Cyclophosphamide + Ruxolitinib for Graft-versus-Host Disease Prophylaxis

Recruiting in Palo Alto (17 mi)

Overseen by Sameem M. Abedin

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Medical College of Wisconsin

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

No Placebo Group

Prior Safety Data

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.

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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.

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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.

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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

Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Froedtert Hospital & the Medical College of Wisconsin Milwaukee, WI

Who Is Running the Clinical Trial?

Medical College of Wisconsin Lead Sponsor

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] Ruxolitinib is a potent inhibitor of JAK1/2 with proven efficacy in myelofibrosis. In recent years, research in graft versus host disease (GVHD) has revealed the role of activation of JAK pathways in alloreactive lymphocytes. Some reports have shown significant responses in refractory GVHD patients.

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

Ruxolitinib on acute graft-versus-host disease prophylaxis after modified donor lymphocyte infusion. [2023] To evaluate the effectiveness of ruxolitinib on acute graft-versus-host disease (aGVHD) prophylaxis and its impact on graft-versus-leukemia (GVL) effect in patients after modified donor lymphocyte infusion (mDLI).

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

Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. [2021] Inhibition of the Janus-associated kinases (JAK) with ruxolitinib (RUX) reduces graft-versus-host disease (GVHD) in preclinical and clinical models. In total 19 allograft recipients with moderate/severe steroid-dependent chronic GVHD received RUX as ≥2nd line salvage. RUX was well tolerated, and led to complete/partial resolution of oral (92/7%), cutaneous (82/0%), hepatic (71/28%), gastro-intestinal (75/17%), musculoskeletal (33/67%), pulmonary (0/80%), scleroderma (0/75%), vaginal (0/75%), and ocular (0/100%) chronic GVHD. Overall 18 achieved partial response and 1 complete response according to NIH Consensus Criteria. Responses occurred early and were sustained which enabled discontinuation (68%) or reduction of steroids to physiologic doses (21%). We conclude that RUX is an effective steroid-sparing agent in chronic GVHD.

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

Ruxolitinib for the treatment of graft-versus-host disease. [2021] Introduction: Ruxolitinib is an oral selective JAK1/JAK2 inhibitor, initially approved by the FDA for the treatment of intermediate-2 or high-risk myelofibrosis and patients with polycythemia vera who have had an inadequate response or are intolerant to hydroxyurea.Areas covered: Accumulating evidence supports the role of JAK1/JAK2 pathways in the pathogenesis of graft-versus-host disease (GVHD), and preclinical studies have demonstrated promising efficacy of ruxolitinib in treatment/prevention of GVHD. Early clinical observations that ruxolitinib was effective in treatment of steroid-refractory (SR) acute and chronic GVHD led to the development of prospective clinical trials; Phase II REACH1 (NCT02953678), Phase III REACH2 (NCT02913261), and REACH3 (NCT03112603). Based on the data from the REACH1 trial, ruxolitinib was approved by the FDA in May 2019 for SR acute GVHD in adult and pediatric patients 12 years and older.Expert opinion: Ruxolitinib and other JAK1/JAK2 inhibitors hold promise in other treatment settings such as GVHD prevention and/or first-line therapy.

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] Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects.

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

Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib. [2021] The Janus-activated kinase 1 (JAK1) and JAK2 inhibitor ruxolitinib is effective in decreasing symptomatic splenomegaly and myelofibrosis (MF)-related symptoms. However, allogeneic hematopoietic cell transplantation (HCT) remains the only curative option. We evaluated the impact of ruxolitinib on the outcome after HCT. A cohort of 14 patients (median age 58 years) received a subsequent graft from related (n=3) and unrelated (n=11) donors after a median exposure of 6.5 months to ruxolitinib. At HCT, MF risk for survival according to the International Prognostic Scoring System was intermediate-2 or high risk in 86% of patients. Under ruxolitinib, MF-related symptoms were ameliorated in 10 (71.4%) patients and the palpable spleen reduced by a median of 41% in 7 (64%) of 11 patients with splenomegaly. Engraftment occurred in 13 (93%) patients. Acute GvHD grade-III occurred in 2 (14%) patients. Median follow-up was 9 months. Survival, EFS and treatment-related mortality were 78.6, 64 and 7%, respectively. Through the anti-JAK-mediated reduction in both cytokines and splenomegaly as well as improvement in performance status, ruxolitinib might improve outcome after allogeneic HCT in patients with MF. The downregulation of inflammatory cytokines might have a beneficial impact on graft failure and acute GvHD.

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

Hypoxemic Respiratory Failure Following Ruxolitinib Discontinuation in Allogeneic Hematopoietic Cell Transplantation Recipients. [2021] Ruxolitinib, a selective inhibitor of Janus kinases 1 and 2, is increasingly being used in allogeneic hematopoietic cell transplantation (HCT) recipients following its approval by the U.S. Food and Drug Administration for the treatment of steroid-refractory acute graft-versus-host disease. Although there is extensive experience using ruxolitinib for patients with myeloproliferative neoplasms, the biologic effects and clinical implications of its dosing, tapering, and discontinuation for allogeneic HCT recipients are incompletely characterized. We describe three allogeneic HCT recipients who developed acute hypoxemic respiratory failure within 3 months of ruxolitinib discontinuation. Radiographic findings included marked bilateral ground-glass opacities. Systemic corticosteroids and reinitiation of ruxolitinib resulted in rapid clinical improvement in all three patients. All three patients achieved a significant clinical response, with decrease in oxygen requirement and improvement in radiographic changes. Given the increasing use of ruxolitinib in allogeneic HCT recipients, there is significant impetus to characterize the biologic and clinical effects resulting from discontinuation of ruxolitinib, to better tailor treatment plans and prevent potential adverse effects.

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] Graft-versus-host disease (GVHD) is a serious complication in allogeneic transplantation. The first-line treatment is high doses of corticosteroids. In the absence of response to corticosteroids, several immunosuppressive drugs can be used, but they entail an elevated risk of severe infections. Added to this, there are patients who do not improve on any immunosuppressive treatment, with subsequent deteriorated quality of life and high mortality. Ruxolitinib has been shown to induce responses in refractory patients. In this study we have presented our real-life experience.

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

Ruxolitinib for the Treatment of Chronic GVHD and Overlap Syndrome in Children and Young Adults. [2022] Ruxolitinib, a JAK1/2 inhibitor, is used to treat chronic graft versus host disease (cGVHD) in adult allogeneic hematopoietic stem cell transplant patients, but experience in children is limited, perhaps because of lack of pediatric dosing information. In this report, we describe our pediatric and young adult dosing strategy experience in cGVHD.