Cyclophosphamide + Ruxolitinib for Graft-versus-Host Disease Prophylaxis

Overseen By Medical College of Wisconsin Cancer Center Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Medical College of Wisconsin

Disqualifiers: Prior allogeneic HCT, Liver dysfunction, Renal impairment, Cardiac dysfunction, 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: Unknown

56 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label phase 2 study designed to explore the efficacy and safety of low-dose PTCy-ruxolitinib GVHD prophylaxis in older adults undergoing allogeneic HCT with a matched sibling or unrelated donor with a peripheral blood stem cell graft.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Ruxolitinib for graft-versus-host disease prophylaxis?

Research shows that Ruxolitinib, a drug that blocks certain pathways in the body, has been effective in treating graft-versus-host disease (GVHD), especially in patients who do not respond to steroids. Studies have demonstrated that it can help reduce symptoms and allow patients to lower their steroid use. ^{1 2 3 4 5}

Is the combination of Cyclophosphamide and Ruxolitinib generally safe for humans?

Ruxolitinib has been used safely in patients with graft-versus-host disease (GVHD), showing good tolerance and significant improvement in symptoms. However, stopping ruxolitinib suddenly can lead to breathing problems, so careful management is needed when discontinuing the drug. ^{1 2 3 6 7}

How is the drug combination of Cyclophosphamide and Ruxolitinib unique for preventing graft-versus-host disease?

This drug combination is unique because Ruxolitinib, a JAK1/2 inhibitor, has shown effectiveness in reducing graft-versus-host disease (GVHD) symptoms and can be used as a steroid-sparing agent, potentially reducing the need for high-dose steroids and their associated side effects. ^{1 2 3 8 9}

Research Team

Sameem M. Abedin

Principal Investigator

Medical College of Wisconsin

Eligibility Criteria

Adults with certain blood cancers who are in remission can join this trial if they have a matched stem cell donor and meet health criteria like good performance status, normal organ function, and no recent other cancers. They must agree to contraception use.

Inclusion Criteria

I am scheduled for a milder form of pre-transplant treatment.

Ability to understand a written informed consent document, and the willingness to sign it

I have a stem cell donor who is a perfect match for me.

Exclusion Criteria

My lung function tests are below 50% of what's expected.

I have had a bone marrow transplant or CAR-T cell therapy before.

Pregnant or lactating subjects

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplant

Participants undergo reduced intensity conditioning and receive an 8/8-matched peripheral blood stem cell transplant on Day 0

1 week

GVHD Prophylaxis

Participants receive cyclophosphamide on Day +3 and +4, tacrolimus from Day +5 through Day +180, mycophenolate mofetil from Day +5 through Day +35, and ruxolitinib starting after engraftment through one year post-transplant

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments for acute and chronic GVHD and overall survival

1 year

Treatment Details

Interventions

• Cyclophosphamide
• Ruxolitinib

Trial Overview The study tests a combination of low-dose Cyclophosphamide (PTCy) and Ruxolitinib for preventing GVHD in older adults receiving stem cell transplants from matched donors, using reduced intensity conditioning therapy.

Participant Groups

Group I: Graft-versus-host disease prophylaxis Experimental Treatment 4 Interventions

Following reduced intensity conditioning and 8/8-matched peripheral blood transplant on Day 0, all patients will receive a GVHD prophylaxis post-transplant composed of the following: (i) cyclophosphamide administered at 25 mg/kg on Day +3 and +4, (ii) tacrolimus beginning on Day +5 and through Day +180 and administered with a trough target of 5-10 ng/ml through Day +90 and tapered thereafter; (iii) mycophenolate mofetil (MMF) administered at 15 mg/kg thrice daily beginning on Day +5 through Day +35; and (iv) ruxolitinib administered at 5 mg twice daily starting after engraftment (between Days +30 and +60) and continuing through one year post transplant.

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?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

Findings from Research

In a study of 8 patients with acute or chronic graft versus host disease (GVHD) who were unresponsive to standard treatments, ruxolitinib demonstrated a high overall response rate of 85%, with 50% achieving complete response.

Ruxolitinib was well-tolerated, indicating it could be a promising rescue therapy for patients suffering from refractory GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis. Sarmiento Maldonado, M., Ramírez Villanueva, P., Bertín Cortes-Monroy, P., et al.[2022]

Ruxolitinib prophylaxis showed a 41.2% incidence of acute graft-versus-host disease (aGVHD) in patients after modified donor lymphocyte infusion, indicating it can help reduce the severity of aGVHD in high-risk leukemia patients post-transplant.

