Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

Study Overview
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Brief Summary
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The purpose of this study is to understand the impact of sirolimus on idiopathic multicentric Castleman disease.

Detailed Description
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Human herpesvirus(HHV)-8-negative, idiopathic multicentric Castleman disease (iMCD) is a rare hematologic illness. Current therapeutic options are limited and provide benefit for only a subset of patients. Blockade of IL-6 signaling with siltuximab or tocilizumab abrogates symptoms and improves lymphadenopathy in a portion of patients. However, 66% of patients in the siltuximab Phase II clinical trial did not meet response criteria, and recent studies found that IL-6 is not significantly elevated in many iMCD patients. Recent research has suggested a key role for the phosphoinositide 3-kinase(PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway in iMCD pathogenesis and off-label administration of sirolimus, an mTOR inhibitor, has shown clinical activity. Based on these experiences, we plan to evaluate the efficacy of sirolimus as a therapy for iMCD patients who are either unable to tolerate anti-IL-6 blockade therapy (siltuximab or tocilizumab), or who fail, relapse, or are refractory to such treatment. This study is a Phase II open label study of daily administration of sirolimus in up to 24 evaluable male or female adults. Participants with iMCD who have failed previous therapy will take daily oral sirolimus for 12 months. Information that is collected as per standard of care will be used to review efficacy, in addition to samples collected specifically for research.

Official Title
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A Phase II, Single-arm Open-label Multi-center Study of Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

Conditions
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Castleman Disease, Castleman's Disease, Multicentric

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 2-80 Documented disease history consistent with the diagnostic criteria for iMCD Failed/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 as at least two abnormalities in the criteria comprising the CBR criteria, including at least one objective measurement (hemoglobin, weight loss, or lymph node size) Ability to consume oral medication in the form of a tablet Ability to provide, or for a legally authorized representative to provide on their behalf, informed consent prior to any study-specific activities Exclusion Criteria: Subjects cannot be pregnant or nursing females Except for anti-IL6 blockade therapy (siltuximab or tocilizumab), the last dose of which must be ≥ 14 days prior to enrollment (unless subjects cannot or are unwilling to undergo a 14 day washout period), subjects cannot have received any systemic therapy(ies) intended to treat iMCD other than corticosteroids within 28 days of enrollment Subjects cannot have previously received sirolimus monotherapy to treat iMCD Subjects cannot have any of the following: ECOG >3 (or Karnofsky/Lansky score ≤ 60 in children); Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 or creatinine > 3.0 mg/dL; Absolute neutrophil count (ANC) < 1000 x 109/L ((< 500 x 109/L in children); 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 uncontrolled infection or infectious disease(s) that is/are exclusionary for / mimickers of iMCD 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 Subjects cannot have a documented history of human immunodeficiency virus (HIV) or HHV-8 infection, or severe combined immunodeficiency syndrome Subjects cannot have a history of liver or lung transplantation 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 sirolimus, 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 compromises the 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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus<br>Oral sirolimus: For adults, loading dose of 5 mg/m^2, rounded to the nearest mg, on day 1. For adults, starting on day 2, oral sirolimus daily at 2.5 mg/m^2/day (rounded to the nearest mg), target trough level 10-15 ng/mL by HPLC, for 12 months. For children, 2 mg/m^2/day, target trough level 5-15 ng/mL by HPLC. | Drug: Sirolimus<br>* Sirolimus (also known as rapamycin) inhibits the mTOR protein kinase and is approved by the USA FDA for the prevention of allograft rejection in renal transplant patients ≥ 13 years of age and for the treatment of lymphangioleiomyomatosis.<br>* Other names: Rapamycin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving a positive clinical benefit response (CBR) |  | 12 ± 1 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving a positive clinical benefit response (CBR) |  | 3, 6, and 9 months ± 2 weeks | 
| Proportion of patients that remain on study drug for the duration of the study |  | Up to 73 weeks | 
| Proportion of patients that indicate that they are currently receiving sirolimus at the end of the Follow Up Phase |  | Up to 73 weeks | 
| Disease activity, as measured by the CHAP scale | The CHAP scale consists of C-reactive protein (CRP), hemoglobin, albumin, and Eastern Cooperative Oncology Group (ECOG) performance score, each with a subscale range of 0-4. Each criterion in the CHAP scoring system provides a graded measure for a patient's disease activity. The sum of the four scores provides an objective scale for measuring a patient's disease activity and monitoring how it changes over time (scale range 0-16). A higher score indicates greater disease activity. | 3, 6, 9, and 12 months ± 2 weeks | 
| Disease activity, as measured by the MCD-related Overall Symptom Score | MCD-related Overall Symptom Score is measured by 34 MCD-related outcome measures | 3, 6, 9, and 12 months ± 2 weeks | 
| Proportion of patients achieving a lymph node response, following the modified Cheson response criteria |  | 3, 6, 9, and 12 months ± 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Castleman, iMCD, Castleman's Disease, multicentric Castleman's disease, multicentric Castleman disease, idiopathic Castleman disease, idiopathic Castleman's disease, CD, MCD, Castleman Disease