Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

Phase 2

Active, not recruiting

Conditions: Castleman's Disease, Multicentric
Castleman Disease

Interventions: Drug: Sirolimus

Registration Number: NCT03933904

Lead Sponsor: University of Pennsylvania

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

Detailed Description: 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 7

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sirolimus	Sirolimus	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR)	12 ± 1 months	Clinical Benefit Response (CBR): The CBR was defined by improvements in clinical symptoms such as fatigue, anorexia, fever, and night sweats.6 Laboratory markers such as hemoglobin levels and weight change were also included in the CBR criteria (Table 1). A CBR was considered positive if there was at least a 25% reduction in the size of the largest lymph node (measured by modified Cheson criteria), a significant improvement in at least one laboratory marker (e.g., hemoglobin), and improvement in at least one clinical symptom without worsening of others.

Secondary Outcome Measures

Name	Time	Method
Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 3	Month 3
Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 6	Month 6
Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 9	Month 9
Percentage of Patients That Remain on Study Drug for the Duration of the Study	Up to 73 weeks
Percentage 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	12 months ± 2 weeks	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.
Disease Activity, as Measured by the MCD-related Overall Symptom Score	Month 12	MCD-related Overall Symptom Score is measured by 34 MCD-related outcome measures. These scores addressed fatigue, weight change, night sweats, etc. The scores were evaluated and graded (as per CTCAE version 4.0, May, 2009), which was used to assess the efficacy of the study intervention. Each symptom score was measured on a numeric scale, ranging from 1 (no symptom) to 5 (very severe or disabling). Scores were combined to create a combined score per patient at each time point. Patients were then assessed as having no response, a symptomatic response, or a durable symptomatic response. A symptomatic response was defined as a ≥50% decrease in the 34-point symptom score, a durable symptomatic response is a ≥50% decrease in the 34-point symptom score from baseline that was maintained for a minimum of 18 weeks.
Proportion of Patients Achieving a Lymph Node Response, Following the Modified Cheson Response Criteria	Month 12	Radiological response was assessed using the modified Cheson criteria, which quantify changes in lymph node size. A lymph node response was defined as a 25% reduction in bi-dimensional measurements of the largest lymph node compared to baseline. Patients were then assessed according to the following responses: Complete Response: All index lesion(s) must have regressed to normal size (≤1.0 cm in their greatest transverse diameter. No new sites of lymphadenopathy \>1.5 cm in longest dimension. Partial Response: ≥50% decrease in sum of the products of the greatest diameters (SPD) of index lesion(s), and no new sites of lymphadenopathy \>1.5 cm in longest dimension. Stable Disease: Failure to achieve a CR or PR (see above) without evidence of progressive disease. Progressive Disease: ≥50% increase from nadir in the SPD of any index lesion, or appearance of any new sites of lymphadenopathy that measure \>1.5 cm in longest dimension during or at the end of therapy.

Trial Locations

Locations (4): University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
University of California - San Diego
🇺🇸
La Jolla, California, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States