Among the 17 patients studied, 58.8% achieved a complete response, suggesting that ruxolitinib may effectively maintain the graft-versus-leukemia (GVL) effect while managing aGVHD, despite a median follow-up of only 8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib on acute graft-versus-host disease prophylaxis after modified donor lymphocyte infusion. Tang, Y., Yang, D., Xie, R., et al.[2023]

Ruxolitinib (RUX) was well tolerated and led to significant improvements in chronic graft-versus-host disease (GVHD) symptoms in 19 allograft recipients, with high response rates in various affected areas, such as oral (92%) and cutaneous (82%) regions.

The treatment allowed for a reduction or discontinuation of steroid use in 68% of patients, demonstrating RUX's effectiveness as a steroid-sparing agent in managing chronic GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. Khoury, HJ., Langston, AA., Kota, VK., et al.[2021]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, was approved by the FDA for treating steroid-refractory acute graft-versus-host disease (GVHD) based on promising results from the Phase II REACH1 trial.

The drug shows potential not only for treating SR acute GVHD but also for preventing GVHD and possibly serving as a first-line therapy, highlighting its versatility in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of graft-versus-host disease. Ali, H., Salhotra, A., Modi, B., et al.[2021]

In a study of 29 patients with graft versus host disease (GvHD), Ruxolitinib exposure was found to be significantly higher than in myelofibrosis patients, indicating altered drug metabolism in GvHD.

Increased Ruxolitinib levels were linked to reduced drug clearance and the use of CYP3A4 or CYP2C9 inhibitors, suggesting that higher trough concentrations may indicate a risk of toxicity and necessitate careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial. Isberner, N., Kraus, S., Grigoleit, GU., et al.[2022]

In a study of 14 patients with myelofibrosis who received allogeneic hematopoietic cell transplantation after treatment with ruxolitinib, 71.4% experienced relief from myelofibrosis-related symptoms, and 64% had a significant reduction in spleen size.

Ruxolitinib treatment prior to transplantation was associated with a high engraftment rate of 93% and may improve outcomes by reducing inflammatory cytokines, potentially lowering the risk of graft failure and acute graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib. Jaekel, N., Behre, G., Behning, A., et al.[2021]

Ruxolitinib, a drug used to treat steroid-refractory acute graft-versus-host disease in allogeneic hematopoietic cell transplantation (HCT) recipients, can lead to acute hypoxemic respiratory failure upon discontinuation, as observed in three patients within three months of stopping the medication.

Reinitiating ruxolitinib along with systemic corticosteroids resulted in rapid clinical improvement for these patients, highlighting the need for careful management of ruxolitinib dosing and discontinuation to avoid serious respiratory complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypoxemic Respiratory Failure Following Ruxolitinib Discontinuation in Allogeneic Hematopoietic Cell Transplantation Recipients. Anandappa, AJ., Hobbs, GS., Dey, BR., et al.[2021]

In a retrospective study of 17 patients with severe graft-versus-host disease (GVHD) who were unresponsive to corticosteroids and other treatments, ruxolitinib demonstrated an 80% overall response rate in acute GVHD, with 40% achieving complete remission.

Ruxolitinib also showed a 79% response rate in chronic GVHD, indicating its potential as an effective rescue therapy; however, mortality in acute GVHD patients remained high at 40%, highlighting the need for improved treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real life use of ruxolitinib in patients with acute and chronic graft versus host disease refractory to corticosteroid treatment in Latin American patients. Sarmiento, M., Jara, V., Soto, K., et al.[2021]

In a study of 20 pediatric and young adult patients with chronic graft versus host disease (cGVHD), ruxolitinib showed a 70% overall response rate, with 2 patients achieving complete response and 12 achieving partial response after a median of 48 days.

The dosing strategy of ruxolitinib was effective in inhibiting JAK signaling, as indicated by decreased phosphorylation of STAT5 in lymphocytes, although some patients experienced side effects like neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the Treatment of Chronic GVHD and Overlap Syndrome in Children and Young Adults. Wang, YM., Teusink-Cross, A., Elborai, Y., et al.[2022]

References

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

Compassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Ruxolitinib on acute graft-versus-host disease prophylaxis after modified donor lymphocyte infusion. [2023]

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

Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of graft-versus-host disease. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib. [2021]

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

Hypoxemic Respiratory Failure Following Ruxolitinib Discontinuation in Allogeneic Hematopoietic Cell Transplantation Recipients. [2021]

8. Brazil pubmed.ncbi.nlm.nih.gov

A real life use of ruxolitinib in patients with acute and chronic graft versus host disease refractory to corticosteroid treatment in Latin American patients. [2021]

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

Ruxolitinib for the Treatment of Chronic GVHD and Overlap Syndrome in Children and Young Adults. [2022]