This study is in progress, not accepting new patients

Use Of A Response-Adapted Ruxolitinib-Containing Regimen For The Treatment Of Hemophagocytic Lymphohistiocytosis

a study on Hemophagocytic Lymphohistiocytosis

Eligibility: for people ages up to 22 years (full criteria)
Location: at UCSF
Dates: study started July 2021
completion around August 2026

Description

Summary

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.

Details

Frontline Arm: Safety Phase and Expansion Phase

Safety Phase: The Frontline Arm will begin with a Safety Phase to identify a feasible and safe dose of ruxolitinib to be given in combination with the "gold standard" HLH-directed agents dexamethasone and etoposide using a response-adapted approach. For this part of the trial, a minimum of 6 newly diagnosed HLH patients will be included. These patients will first receive ruxolitinib 25 mg/m²/dose by mouth BID (twice a day) and dexamethasone 5 mg/m²/dose PO or IV BID. For patients whose HLH responds favorably (as outlined in the protocol), ruxolitinib will be continued for 8 weeks if it is tolerated. Dexamethasone will be weaned, as tolerated, over 8 weeks and then discontinued. For patients whose HLH does not respond favorably (as outlined in the protocol), etoposide 150 mg/m2 IV weekly will be added. The dose of ruxolitinib may be escalated or de-escalated as needed, based on observed toxicities and surrogates of disease response.

Expansion Phase: When a dose of ruxolitinib deemed feasible and safe is identified, the Expansion Phase of the Frontline Arm will begin. Patients with newly diagnosed HLH in the Expansion Phase will receive ruxolitinib (at the maximally tolerated dose [MTD] established in the Safety Phase) and dexamethasone 5 mg/m²/dose by mouth or IV BID. For patients whose HLH responds favorably (as outlined in the protocol), ruxolitinib will be continued for 8 weeks if it is tolerated. Dexamethasone will be weaned, as tolerated, over 8 weeks and then discontinued. For patients whose HLH does not respond favorably (as outlined in the protocol), etoposide 150 mg/m² IV weekly will be added. The first dose of dexamethasone will be given at least 8 hours after the first dose of ruxolitinib for PK testing purposes, but patients will not be excluded if dexamethasone has already been started before initiating of ruxolitinib. Disease response evaluations will be completed at 1, 2, 4, 6, and 8 weeks. Treatment will be individualized based on response.

Patients whose HLH responds favorably after 1 week (SD 8) of therapy (e.g., favorable response (FR), Week 1) will remain on ruxolitinib and dexamethasone. As long as patients show a CR or partial response (PR) at Week 2 (SD15), ruxolitinib and dexamethasone are tolerated, and patients are clinically stable, they will remain on both agents for the remainder of the 8-week study period. Dexamethasone will be weaned every 2 weeks as tolerated. In case of disease reactivation, therapy will be re-intensified.

Patients whose HLH responds unfavorably after 1 week (SD8) of therapy (e.g., unfavorable response, Week 1) will have etoposide added (150 mg/m²/dose, IV weekly). If patient meets CR or PR at Week 2 (SD15), then combination treatment with ruxolitinib, dexamethasone, and etoposide will be continued until Week 4 disease evaluation (SD 29). If patients have a CR or PR at the Week 4 disease evaluation (SD 29) or later, further etoposide doses may be held at site PI discretion. Dexamethasone weaning may continue beyond the 8-week study period. Patients whose HLH does not respond favorably (e.g., exhibit non-response (NR), progressive disease (PD)) despite treatment with ruxolitinib, dexamethasone, and etoposide will be taken off treatment and salvage therapy will be considered and decided by the treating physician.

Salvage Arm: Patients with relapsed/refractory HLH will be treated on the Salvage Arm. They will not be included in the Safety Phase but will use the same response-adapted approach. Patients may be enrolled on the Salvage Arm as the Safety Phase is ongoing. Patients will receive ruxolitinib 25 mg/m²/dose by mouth BID and dexamethasone 5 mg/m²/dose by mouth or IV BID. The first dose of dexamethasone will be given at least 8 hours after the first dose of ruxolitinib for PK testing purposes, but patients will not be excluded if dexamethasone has already been started before starting ruxolitinib. Disease response evaluations will be completed at 1, 2, 4, 6, and 8 weeks. Treatment will be individualized based on response as described for the Expansion Phase of the Frontline Arm. When the MTD of ruxolitinib has been determined on the Safety Phase of the Frontline Arm, it will be the dose used for any additional patients enrolled on the Salvage Arm. Any patients already on the Salvage Arm who show no adverse effects or toxicity at an assigned dose of 25 mg/m² BID will be continued on this dose for the 8 week study period.

