Ruxolitinib-Based Regimen for Hemophagocytic Lymphohistiocytosis

Recruiting at 14 trial locations

Overseen By Kim E. Nichols, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Rifampin, St. John's Wort

Disqualifiers: Rheumatologic disorder, Active malignancy, others

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

Compensation: Varies

Number of Visits: 2

10 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 you cannot participate if you are taking rifampin, St. John's Wort, or another investigational agent. If you are on these, you may need to stop them before joining the trial.

What data supports the effectiveness of the drug Ruxolitinib for treating hemophagocytic lymphohistiocytosis?

Research shows that Ruxolitinib, when used in combination with other drugs, has been effective in treating hemophagocytic lymphohistiocytosis (HLH), with studies reporting high response rates and improved survival in patients. It has been particularly noted for its ability to modulate cytokines (proteins important in cell signaling) and has shown promise in both primary and secondary forms of HLH. ^{1 2 3 4 5}

Is the Ruxolitinib-based regimen safe for treating hemophagocytic lymphohistiocytosis?

Ruxolitinib has been used in various studies for treating hemophagocytic lymphohistiocytosis (HLH) and is generally considered safe, with patients tolerating it well. The most common side effects are related to blood cell counts, but it has shown potential to reduce the intensity of chemotherapy needed. ^{2 3 5 6 7}

What makes the Ruxolitinib-based drug regimen unique for treating hemophagocytic lymphohistiocytosis?

The Ruxolitinib-based regimen is unique because it includes Ruxolitinib, a drug that modulates cytokines (proteins important in cell signaling) and has a safer profile compared to traditional high-dose treatments. This regimen can reduce the intensity of chemotherapy needed and is effective as a bridge to stem-cell transplantation, especially in children with primary hemophagocytic lymphohistiocytosis. ^{1 2 3 5 7}

What is the purpose of this trial?

This study is a multi-site Phase Ib/II, 2-arm non-randomized clinical trial to determine the efficacy and tolerability of a response-adapted regimen combining ruxolitinib, dexamethasone, and etoposide as Frontline therapy for patients with newly diagnosed hemophagocytic lymphohistiocytosis (HLH) or as Salvage therapy for patients with relapsed/refractory HLH. Primary Objective * To determine the efficacy and tolerability of a response-adapted ruxolitinib-containing regimen for patients with newly diagnosed HLH. Secondary Objectives * To describe the efficacy and tolerability of a response-adapted ruxolitinib-containing regimen for patients with relapsed/refractory HLH. * To describe the overall response and outcome for patients with newly diagnosed or relapsed/refractory HLH who are treated with this response-adapted ruxolitinib-containing regimen. Exploratory Objectives * To estimate the pharmacokinetic (PK) parameters of ruxolitinib, assess covariates of ruxolitinib pharmacokinetics, and test whether the drug's effectiveness is correlated with systemic drug exposure. * To query specific immunologic biomarkers and determine whether the levels of these biomarkers correlate with disease response and outcome.

Research Team

Melissa Hines, MD

Principal Investigator

St. Jude Children's Research Hospital

Kim E. Nichols, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for patients aged 6 weeks to 22 years with newly diagnosed or relapsed/refractory Hemophagocytic Lymphohistiocytosis (HLH). They must weigh at least 3 kg and be able to take oral medication or agree to an NG tube. Participants should meet specific HLH diagnostic criteria but not have received certain prior treatments, except steroids or anakinra. Pregnant individuals, those with severe organ dysfunction, active malignancy, or on other investigational drugs are excluded.

Inclusion Criteria

Patient, parent, or legal authorized representative (LAR) must provide informed consent.

I am willing to use a feeding tube if I can't take medicine by mouth.

I have a genetic form of HLH and meet at least 4 of its diagnostic criteria.

Exclusion Criteria

I have been treated with a JAK inhibitor or alemtuzumab in the last 3 months.

My liver is not severely damaged (ALT not over 1000 U/L).

I have an active cancer diagnosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Phase

Identify a feasible and safe dose of ruxolitinib in combination with dexamethasone and etoposide for newly diagnosed HLH patients

8 weeks

Weekly visits for dose adjustments and response evaluations

Expansion Phase

Administer ruxolitinib at the maximally tolerated dose with dexamethasone, adding etoposide based on response

8 weeks

Visits at 1, 2, 4, 6, and 8 weeks for disease response evaluations

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Regular follow-up visits up to 1 year after starting protocol therapy or HSCT

Treatment Details

Interventions

• Dexamethasone
• Etoposide
• Ruxolitinib

Trial Overview The study tests a regimen combining Ruxolitinib with Dexamethasone and Etoposide in two scenarios: as initial treatment for new HLH cases (Frontline therapy) and as secondary treatment when previous therapies failed (Salvage therapy). It's a Phase Ib/II trial aiming to assess the efficacy and tolerability of this combination while also exploring pharmacokinetics and immunologic biomarkers.

