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

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ClinicalTrials.gov Identifier: NCT04551131
Recruitment Status : Recruiting
First Posted : September 16, 2020
Last Update Posted : July 28, 2021
Sponsor:
Collaborators:
Incyte Corporation
North American Consortium for Histiocytosis
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Brief 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.

Condition or disease Intervention/treatment Phase
Hemophagocytic Lymphohistiocytosis Drug: Ruxolitinib Drug: Dexamethasone Drug: Etoposide Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Use Of A Response-Adapted Ruxolitinib-Containing Regimen For The Treatment Of Hemophagocytic Lymphohistiocytosis
Actual Study Start Date : July 13, 2021
Estimated Primary Completion Date : August 2025
Estimated Study Completion Date : August 2026


Arm Intervention/treatment
Experimental: Frontline Arm

Safety Phase:

Patients with newly diagnosed HLH will receive ruxolitinib PO or NGT, dexamethasone, PO or IV and etoposide IV.

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.

Drug: Ruxolitinib
Given orally (PO) or per nasogastric tube (NGT) twice a day for 8 weeks
Other Name: Jakafi®

Drug: Dexamethasone
Given intravenously (IV) or orally (PO) twice a day for 8 weeks
Other Names:
  • Decadron®
  • Hexadrol®
  • Dexone®
  • Dexameth®

Drug: Etoposide
Given intravenously (IV) once a week for 8 weeks
Other Names:
  • Etoposide Phosphate
  • VePesid®
  • Etopophos®
  • VP-16

Experimental: Salvage Arm
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.
Drug: Ruxolitinib
Given orally (PO) or per nasogastric tube (NGT) twice a day for 8 weeks
Other Name: Jakafi®

Drug: Dexamethasone
Given intravenously (IV) or orally (PO) twice a day for 8 weeks
Other Names:
  • Decadron®
  • Hexadrol®
  • Dexone®
  • Dexameth®

Drug: Etoposide
Given intravenously (IV) once a week for 8 weeks
Other Names:
  • Etoposide Phosphate
  • VePesid®
  • Etopophos®
  • VP-16




Primary Outcome Measures :
  1. Complete Response (CR) [ Time Frame: 8 weeks ]
    Will be reported as number and percentage of patients meeting complete response criteria at the end of 8 weeks of therapy

  2. Adverse events (AEs) associated with the ruxolitinib-containing regimen [ Time Frame: up to 8 weeks ]
    Cumulative incidence will be estimated by the Kalbfleisch-Prentice method for severe toxicities that lead to morbidity and mortality.

  3. Adverse events (AEs) associated with the ruxolitinib-containing regimen [ Time Frame: up to 1 year after diagnosis ]
    Cumulative incidence will be estimated by the Kalbfleisch-Prentice method for severe toxicities that lead to morbidity and mortality.


Secondary Outcome Measures :
  1. Overall Response (Complete Response (CR) plus Partial Response [PR]) [ Time Frame: 8 weeks ]
    Will be reported as number and percentage/proportion of patients meeting response (complete plus partial response) criteria at the end of 8 weeks of therapy

  2. Survival to eight weeks [ Time Frame: 8 weeks ]
    The proportion (probability) of patients surviving to the end of 8 weeks will be estimated by sample proportions along with the 95% exact binomial CIs in the Frontline and Salvage Arms, respectively.

  3. Survival to allogeneic hematopoietic stem cell transplantation (HSCT) in patients for whom an allogeneic HSCT is planned [ Time Frame: up to 1 year ]
    The proportion (probability) of surviving to HSCT will be estimated by sample proportions along with 95% exact binomial CIs in the Frontline and Salvage Arms, respectively.

  4. Survival to one year after initiation of the treatment protocol [ Time Frame: 1 year after initiation of treatment ]
    One-year Overall Survival (OS) rate will be estimated in all patients

  5. Survival one year after HSCT [ Time Frame: 1 year post HSCT ]
    One-year post-HSCT Overall Survival (OS) rate will be estimated in patients who receive transplantation, in the Frontline and Salvage Arms, respectively.