HLH Reactivation: For patients who initially respond favorably but then worsen (e.g., "reactivate") during the later phases of induction when dexamethasone is weaned, dexamethasone will be increased back to 5 mg/m²/dose PO/IV BID (10 mg/m²/day). If the patient is on a reduced dose of ruxolitinib due to prior toxicity(ies), the ruxolitinib dose may be increased to patient's starting dose, provided the prior toxicity(ies) has resolved for at least 1 week. Patients whose HLH responds favorably will continue to receive ruxolitinib and dexamethasone or ruxolitinib, dexamethasone and etoposide. Patients receiving ruxolitinib, dexamethasone and etoposide whose HLH responds unfavorably will be taken off treatment and be considered for an alternative salvage therapy. For patients receiving ruxolitinib and dexamethasone whose HLH responds unfavorably, etoposide may be added. If the response is favorable, the patient will continue on all 3 medications. If the response is unfavorable after adding etoposide, the patient will be taken off treatment and will be considered for an alternative salvage therapy.

All patients with CNS disease will receive intrathecal (IT) MTX and hydrocortisone (HC), per age-based dosing, once per week for up to 4 weeks.

Patients will be followed for one year after starting protocol therapy or 1 year after HSCT (for those undergoing HSCT).

Keywords

Hemophagocytic Lymphohistiocytosis, Newly Diagnosed, Frontline therapy, Refractory, Relapsed, Response-adapted, Salvage therapy, Dexamethasone, Etoposide, Etoposide phosphate, Ruxolitinib

Eligibility

You can join if…

Open to people ages up to 22 years

Frontline Arm:

Patient is ≥6 weeks and ≤22 years of age.
Patient weighs ≥3 kg.
Patient is able to take medication PO and/or patient or parent is willing to have NG tube placed if patient is unable to take medications PO.
Patient has active HLH if:
- Patient has ≥5 of 8 Diagnostic HLH criteria listed below, OR
- Patient has known fHLH (e.g., patient has pathogenic/likely pathogenic germline variant(s) in genes such as PRF1, UNC13D, STX11, STXBP2, LYST, RAB27A, XIAP, SH2D1A, NLCR4) and meets ≥4 of the diagnostic HLH criteria listed below, OR
- Patient has high likelihood of fHLH based on absent perforin, SAP, XIAP expression and meets ≥4 of the Diagnostic HLH Criteria listed below:
  - Fever
  - Splenomegaly (If present at any point prior to starting study drug)
  - Cytopenias affecting ≥2 of 3 cell lineages in the peripheral blood (hemoglobin <9 g/dL, platelets <100 × 10⁹/L, ANC <1000/mm³)
  - Hypertriglyceridemia (fasting triglycerides ≥265 mg/dL) or hypofibrinogenemia (fibrinogen ≤150 mg/dL)
  - Presence of hemophagocytosis in BM or other tissues
  - Low or absent NK-cell activity (if present at any point prior to starting study drug) OR decreased CD107a mobilization (if present at any point prior to starting study drug)
  - Ferritin ≥500 ng/mL
  - Soluble IL-2 receptor (CD25) ≥2400 U/mL
Patient has not received prior HLH therapy, except steroids (any dose or length of therapy is allowed) OR anakinra (any dose or length of therapy is allowed).
Patient, parent, or legal authorized representative (LAR) must provide informed consent.

