[2023]

In a phase 3 study involving 439 patients with acute graft-versus-host disease (GVHD), the Janus kinase 1 inhibitor itacitinib showed a higher overall response rate (ORR) of 74% compared to 66% for placebo when combined with corticosteroids, although this difference did not reach statistical significance.

Both treatment groups experienced a high rate of grade 3 or worse adverse events, with similar safety profiles, indicating that while itacitinib may improve response rates, its safety is comparable to standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Zeiser, R., Socié, G., Schroeder, MA., et al.[2022]

Trametinib, a MEK inhibitor approved for melanoma, effectively suppresses graft-versus-host disease (GVHD) in mice without compromising the beneficial graft-versus-tumor (GVT) effects, indicating its potential as a safe treatment option.

In vivo studies showed that trametinib prolonged survival in GVHD mice and reduced symptoms, while selectively inhibiting alloreactive T cells and sparing virus-specific T cells, making it a promising candidate for preventing or treating GVHD in transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects. Itamura, H., Shindo, T., Tawara, I., et al.[2019]

In a study of 53 pediatric patients with graft-versus-host disease (GVHD), ruxolitinib demonstrated a high overall response rate of 75.5%, with 80.6% efficacy in chronic GVHD (cGVHD) cases compared to 64.7% in acute GVHD (aGVHD).

Ruxolitinib treatment allowed 39% of patients to discontinue steroids and 22.2% to reduce their steroid dosage, although it was associated with a high incidence of adverse events (94.1%) in the aGVHD group, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effectiveness of Ruxolitinib for Acute/Chronic Graft-versus-Host Disease in Children: A Retrospective Study. Yang, W., Zhu, G., Qin, M., et al.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Successful therapy of refractory graft versus host disease with tacrolimus and Psoralen plus ultraviolet light. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

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]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Chronic graft-versus-host disease: Pathogenesis and clinical management. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Lack of a significant pharmacokinetic interaction between maraviroc and tacrolimus in allogeneic HSCT recipients. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Optimum use of tacrolimus in the prophylaxis of graft versus host disease. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Prophylaxis regimens for GVHD: systematic review and meta-analysis. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

New Indication for Ruxolitinib. [2023]

13. England pubmed.ncbi.nlm.nih.gov

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]

14. United States pubmed.ncbi.nlm.nih.gov

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects. [2019]

15. New Zealand pubmed.ncbi.nlm.nih.gov

The Effectiveness of Ruxolitinib for Acute/Chronic Graft-versus-Host Disease in Children: A Retrospective Study. [2022]