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

59 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Itacitinib, Tacrolimus, and Sirolimus for treating leukemia?

Research suggests that m-TOR inhibitors like Sirolimus (also known as rapamycin) can enhance the effects of chemotherapy drugs in leukemia, indicating potential benefits when used in combination therapies. Additionally, a study showed that combining decitabine with rapamycin was safe and feasible for patients with relapsed/refractory acute myeloid leukemia, suggesting that similar combinations might be effective. ^{1 2 3 4 5}

Is the combination of Itacitinib, Tacrolimus, and Sirolimus safe for humans?

Tacrolimus, used in kidney transplants, has a similar safety profile in its different formulations (Advagraf and Prograf), with risks including potential kidney damage and diabetes. Sirolimus, often used with Tacrolimus, is generally safe but may prevent certain infections. No specific safety data for Itacitinib in this combination is available, but Tacrolimus and Sirolimus have been studied extensively in humans. ^{6 7 8 9 10}

What makes the drug Itacitinib + Tacrolimus + Sirolimus unique for treating leukemia?

This treatment combines Itacitinib, Tacrolimus, and Sirolimus, which are typically used in transplant medicine to prevent organ rejection, but here they are being explored for leukemia. The combination is unique because it uses immunosuppressive drugs in a novel way to potentially target leukemia cells, which is different from standard chemotherapy treatments. ^{6 7 8 9 11}

What is the purpose of this trial?

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 works in preventing graft-versus-host-disease (GVHD) in patients with acute leukemia, myelodysplastic syndrome or myelofibrosis who are undergoing reduced intensity conditioning donor stem cell transplantation. GVHD is a common complication after donor stem cell transplantation, resulting from donor immune cells recognizing recipients' cells and attacking them. Adding itacitinib to tacrolimus and sirolimus may reduce the risk GVHD and ultimately improve overall outcome and survival after donor stem cell transplantation.

Research Team

Haris Ali

Principal Investigator

City of Hope Comprehensive Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Glasdegib plus low-dose cytarabine for acute myeloid leukemia: Practical considerations from advanced practitioners and pharmacists. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Finding the optimal combination therapy for the treatment of newly diagnosed AML in older patients unfit for intensive therapy. [2019]

3. England pubmed.ncbi.nlm.nih.gov

In-vitro synergism of m-TOR inhibitors, statins, and classical chemotherapy: potential implications in acute leukemia. [2022]

4. New Zealand 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. [2023]

5. England pubmed.ncbi.nlm.nih.gov

A phase I study of decitabine and rapamycin in relapsed/refractory AML. [2018]

6. United States 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. [2022]

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

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. [2021]

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

Therapeutic drug monitoring in de novo kidney transplant receiving the modified-release once-daily tacrolimus. [2013]

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

Overview of extended release tacrolimus in solid organ transplantation. [2022]

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

De novo Prograf versus de novo Advagraf: are trough level profile curves similar? [2021]

11. United States 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. [2021]