Inclusion Criteria: Salvage Arm:

Patient is ≥6 weeks and ≤22 years of age.
Patient weighs ≥3 kg.
Patient or parent is willing to have the NG tube placed if patient is unable to take medications PO.
Patient has past history of HLH, defined as meeting ≥5 of 8 HLH- 2004 diagnostic criteria for those with no known HLH-associated mutations, OR ≥4 of 8 HLH-2004 diagnostic criteria for those with known familial disease.
Patient must have active HLH at the time of eligibility assessment, defined as 3 or more of the following Relapsed/Refractory HLH Criteria:
- Fever
- Splenomegaly (recurrent or worsening)
- ANC <1000/mm³ × 2 assessments over at least 3 days OR platelets <100 × 10⁹/L × 2 assessments over at least 3 days, OR need for platelet transfusions
- Hypofibrinogenemia (fibrinogen ≤150 mg/dL)
- Soluble IL-2 receptor level ≥ 2400 U/mL
- Worsening CNS symptoms OR new abnormal brain magnetic resonance imaging (MRI) findings deemed consistent with CNS HLH by the primary treating physician OR CSF cell count ≥5 mm³ (with or without hemophagocytosis) OR CSF protein higher than the institutional upper limit of normal OR CSF neopterin higher than the institutional upper limit of normal
- Presence of hemophagocytosis in the BM or other tissues
- Increasing ferritin × 2 assessments over at least 3 days (both levels must be ≥2000 ng/mL)
Patient must be deemed by the primary treating physician to have not responded to prior therapy by either not having or maintaining a response
Patient must have received prior HLH-directed therapy:
- At least 2 weeks of steroids (equivalent to at least 5 mg/m²/day dexamethasone or 1 mg/kg/day methylprednisolone) AND at least 2 doses of etoposide; OR
- At least 1 dose of ATG
Patient or parent/LAR must provide informed consent.

Laboratory findings must be given on at least 2 assessments, each completed at least 1 day apart, EXCEPT CNS radiologic/laboratory findings in which a single abnormal value is sufficient.

You CAN'T join if...

Frontline and Salvage Arms:

Patient is <6 weeks or >22 years of age.
Patient weighs <3 kg.
Patient has isolated CNS disease.
Life expectancy is <2 weeks.
Patient is likely to require <4 weeks of therapy (i.e., HSCT is imminent).
Patients with creatinine clearance (CrCl) <15 mL/min who are NOT receiving dialysis.
Patient has evidence of severe organ dysfunction, defined as: Severe liver dysfunction (ALT >1000 U/L), OR Cardiorespiratory failure requiring any ionotropic support OR extracorporeal life support, OR high frequency oscillatory ventilation, other forms of respiratory support or ventilation are allowed if the patient is not on vasopressors)
Patient with pre-existing rheumatologic disorder.
Patient with known active malignancy.
Patient with previous HSCT, except when HSCT was for treatment of HLH.
Patient is pregnant or lactating.
Patients who expect to conceive or father children within the projected duration of the study and/or who are unwilling to use highly effective methods of contraception throughout the duration of the study, starting with the screening visit through the end of the treatment visit.
Patient has suspected or known fungal disease.
Patient is unable to tolerate administration of drugs PO or NG.
Patient is taking rifampin or St. John's Wort.
Patient is taking another investigational agent or is enrolled on another treatment protocol.
Patient, parent, or LAR are unable or unwilling to provide informed consent.

Additional Exclusion Criteria for the Frontline Arm:

Patient has or is receiving treatment with a JAK inhibitor (including ruxolitinib), ATG, alemtuzumab, etoposide, tocilizumab, emapalumab or any other HLH-directed therapy other than steroids or anakinra (as defined in the Frontline Arm Inclusion Criteria, #5).

Additional Exclusion Criteria for the Salvage Arm:

Patient has or is receiving treatment with a JAK inhibitor (including ruxolitinib) or alemtuzumab within the last 3 months.
Patient has received therapy on the Frontline Arm of this trial.

Locations

University of California San Francisco
San Francisco California 94158 United States
Children's Hospital of Orange County
Orange California 92868 United States

Details

Status: in progress, not accepting new patients
Start Date: July 2021
Completion Date: August 2026 (estimated)
Sponsor: St. Jude Children's Research Hospital
Links: St. Jude Children's Research Hospital ClinicalTrials Open at St. Jude
ID: NCT04551131
Phase: Phase 1/2 Hemophagocytic Lymphohistiocytosis Research Study
Study Type: Interventional
Participants: About 10 people participating
Last Updated: February 17, 2025