Ruxolitinib for Sickle Cell Disease

(RUX-HAPLO Trial)

Not yet recruiting at 3 trial locations

Overseen By Laura McLaughlin, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Colorado, Denver

Must not be taking: Ruxolitinib metabolism interferers

Disqualifiers: HLA-matched sibling, Uncontrolled infection, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding ruxolitinib, a JAK inhibitor, to a treatment plan can reduce complications after a bone marrow transplant for individuals with sickle cell disease, a condition characterized by misshaped red blood cells. The goal is to determine if this approach can lower the risk of transplant failure for those undergoing a specific type of transplant using a relative's bone marrow. The trial seeks participants aged 12 to 45 with sickle cell disease who experience recurrent pain events or require regular blood transfusions. Participants must also have a close family member who can donate bone marrow. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Is there any evidence suggesting that ruxolitinib is likely to be safe for humans?

Studies have shown that ruxolitinib is generally well-tolerated, although some serious side effects have been reported. One study found serious side effects in 46.4% of participants. This indicates that while many people did not encounter major problems, some experienced serious issues.

Ruxolitinib has already received approval for other uses, indicating it has passed safety tests for those conditions. However, using it in new ways, as in this study, might present different risks. Weighing the potential benefits against the risks is important. Always consult a healthcare provider to understand what these findings could mean. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sickle cell disease?

Unlike the standard treatments for sickle cell disease, which often focus on managing symptoms or preventing complications, Ruxolitinib offers a novel approach by targeting the JAK-STAT pathway. This pathway is involved in inflammatory and immune responses, and its modulation could help reduce the inflammation and immune activation associated with sickle cell disease. Researchers are excited because Ruxolitinib might not only improve symptoms but also enhance the effectiveness of haploidentical hematopoietic cell transplantation (HCT), potentially offering a more comprehensive treatment strategy for patients.

What evidence suggests that ruxolitinib might be an effective treatment for sickle cell disease?

Research has shown that ruxolitinib might help treat sickle cell disease (SCD) by raising levels of fetal hemoglobin (HbF). More HbF can prevent red blood cells from becoming sickle-shaped, a major issue in SCD. Studies suggest that ruxolitinib can also reduce inflammation, which may help manage SCD symptoms. Additionally, it has been found to potentially decrease spleen size, improving overall blood health. While more research is needed, these findings suggest that ruxolitinib could be a promising treatment for SCD. Participants in this trial will receive ruxolitinib as part of a Ruxolitinib-Enhanced RIC regimen, which includes additional treatments for those undergoing haplo HCT for SCD. ^{2 4 5 6 7}

Who Is on the Research Team?

Laura McLaughlin, MD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for children and young adults with Sickle Cell Disease who are undergoing a haploidentical hematopoietic cell transplant. Participants should be suitable for the transplant procedure and meet specific health criteria set by the study.

Inclusion Criteria

Participants with any genotypic form of SCD aged 12 - 45 years at enrollment with ≥1 of the following: History of stroke and/or vasculopathy, including evidence of asymptomatic cerebrovascular disease for pediatric patients; Recurrent moderate-severe acute chest syndrome (ACS); Recurrent vaso-occlusive pain episodes requiring parenteral analgesia despite the institution of supportive care; Need for chronic transfusion therapy to prevent vaso-occlusive complications (i.e. pain, stroke, and ACS); For adult patients, an echocardiographic finding of tricuspid valve regurgitant jet velocity (TRJV) ≥ 2.7 m/sec; Participants must have an HLA haploidentical first degree relative (parent, sibling, or half sibling) who is willing and able to donate bone marrow; Participants must meet institutional eligibility criteria for HCT