Participant Groups

Group I: Salvage Arm Experimental Treatment 3 Interventions

Patients with relapsed/refractory HLH will receive ruxolitinib PO or NGT and dexamethasone PO or IV. Etoposide IV will be added based on disease response.

Group II: Frontline Arm Experimental Treatment 3 Interventions

Safety Phase: Patients with newly diagnosed HLH will receive ruxolitinib PO or NGT and dexamethasone, PO or IV. Etoposide IV will be added based on disease response. Expansion Phase: Patients with newly diagnosed HLH treatment will begin with ruxolitinib PO or NGT at the MTD dose. Dexamethasone will be administered PO or IV. Etoposide IV will be added based on disease response.

Dexamethasone is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

North American Consortium for Histiocytosis

Collaborator

Trials

5

Recruited

1,700+

Cures Within Reach

Collaborator

Trials

25

Recruited

2,100+

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

Findings from Research

In a study of 70 patients with lymphoma-associated hemophagocytic syndrome (LAHS), the R-DED treatment regimen (which includes ruxolitinib) significantly improved clinical responses, with an 83.3% response rate at 2 weeks compared to 54.8% for the HLH-94 regimen.

Patients treated with the R-DED regimen also had a significantly longer overall survival (5 months) compared to those on HLH-94 (1.5 months), indicating that ruxolitinib may enhance treatment efficacy without increasing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib combined with doxorubicin, etoposide, and dexamethasone for the treatment of the lymphoma-associated hemophagocytic syndrome. Zhou, L., Liu, Y., Wen, Z., et al.[2021]

Baricitinib, a JAK1/JAK2 inhibitor, was effective in treating a case of hemophagocytic lymphohistiocytosis (HLH) that did not respond to traditional treatments like glucocorticoids and cyclosporine.

This case suggests that JAK inhibitors like baricitinib may offer a promising alternative treatment for treatment-resistant HLH, highlighting the need for further research to confirm its efficacy in larger patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of hemophagocytic lymphohistiocytosis with a significant response to baricitinib: a first report with review of literature. Irino, K., Jinnouchi, F., Nakano, S., et al.[2023]

Ruxolitinib, a JAK1/2 inhibitor, showed rapid and sustained improvement in four adult patients with secondary hemophagocytic lymphohistiocytosis (HLH), indicating its efficacy in managing this severe condition.

While three patients experienced manageable infections after treatment, the overall safety profile of ruxolitinib appears favorable, making it a promising option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib as adjunctive therapy for secondary hemophagocytic lymphohistiocytosis: A case series. Hansen, S., Alduaij, W., Biggs, CM., et al.[2021]

In a pilot study involving five adults with secondary hemophagocytic lymphohistiocytosis, ruxolitinib demonstrated a 100% overall survival rate at 2 months, indicating its potential efficacy as a treatment.

Ruxolitinib was well tolerated, with improvements in symptoms and laboratory abnormalities observed in all patients, and only one serious adverse event reported, suggesting it may be a safe option for managing this severe inflammatory syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. Ahmed, A., Merrill, SA., Alsawah, F., et al.[2021]

Ruxolitinib was effective in treating refractory hemophagocytic lymphohistiocytosis (HLH) in two children after hematopoietic cell transplantation, leading to resolution of symptoms like fever and hyperferritinemia.

The treatment also showed a positive impact on the cytokine storm associated with HLH, suggesting that ruxolitinib could be a promising therapeutic option for this severe complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for hematopoietic cell transplantation-associated hemophagocytic lymphohistiocytosis. Ono, R., Ashiarai, M., Hirabayashi, S., et al.[2021]

References

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

Ruxolitinib-combined doxorubicin-etoposide-methylprednisolone regimen as a salvage therapy for refractory/relapsed haemophagocytic lymphohistiocytosis: a single-arm, multicentre, phase 2 trial. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Ruxolitinib combined with doxorubicin, etoposide, and dexamethasone for the treatment of the lymphoma-associated hemophagocytic syndrome. [2021]

3. Italy pubmed.ncbi.nlm.nih.gov

Ruxolitinib-based regimen in children with primary hemophagocytic lymphohistiocytosis. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

A case of hemophagocytic lymphohistiocytosis with a significant response to baricitinib: a first report with review of literature. [2023]

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

Ruxolitinib as adjunctive therapy for secondary hemophagocytic lymphohistiocytosis: A case series. [2021]

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

Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. [2021]

7. Japan pubmed.ncbi.nlm.nih.gov

Ruxolitinib for hematopoietic cell transplantation-associated hemophagocytic lymphohistiocytosis. [2021]