  6. Time to Response (CR or PR) [ Time Frame: At weeks 2, 4, 6, and 8 ]
    The mean time to CR/PR will be estimated by the sample mean along with 95% CIs, in the Frontline and Salvage Arms, respectively. The median time will be estimated by the sample median along with the 95% finite- sample CI.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Weeks to 22 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: Frontline Arm:

  1. Patient is ≥6 weeks and ≤22 years of age.
  2. Patient weighs ≥3 kg.
  3. 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.
  4. Patient has active HLH if ≥5 of 8 HLH-2004 diagnostic 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 HLH-2004 diagnostic criteria listed below:

    • Fever
    • Splenomegaly
    • Cytopenias affecting ≥2 of 3 cell lineages in the peripheral blood (hemoglobin <9 g/dL, platelets <100 × 10^9/L, neutrophils <1000 × 10^6/L)
    • Hypertriglyceridemia (fasting triglycerides ≥265 mg/dL) or hypofibrinogenemia (fibrinogen ≤150 g/dL)
    • Presence of hemophagocytosis in BM or other tissues
    • Low or absent NK-cell activity OR decreased CD107a mobilization
    • Ferritin ≥500 ng/mL
    • Soluble IL-2 receptor (CD25) ≥2400 U/mL
  5. Patient has not received prior HLH therapy, except steroids (any dose is allowed, but patient must not have been treated for more than 2 consecutive weeks) OR anakinra (any dose or length of therapy is allowed).
  6. Patient, parent, or legal authorized representative (LAR) must provide informed consent.

Inclusion Criteria: Salvage Arm:

  1. Patient is ≥6 weeks and ≤22 years of age.
  2. Patient weighs ≥3 kg.
  3. Patient or parent is willing to have the NG tube placed if patient is unable to take medications PO.
  4. 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.
  5. 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)
    • Neutrophils <1000 × 10^6/L × 2 assessments over at least 3 days OR platelets <100 × 10^9/L × 2 assessments over at least 3 days, OR need for platelet transfusions
    • Hypofibrinogenemia (fibrinogen <150 g/dL)
    • Soluble IL-2 receptor level ≥ 2400 U/L
    • 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 (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/dL)
  6. Patient must be deemed by the primary treating physician to have not responded to prior therapy by either not having or maintaining a response
  7. Patient must have received prior HLH-directed therapy:

    • At least 2 weeks of steroids (equivalent to at least 5 mg/m^2/day dexamethasone or 1 mg/kg/day methylprednisolone) AND at least 2 doses of etoposide (with at least 7 days between the last etoposide dose and starting ruxolitinib); OR
    • At least 1 dose of ATG (with at least 7 days between the last ATG dose and starting ruxolitinib)
  8. Patient or parent/LAR must provide informed consent.

Exclusion Criteria: Frontline and Salvage Arms:

  1. Patient is <6 weeks or >22 years of age.
  2. Patient weighs <3 kg.
  3. Patient has isolated CNS disease.
  4. Life expectancy is <2 weeks.
  5. Patient is likely to require <4 weeks of therapy (i.e., HSCT is imminent).
  6. Patients with creatinine clearance (CrCl) <15 mL/min who are NOT receiving dialysis.
  7. 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)
  8. Patient with pre-existing rheumatologic disorder.
  9. Patient with known active malignancy.
  10. Patient with previous HSCT, except when HSCT was for treatment of HLH.
  11. Patient is pregnant or lactating.
  12. 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.
  13. Patient has suspected or known fungal disease.
  14. Patient is unable to tolerate administration of drugs PO or NG.
  15. Patient is taking rifampin or St. John's Wort.
  16. Patient is taking another investigational agent or is enrolled on another treatment protocol.
  17. Patient, parent, or LAR are unable or unwilling to provide informed consent.

Additional Exclusion Criteria for the Frontline Arm:

  1. 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:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04551131


Contacts
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Contact: Melissa Hines, MD 866-278-5833 referralinfo@stjude.org
Contact: Kim E. Nichols, MD 866-278-5833 referralinfo@stjude.org

Locations
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United States, California
Children's Hospital of Orange County Recruiting
Orange, California, United States, 92868
Contact: Lilibeth Torno, MD    714-509-4348    ltorno@choc.org   
Principal Investigator: Lilibeth Torno, MD         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Melissa Hines, MD    866-278-5833    referralinfo@stjude.org   
Principal Investigator: Melissa Hines, MD         
Principal Investigator: Kim E. Nichols, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Incyte Corporation
North American Consortium for Histiocytosis
Investigators
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Study Chair: Melissa Hines, MD St. Jude Children's Research Hospital
Study Chair: Kim E. Nichols, MD St. Jude Children's Research Hospital
Additional Information:
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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT04551131    
Other Study ID Numbers: HLHRUXO
NCI-2020-08320 ( Registry Identifier: NCI Clinical Trial Registration )
First Posted: September 16, 2020    Key Record Dates
Last Update Posted: July 28, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data will be made available at the time of article publication.
Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Jude Children's Research Hospital:
Hemophagocytic lymphohistiocytosis
Newly Diagnosed
Frontline therapy
Refractory
Relapsed
Response-adapted
Salvage therapy
Additional relevant MeSH terms:
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Lymphohistiocytosis, Hemophagocytic
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases
Dexamethasone
Etoposide
Etoposide phosphate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action