Clinical trial NCT03933904: Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease
Official title: A Phase II, Single-arm Open-label Multi-center Study of Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Castleman Disease
Castleman's Disease, Multicentric
Keywords: Castleman
iMCD
Castleman's Disease
multicentric Castleman's disease
multicentric Castleman disease
idiopathic Castleman disease
idiopathic Castleman's disease
CD
MCD
Castleman Disease
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
First posted: 2019-05-01
Enrollment: 7
Sex: ALL
Minimum age (years): 2
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of patients achieving a positive clinical benefit response (CBR)
timeFrame: 12 ± 1 months
Secondary outcomes:
measure: Proportion of patients achieving a positive clinical benefit response (CBR)
timeFrame: 3, 6, and 9 months ± 2 weeks
measure: Proportion of patients that remain on study drug for the duration of the study
timeFrame: Up to 73 weeks
measure: Proportion of patients that indicate that they are currently receiving sirolimus at the end of the Follow Up Phase
timeFrame: Up to 73 weeks
measure: Disease activity, as measured by the CHAP scale
timeFrame: 3, 6, 9, and 12 months ± 2 weeks
measure: Disease activity, as measured by the MCD-related Overall Symptom Score
timeFrame: 3, 6, 9, and 12 months ± 2 weeks
measure: Proportion of patients achieving a lymph node response, following the modified Cheson response criteria
timeFrame: 3, 6, 9, and 12 months ± 2 weeks
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: La Jolla
country: United States
facility: University of California - San Diego
state: California
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: David C Fajgenbaum, MD, MBA, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Rhee F, Oksenhendler E, Srkalovic G, Voorhees P, Lim M, Dispenzieri A, Ide M, Parente S, Schey S, Streetly M, Wong R, Wu D, Maillard I, Brandstadter J, Munshi N, Bowne W, Elenitoba-Johnson KS, Fossa A, Lechowicz MJ, Chandrakasan S, Pierson SK, Greenway A, Nasta S, Yoshizaki K, Kurzrock R, Uldrick TS, Casper C, Chadburn A, Fajgenbaum DC. International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease. Blood Adv. 2020 Dec 8;4(23):6039-6050. doi: 10.1182/bloodadvances.2020003334.
citation: Arenas DJ, Floess K, Kobrin D, Pai RL, Srkalovic MB, Tamakloe MA, Rasheed R, Ziglar J, Khor J, Parente SAT, Pierson SK, Martinez D, Wertheim GB, Kambayashi T, Baur J, Teachey DT, Fajgenbaum DC. Increased mTOR activation in idiopathic multicentric Castleman disease. Blood. 2020 May 7;135(19):1673-1684. doi: 10.1182/blood.2019002792.
citation: Fajgenbaum DC, Langan RA, Japp AS, Partridge HL, Pierson SK, Singh A, Arenas DJ, Ruth JR, Nabel CS, Stone K, Okumura M, Schwarer A, Jose FF, Hamerschlak N, Wertheim GB, Jordan MB, Cohen AD, Krymskaya V, Rubenstein A, Betts MR, Kambayashi T, van Rhee F, Uldrick TS. Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease. J Clin Invest. 2019 Aug 13;129(10):4451-4463. doi: 10.1172/JCI126091.