Ruxolitinib With De-Intensified HLH-94 for the Treatment of Hemophagocytic Lymphohistiocytosis (HLH)

NCT06160791 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 232513NCI-2023-09578
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 3

Brief Summary

This phase II trial tests the effects of ruxolitinib in combination with a de-intensified HLH-94 drug regimen has on patients with newly diagnosed hemophagocytic lymphohistiocytosis (HLH), a disorder caused by dysregulated immune responses (that is, immune responses that are too strong and cause inflammatory damage to normal tissues). The therapy used for HLH decreases the activity of the immune system. Ruxolitinib is a type of drug called a kinase inhibitor. It works by blocking the signals that cause inflammatory cells to multiply. De-intensified HLH-94 is a treatment regimen that includes 4 weeks of dexamethasone with the dose being decreased each week, and up to 4 weeks of etoposide. This combination is commonly used to treat HLH. Dexamethasone is a steroid medication that works by fighting inflammation. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill cancer cells and is used to kill the types of white blood cells in HLH that are attacking the body. Giving ruxolitinib in combination with a de-intensified HLH-94 drug regimen may reduce toxic exposure to therapy while maintaining efficacy in patients with HLH.

Conditions

Hemophagocytic Lymphohistiocytoses

Keywords

HLH-94

Outcome Measures

Primary Outcomes (1)

• Overall response rate (ORR)

  The proportion of responder (complete response (CR), complete response with incomplete hematologic recovery, or partial response (PR)) or non-responder at the end of induction using a physician developed response criteria will be reported. Those with non-malignant HLH (nmHLH) will be assessed for response, defined as complete response (CR) + partial response (PR) at 4 weeks. Participants diagnosed with a malignant trigger are recommended to undergo cancer-directed therapy once acute hypercytokinemia improves. The primary endpoint for malignant HLH (mHLH) is achievement of PR or better and initiation of cancer-directed therapy (non-HLH specific therapy) by 4 weeks.

  4 weeks

Secondary Outcomes (9)

• Proportion of participants reporting high-grade adverse events

  Up to 1 year

• Best Response Rate

  Up to 1 year

• Median Time to Best Response

  Up to 12 months after the end of continuation therapy, approximately 2 years total

• Median Duration of Best Response

  Up to 12 months after the end of continuation therapy, approximately 2 years total

• Median progression free survival (PFS)

  Up to 1 year

Study Arms (1)

Treatment (ruxolitinib, dexamethasone, etoposide)

EXPERIMENTAL

During induction therapy, participants receive ruxolitinib orally (PO) twice daily (BID) plus de-intensified HLH-94 induction with dexamethasone PO or intravenously (IV) once daily (QD) or BID for 4 weeks and etoposide IV twice a week (BIW) for 2 weeks and then based on response, once a week (QW) for another 2 weeks in the absence of disease progression or unacceptable toxicity. After induction therapy, participants receive continuation therapy with ruxolitinib PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for a total of up to 6 months after first administration of study drug in the absence of disease progression or unacceptable toxicity.

Drug: Ruxolitinib; Drug: Etoposide; Drug: Dexamethasone; Procedure: Non-interventional Imaging; Procedure: Research Biopsy; Procedure: Biospecimen Collection

Interventions

Ruxolitinib DRUG

Administered Orally (PO)

Also known as: INCB18424, Oral JAK

Treatment (ruxolitinib, dexamethasone, etoposide)

Etoposide DRUG

Administered IV

Also known as: Toposar, Lastet

Treatment (ruxolitinib, dexamethasone, etoposide)

Dexamethasone DRUG

Administered PO or IV

Also known as: Dexa

Treatment (ruxolitinib, dexamethasone, etoposide)

Research Biopsy PROCEDURE

Bone marrow biopsy and lymph node biopsy will be obtained during screening and as clinically indicated throughout the trial.

Also known as: Biopsy

Treatment (ruxolitinib, dexamethasone, etoposide)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Specimen collection

Treatment (ruxolitinib, dexamethasone, etoposide)

Non-interventional Imaging PROCEDURE

Participants undergo abdominal ultrasound and/or magnetic resonance imaging (MRI)

Also known as: Ultrasound, Magnetic resonance imaging (MRI)

