Itacitinib + Tacrolimus + Sirolimus for Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must be taking: Tacrolimus, Sirolimus

Must not be taking: Chemotherapy, Radiation therapy

Disqualifiers: Uncontrolled illness, Active infection, 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: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments to prevent graft-versus-host disease (GVHD) in individuals with certain blood cancers, such as acute leukemia, who are receiving stem cell transplants. GVHD occurs when the donor's immune cells attack the patient's body after a transplant. The study combines a new drug, itacitinib (a Janus kinase inhibitor), with standard treatments, tacrolimus and sirolimus, to determine if this combination reduces the risk of GVHD and improves overall recovery. Individuals diagnosed with specific blood cancers and scheduled to receive a donor stem cell transplant might be suitable candidates for this trial. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require that you have not had chemotherapy, radiation, biological, or immunotherapy within 21 days before starting the trial. It's best to discuss your current medications with the trial team to see if they might affect your eligibility.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have generally found itacitinib to be safe, though some patients experienced serious side effects like low platelet counts, known as thrombocytopenia. About 28% of patients had significant drops in platelet levels, increasing the risk of bleeding.

Tacrolimus, already used to prevent GVHD, is considered safe when used alone. Some patients in studies have experienced chronic GVHD, a known risk when preventing GVHD. The treatment is usually well-tolerated when blood levels remain within a certain range.

Research suggests that sirolimus improves remission rates in certain cancers. Its safety is generally acceptable, though monitoring for side effects is important, especially when combined with other drugs.

Overall, while itacitinib, tacrolimus, and sirolimus have shown some side effects, many patients generally tolerate them well. Participants in a clinical trial with these treatments will be closely monitored for any adverse effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using itacitinib adipate in combination with tacrolimus and sirolimus for leukemia because this combo offers a novel approach to preventing graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Unlike standard treatments that mainly rely on tacrolimus and methotrexate, this regimen incorporates itacitinib, a JAK1 inhibitor, which may provide enhanced control over immune responses. By targeting specific pathways involved in inflammation and immune activation, this treatment has the potential to reduce GVHD more effectively, improving patient outcomes without adding significant toxicity.

What evidence suggests that this treatment might be an effective treatment for GVHD?

Research has shown that adding itacitinib to the drugs tacrolimus and sirolimus, which participants in this trial will receive, can help prevent graft-versus-host disease (GVHD) after stem cell transplants. One study found that this combination was 54% successful in preventing GVHD after one year, outperforming other drug combinations like Tac/Siro or Tac/methotrexate. This suggests that the itacitinib combination might help patients live longer after receiving stem cell transplants. The treatment reduces the immune system's attack on the patient's body, the main cause of GVHD. These findings provide promising evidence that this combination can effectively reduce complications after transplantation. ^{6 7 8 9 10}

Who Is on the Research Team?

Haris Ali

Principal Investigator

City of Hope Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with acute leukemia, myelodysplastic syndrome, or myelofibrosis planning to undergo stem cell transplantation. Participants need a matched donor, good organ function, and must not be pregnant or breastfeeding. They should agree to use birth control and cannot have other active cancers or uncontrolled illnesses.

Inclusion Criteria

My lung function tests are good or my oxygen levels are above 92% without extra oxygen.

All candidates for this study must have a matched related donor (MRD) who is willing to donate BM or peripheral blood stem cells or an 8/8 allele matched unrelated donor (MUD)

Note: To be performed within 28 days prior to day 1 of protocol therapy

Exclusion Criteria

I haven't had chemotherapy, radiation, or immunotherapy in the last 21 days.

You have had allergic reactions in the past to drugs that are similar to the study medication.

I have ongoing diarrhea because of a bowel condition or absorption issue.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Reduced Intensity Conditioning (RIC)

Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4

1 week

Daily visits for infusions

Allogeneic Hematopoietic Stem Cell Transplant (HSCT)

Patients undergo HSCT on day 0

1 day

1 visit (in-person)

GVHD Prophylaxis

Patients receive itacitinib, tacrolimus, and sirolimus from day -3 to day 100

14 weeks

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Periodic visits

What Are the Treatments Tested in This Trial?

Interventions

• Itacitinib Adipate
• Sirolimus
• Tacrolimus

Trial Overview The study tests if adding Itacitinib to standard GVHD prevention drugs Tacrolimus and Sirolimus can better prevent graft-versus-host disease in patients receiving reduced intensity conditioning donor stem cell transplants. The effectiveness of this combination will also be assessed through quality-of-life questionnaires.

How Is the Trial Designed?

Group I: Treatment (itacitinib adipate, tacrolimus, sirolimus) Experimental Treatment 7 Interventions

RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HSCT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.

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+

Published Research Related to This Trial

The extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) shows similar efficacy to the immediate-release version (Prograf®) in kidney transplant recipients, with no significant differences in patient/graft survival, acute rejection rates, or renal function across studies involving over 2,500 patients.

Advagraf® significantly improves medication adherence compared to Prograf®, which is crucial for long-term transplant success, and it has also been associated with favorable outcomes when combined with mTOR inhibitors, potentially reducing the risk of late-onset cytomegalovirus infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. Noble, J., Jouve, T., Rostaing, L., et al.[2021]

A systematic review and network meta-analysis of 68 studies found that long-term outcomes, such as graft loss and patient mortality, are generally comparable between the once-daily tacrolimus formulation (Advagraf) and the twice-daily formulation (Prograf) in kidney transplant recipients.