Exclusion Criteria

Presence of an HLA-matched sibling who is willing and able to donate bone marrow; Uncontrolled infection, evidence of active TB, Hepatitis B or C infection, or HIV seropositivity or infection; Previous HCT or solid organ transplant; CNS revascularization procedure, myocardial infarction, pulmonary embolus or deep vein thrombosis in the past 6 months; Use of medications which significantly interfere with ruxolitinib metabolism; Known hypersensitivity or severe reaction to ruxolitinib or any component of the conditioning regimen or its excipients; Inability to swallow and retain oral medication (use of nasogastric or gastrostomy tube permitted); History of malignancy except resected basal cell carcinoma or treated carcinoma in-situ; Participation in another clinical trial involving an investigational or off-label use of a drug or device in the past 3 months; Currently pregnant or breast feeding; Clinically significant, uncontrolled autoimmune disease; High-titer anti-donor specific HLA antibodies (without review and approval by Study Chair); Participant (or guardian) inability or unwillingness to comply with the dose schedule and study evaluations, comprehend or sign informed consent and utilize a highly effective method of contraception (for participants of child-bearing potential); Any condition that would, in the investigator's judgment, interfere with full participation in the study, pose a significant risk to the subject, or interfere with interpretation of study data.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cytoreduction

Participants receive cytoreduction with hydroxyurea for at least 60 days prior to the start of conditioning

8-9 weeks

Conditioning

Participants receive a reduced intensity conditioning regimen consisting of cyclophosphamide, fludarabine, thiotepa, ATG, and TBI, along with ruxolitinib

9 days

Hematopoietic Cell Transplantation (HCT)

Participants undergo haploidentical hematopoietic cell transplantation

1 day

Post-Transplantation

Participants receive post-transplant cyclophosphamide and sirolimus or a calcineurin inhibitor for GVHD prophylaxis, and continue ruxolitinib

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness, including graft failure, GVHD, and other complications

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Ruxolitinib

Trial Overview The trial is testing if adding Ruxolitinib to a reduced intensity conditioning regimen before a stem cell transplant can lower the risk of graft failure in patients with Sickle Cell Disease.

How Is the Trial Designed?

Group I: Ruxolitinib-Enhanced RIC Experimental Treatment 1 Intervention

Pediatric and young adult participants who are undergoing haplo HCT for SCD will receive RIC with fludarabine, cyclophosphamide, thiotepa, ATG and low-dose TBI along with ruxolitinib. Ruxolitinib will continue post-HCT in addition to post-transplant cyclophosphamide and sirolimus or a calcineurin inhibitor for GVHD prophylaxis.

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Emory University

Collaborator

Trials

1,735

Recruited

2,605,000+

Children's Healthcare of Atlanta

Collaborator

Trials

172

Recruited

108,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT07252050?aggFilters=status%3A%2Cphase%3A

Ruxolitinib-Enhanced Haplo HCT for Children and Young ... This trial will determine whether adding ruxolitinib to a reduced intensity conditioning (RIC) regimen reduces the rate of graft failure ...

2. mdpi.com mdpi.com/2039-4365/9/1/8101

Efficacy of Ruxolitinib as Inducer of Fetal Hemoglobin in ... In this study we evaluated the efficacy of ruxolitinib as inducer of HbF production. The analyses were performed in cultured erythroid progenitors.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11960486/

Clinical Outcomes Among Patients With Sickle Cell ... The purpose of this study is to synthesize evidence on disease-specific outcomes in patients with sickle cell disease (SCD) or transfusion-dependent beta- ...

4. ashpublications.org ashpublications.org/blood/article/126/23/2048/105216/Study-on-the-Efficacy-of-a-JAK-Inhibitor

Study on the Efficacy of a JAK Inhibitor Pharmacological Agent ... Our study suggests that ruxolitinib could be considered an inducer of HbF and could be used in vivo for the treatment of hemoglobinopathies.

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/abs/10.1002/pbc.29338

Efficacy and safety of ruxolitinib in ineffective erythropoiesis ... After the first 3 months of ruxolitinib therapy, spleen volume decreased in 9 of 10 cases by 9.1%-67.5% (M = 35.4%) compared with the initial ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT07252050?aggFilters=status%3Anot%2Cphase%3A%2CfunderType%3Aindustry

Ruxolitinib-Enhanced Haplo HCT for Children and Young ... The primary objective is to estimate 1-year event-free survival (EFS) with primary or secondary GF or death counting as events for this endpoint ...

7. astctjournal.org astctjournal.org/article/S1083-8791(18)31084-X/fulltext

Safety Analysis of Patients Who Received Ruxolitinib for ... The mean (range) duration of treatment was 79.6 (1–326) days. SAEs were reported in 13 patients (46.4%).