Treatment (ruxolitinib, dexamethasone, etoposide)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to understand and the willingness to sign a written informed consent document.
• Males and females, 18 years of age or older at the time of enrollment.
• Participants must have active HLH and meet \>= 5 of 8 of the HLH-2004 diagnostic criteria, or have familial/primary HLH with pathogenic/likely pathogenic germline variant(s) in genes known to cause HLH (e.g., PRF1, UNC13D, Syntaxin 11 (STX11), Syntaxin-binding protein 2 (STXBP2), RAB27A, SH2 domain-containing protein 1A (SH2D1A), baculovirus inhibitor of apoptosis repeat containing protein 4 (BIRC4), Lysosomal trafficking regulator (LYST), interleukin-2-inducible T-cell kinase (ITK), SLC7A7, X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN), Hermansky-Pudlak syndrome (HPS), NLR family CARD domain-containing protein 4 (NLCR4) or other immune regulatory genes.
• Fever \>= 38.5 degrees Celsius (C) (or \>= 38 degrees C if acetaminophen given in prior 6 hours).
• Splenomegaly.
• Peripheral cytopenias involving \>= 2 of 3 cell lines (absolute neutrophil count \< 1000/uL; hemoglobin \< 9 g/dL; platelets \< 100,000/uL).
• Hypertriglyceridemia (fasting triglycerides \>= 265 mg/dL) or Hypofibrinogenemia (fibrinogen =\< 150 g/dL).
• Hemophagocytosis on tissue biopsy, such as in the bone marrow, spleen, lymph node, or liver.
• Low/absent natural killer (NK)-cell activity/perforin and/or decreased CD107a mobilization.
• Ferritin \>= 500 ug/L.
• Soluble IL-2 receptor (sCD25) \> 2400 U/mL or two standard deviations above age-adjusted laboratory-specific norms.
• The effects of ruxolitinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception for the duration of study participation and for two months after last administration of study treatment.
• Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and two months after last administration of study treatment.

You may not qualify if:

• Participant is receiving or received any other investigational agent within 1 week of the first dose of treatment.
• Females who are pregnant or breastfeeding. Female participants of child-bearing potential must have a negative pregnancy test within 7 days of treatment and lactating females must discontinue breast feeding during treatment and until two weeks after the final dose of ruxolitinib.
• Males who expect to conceive children, and/or who decline highly effective methods of contraception during the entire duration of the study.
• Patient cannot take medications orally or via a nasogastric/orogastric tube.
• Poor life expectancy \< 2 weeks.
• Clinically significant or uncontrolled cardiovascular disease, including unstable angina, acute myocardial infarction, or stroke within 6 months, New York Heart Association class III or IV. congestive heart failure, and arrhythmia requiring therapy or uncontrolled hypertension (blood pressure \> 170/100 mmHg) unless approved by the sponsor- investigator.
• Estimated creatine clearance (CrCl) \< 15 mL/min while not on dialysis.
• Known (biopsy-confirmed) liver cirrhosis or suspected cirrhosis with a Model for End- Stage Liver Disease (MELD) score of \> 20, or aspartate aminotransferase (AST) or alanine transaminase (ALT) values \> 1000 not expected to improve with HLH therapy.
• Severe organ dysfunction, such as cardiorespiratory failure requiring inotropic medications or extracorporeal life support. Respiratory support including intubation/ventilation is allowed.
• \* Vasopressors are allowed if not required other than low dose vasoconstrictors to compensate the effects of sedation.
• Newly diagnosed acute and clinically active tuberculosis, hepatitis B, and/or hepatitis C.
• Patients with active human immunodeficiency virus (HIV) are not excluded from this study but must be on antiretrovirals.
• Patients with hepatitis B or C viremia can be on study if the hepatitis is not considered clinically active and/or if it is chronic. These patients should be discussed with the principal investigator.
• Individuals with a prior malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
• Individuals with chimeric antigen receptor (CAR)-T-associated HLH.

Sponsors & Collaborators

• Incyte Corporation: collaborator
• Jerry Lee, MD, MSc, MPhil: lead
• UC Hematological Malignancies Consortium (UCHMC): collaborator

Study Sites (3)

University of California, Irvine

Irvine, California, 92697, United States

RECRUITING

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

RECRUITING

University of California, San Francisco

San Francisco, California, 94143, United States

RECRUITING

MeSH Terms

Conditions

Lymphohistiocytosis, Hemophagocytic

Interventions

ruxolitinib; Janus Kinases; Etoposide; Dexamethasone; Absorptiometry, Photon; High-Energy Shock Waves; Magnetic Resonance Spectroscopy; Biopsy; Specimen Handling

Condition Hierarchy (Ancestors)

Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Protein-Tyrosine Kinases; Protein Kinases; Phosphotransferases (Alcohol Group Acceptor); Phosphotransferases; Transferases; Enzymes; Enzymes and Coenzymes; Intracellular Signaling Peptides and Proteins; Proteins; Amino Acids, Peptides, and Proteins; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Radiography; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Densitometry; Photometry; Chemistry Techniques, Analytical; Investigative Techniques; Ultrasonic Waves; Sound; Radiation, Nonionizing; Radiation; Physical Phenomena; Spectrum Analysis; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative

Study Officials

• Jerry Lee, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

UCSF Hematopoietic Malignancies Clinical Trial Recruitment

CONTACT

877-827-3222; HDFCCC.Heme@ucsf.edu

Claudia Ramos

CONTACT

Claudia.Ramos@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Clinical Professor

Study Record Dates

• First Submitted: November 29, 2023
• First Posted: December 7, 2023
• Study Start: October 1, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): November 30, 2029
• Last Updated: April 13, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

US (3)