The analysis showed that the rates of acute rejection and new-onset diabetes mellitus after transplantation varied by treatment, but both Advagraf and Prograf demonstrated similar effectiveness in preventing graft loss and mortality, indicating that either formulation can be a viable option for post-transplant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. T A, M., Chng, R., Yau, WP.[2022]

Extended release tacrolimus (Advagraf©, Astagraf XL©) offers a once-daily dosing option for kidney transplant recipients, potentially improving medication adherence while maintaining a similar safety and efficacy profile to the traditional twice-daily tacrolimus (Prograf©).

While extended release tacrolimus shows comparable pharmacokinetics to the standard formulation, it is not recommended for liver transplant patients due to an increased risk of mortality in female recipients, and there is limited data on its use in heart and lung transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of extended release tacrolimus in solid organ transplantation. Patel, N., Cook, A., Greenhalgh, E., et al.[2022]

In a study comparing Advagraf (AVF) and Prograf (PGF) in 30 de novo kidney transplant patients, it was found that while both medications had similar overall exposure to tacrolimus, patients on AVF required higher median doses (9.8 mg/d) compared to those on PGF (7.9 mg/d) to achieve targeted drug levels in the early post-transplant period.

Despite the higher doses needed for AVF, both formulations showed similar efficacy in terms of drug exposure, suggesting that monitoring should include assessing area under the curve (AUC) or peak levels for patients not reaching target levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic drug monitoring in de novo kidney transplant receiving the modified-release once-daily tacrolimus. Jelassi, ML., Lefeuvre, S., Karras, A., et al.[2013]

In a study of 638 kidney transplant recipients over 4 years, both tacrolimus formulations (Astagraf XL and Prograf) demonstrated similar patient and graft survival rates, with 93.2% and 91.2% survival respectively, compared to 91.7% for cyclosporine (CsA).

Patients on tacrolimus had a higher incidence of new-onset diabetes after transplantation (41.1% for Astagraf XL and 33.6% for Prograf) compared to 21.3% for CsA, but showed comparable renal function between the two tacrolimus formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients. Silva, HT., Yang, HC., Meier-Kriesche, HU., et al.[2021]

The combination of glasdegib (GLAS) and low-dose cytarabine (LDAC) significantly improves overall survival in older patients with previously untreated acute myeloid leukemia (AML) compared to azacitidine (AZA) or decitabine (DEC), based on a systematic review and advanced statistical methods involving indirect and simulated treatment comparisons.

Both standard and covariate-adjusted analyses showed that GLAS + LDAC is superior to AZA and DEC, with hazard ratios indicating a substantial reduction in the risk of death, making it a promising treatment option for patients ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall survival of glasdegib in combination with low-dose cytarabine, azacitidine, and decitabine among adult patients with previously untreated AML: comparative effectiveness using simulated treatment comparisons. Tremblay, G., Westley, T., Cappelleri, JC., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04339101?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(ITACITINIB%20ADIPATE))&rank=4

Itacitinib, Tacrolimus, and Sirolimus for the Prevention of GVHD ... Members are chosen based on the scientific skills and knowledge needed to monitor the particular trial. Also called a data safety and monitoring board, or DSMB.

2. withpower.com withpower.com/trial/phase-3-hematologic-diseases-10-2020-b7873

Itacitinib + Tacrolimus + Sirolimus for Leukemia This phase IIa trial studies the side effects of itacitinib when given together with standard treatment (tacrolimus and sirolimus), and to see how well it ...

3. clinicaltrial.be clinicaltrial.be/en/details/3771?per_page=20&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Itacitinib, Tacrolimus, and Sirolimus for the Prevention... Acute leukemia (AL) in first complete response (CR1) or subsequent complete response (CR) or active disease with bone marrow (BM) blast of < 5% ...

4. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper206169.html

Paper: Final Analysis of Phase 2a Study of Adding Itacitinib ... The study met the primary endpoint of 1-year GRFS at 54%, which is compared favorably to Tac/Siro or Tac/methotrexate as GVHD prophylaxis, ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-01722

Itacitinib, Tacrolimus, and Sirolimus for the Prevention of ... Adding itacitinib to tacrolimus and sirolimus may reduce the risk GVHD and ultimately improve overall outcome and survival after donor stem cell transplantation ...

6. sciencedirect.com sciencedirect.com/topics/medicine-and-dentistry/itacitinib

Itacitinib - an overview | ScienceDirect Topics Combining all 3 treatment groups, 28% of patients receiving itacitinib developed grade 3/4 thrombocytopenia.91 More data is needed to assess safety and efficacy ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11450374/

Differential effects of itacitinib, fedratinib, and ruxolitinib in ... Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG–induced secondary HLH. Conversely, in primary HLH, in which perforin- ...

8. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/16/NCT03584516/Prot_000.pdf

GRAVITAS-309: A Phase 2/3 Study of Itacitinib and ... To evaluate the safety and tolerability of study treatment across the 2 treatment cohorts. Data from clinical safety assessments (eg, AEs,.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11572186/

Safety and efficacy of itacitinib, a selective JAK1 inhibitor ... Itacitinib is hypothesized to be safe and effective in HCC patients that have progressed after first-line therapies. Clinical Trial Registration ...

10. researchgate.net researchgate.net/publication/340880160_A_phase_1_trial_of_itacitinib_a_selective_JAK1_inhibitor_in_patients_with_acute_graft-versus-host_disease

A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in ... Twenty-nine patients (200 mg, n = 14; 300 mg, n = 15) received ≥1 dose of itacitinib and were included in safety and efficacy assessments. One dose-limiting ...