Ruxolitinib in Previously Treated Idiopathic Multicentric Castleman Disease

Official title

A Phase II, Single-Arm Open-Label Multi-Center Study of Ruxolitinib in Previously Treated Idiopathic Multicentric Castleman Disease

Overview

The research study is being done to look at the effects of ruxolitinib in adults with idiopathic Multicentric Castleman Disease (iMCD) that has not gotten better from taking siltuximab or tocilizumab, or who cannot take those medications.

Detailed description

There is currently no agreed-on recommended treatment for iMCD patients whose disease does not respond to siltuximab or tocilizumab, which is a major challenge for patients. The purpose of this study is to find out the effects of a study drug, ruxolitinib (also called Jakafi), in these patients. This study looks at how well the drug is tolerated by participants and its effects on participants' iMCD symptoms.

Interventions

• Drug Ruxolitinib
  Participants will take the study drug in a tablet form, by mouth, every day for the next year, as long as it is helping with their disease and not causing unacceptable side effects.

Primary outcome measures

• The proportion of participants achieving a positive Clinical Benefit Response (CBR) response at 12 months ± 1 month. Assessments at 12 months ± 1 month. will be compared to those at the baseline visit [Time frame: 12 months ± 1 month]

Secondary outcome measures (6)

• The proportion of participants achieving a positive CBR response at 3, 6, 9 months compared to baseline [Time frame: 3, 6, and 9 months compared to baseline]
• Disease activity, as measured by the CHAP scale, at 3, 6, 9, and 12 months ± 1 month. Assessments will be compared to those obtained at the Baseline Visit [Time frame: 3, 6, 9, and 12 months ± 1 month]
• Disease activity, as measured by MCD-related Overall Symptom Score as measured by 34 outcome measures at 3, 6, 9, and 12 months ± 1 month compared to those obtained at the Baseline Visit [Time frame: 3, 6, 9, and 12 months ± 1 month]
• The proportion of participants achieving a lymph node response, following the modified Cheson response criteria compared to baseline [Time frame: Month 12]
• The proportion of participants that remain on study drug for the duration of the study [Time frame: Up to 73 weeks]
• The proportion of participants that indicate that they are currently receiving Ruxolitinib at the end of the Follow-Up Phase [Time frame: Up to 73 weeks]

Eligibility criteria

Inclusion criteria

• Male or female, age 18-80
• Documented disease history consistent with diagnostic criteria for iMCD

• Indication of clinico-histopathological features consistent with iMCD as determined by a licensed pathologist in a diagnostic pathology report, or a CAS grade of at least 3 in the companion registry study (ACCELERATE).
• Refractory (patient did not achieve sufficient disease control with anti-IL-6 therapy, as determined by the site investigator), relapsed (return of symptoms while on therapy), or inability to tolerate anti-IL-6 or anti-IL-6 receptor therapy
• Evidence of active disease, defined by at least two of: constitutional symptoms (fatigue, night sweats, fever, weight change), hemoglobin < lower limit of normal, C-reactive protein > upper limit of normal (or >10 mg/L), or albumin < lower limit of normal (<3.5 g/dL), at lease one lymph node meeting modified Cheson criteria
• Ability to consume oral medication in the form of a tablet
• Ability to provide informed consent prior to any study-specific activities

Exclusion criteria

• Subjects cannot be pregnant or nursing females

• Women of childbearing potential must have a negative pregnancy test documented at the Baseline Visit. Subjects of reproductive potential may not participate unless they have agreed, as part of the informed consent, to use an effective contraceptive method for the duration of the study and for at least 12 weeks after ending treatment
• Subjects cannot have received any systemic therapy(ies) intended to treat iMCD other than corticosteroids or anti-IL-6 therapy within 14 days of enrollment

• Corticosteroid treatment must have been initiated more than 28 days prior to enrollment and be maintained at a stable or tapering dose (prednisone or equivalent up to 1 mg/kg/day) prior to enrollment; dose cannot be elevated for the duration of the study but can be maintained or tapered

• For subjects who cannot or are unwilling to undergo a 14-day washout period from their anti-IL-6 therapy: i. Anti-IL-6 therapy may be permitted if the subject has been on therapy for at least 3 months, no toxicity has been documented, and sufficient disease control is not achieved ii. Anti-IL-6 therapy is recommended to be discontinued within the first 6 weeks after starting ruxolitinib
• Subjects cannot have previously received ruxolitinib monotherapy or combination therapy to treat iMCD
• Subjects cannot have uncontrolled infection or infectious disease(s) that is/are exclusionary for / mimickers of iMCD

• Fungal disease must be stable for at least two weeks before enrollment
• Subjects with history of recent bacteremia must have a documented negative blood culture before enrollment
• Subjects with past history of non-therapy related opportunistic infection should discuss eligibility and possible immunologic evaluation with the licensed site investigator prior to enrollment
• Subjects cannot have:

• ECOG >3
• eGFR <30mL/min/1.73 m2 or creatinine >3.0 mg/dL
• Absolute neutrophil count (ANC) < 1000 x 109/L
• Hemoglobin ≤ 6.5 g/dL (transfusion independent, defined as not receiving a red blood cell transfusion for ≥ 7 days prior)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) laboratory values greater than three times the upper limit of normal
• Albumin < 2 g/dL (transfusion independent, defined as not receiving intravenous albumin for ≥ 7 days prior)
• Platelet count ≤ 40 x 109/L (transfusion independent, defined as not receiving platelet transfusion for ≥ 7 days prior)
• Pulmonary involvement or interstitial pneumonitis with dyspnea (adequate pulmonary function is defined as pulse oximetry > 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest, history of interstitial pneumonitis, etc.)
• Fasting cholesterol > 300 mg/dL or fasting triglyceride > 400 mg/dL
• Subjects cannot have rheumatologic disease(s) that is/are exclusionary for / mimickers of iMCD
• Subjects cannot have a prior malignancy except for: (1) adequately treated basal cell or squamous cell skin cancer, (2) in situ cervical cancer, or (3) other cancer for which the subject has not received treatment within one year prior to enrollment

• Other cancers will only be acceptable if the patient's life expectancy exceeds five years and they are not exclusionary diagnoses for iMCD
• Subjects cannot have a documented history of human immunodeficiency virus (HIV) or HHV-8 infection, or severe combined immunodeficiency syndrome
• Subjects cannot have active infections of mycobacterium tuberculosis, hepatitis B, or hepatitis C due to the potential reactivation with ruxolitinib

• A positive hepatitis B serology indicative of previous immunization (i.e., hepatitis B surface antigen (HBsAb) positive and hepatitis B core antibody (HBcAb) negative), or a fully resolved acute hepatitis B infection is not an exclusion criterion.
• Subjects with an indolent chronic hepatitis B infection (normal ALT, AST, albumin and no radiographic or biopsy evidence of cirrhosis) may be eligible.
• Subjects with active hepatitis C are excluded. Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA).
• Subjects cannot have had any major adverse cardiac events, including ischemic stroke and myocardial infarction, within 6 months of enrollment
• Subjects cannot have ongoing or planned participation in another clinical trial involving iMCD directed treatment or that involves immunomodulatory or anti-neoplastic treatment
• Subjects cannot have prior sensitivity / allergy to any formulation of ruxolitinib, its components, or its analogues
• Subjects cannot have serious medical illness, or psychiatric illness or disorders that could potentially interfere with the completion of treatment according to this protocol or participation in the trial
• Subjects cannot have psychiatric disorders that compromise their ability to provide informed consent
• Subjects cannot have any other condition or finding that, in the opinion of the investigator, would make participation in this trial inappropriate

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Pennsylvania — Philadelphia

Identifiers

NCT: NCT07085039 · 858269

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