Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

• ClinicalTrials.gov Identifier: NCT03933904
• Recruitment Status: Recruiting
• First Posted: May 1, 2019
• Last Update Posted: January 9, 2023
• Sponsor: University of Pennsylvania
• Information provided by (Responsible Party): University of Pennsylvania

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Castleman Disease; Castleman's Disease, Multicentric	Drug: Sirolimus	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Single-arm Open-label Multi-center Study of Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease
• Actual Study Start Date: September 25, 2019
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: December 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: Sirolimus; 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.; Other Names: Rapamune; Rapamycin

Outcome Measures

Primary Outcome Measures :

1. Proportion of patients achieving a positive clinical benefit response (CBR) [ Time Frame: 12 ± 1 months ]

Secondary Outcome Measures :

1. Proportion of patients achieving a positive clinical benefit response (CBR) [ Time Frame: 3, 6, and 9 months ± 2 weeks ]
2. Proportion of patients that remain on study drug for the duration of the study [ Time Frame: Up to 73 weeks ]
3. Proportion of patients that indicate that they are currently receiving sirolimus at the end of the Follow Up Phase [ Time Frame: Up to 73 weeks ]
4. Disease activity, as measured by the CHAP scale [ Time Frame: 3, 6, 9, and 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.
5. Disease activity, as measured by the MCD-related Overall Symptom Score [ Time Frame: 3, 6, 9, and 12 months ± 2 weeks ]
   MCD-related Overall Symptom Score is measured by 34 MCD-related outcome measures
6. Proportion of patients achieving a lymph node response, following the modified Cheson response criteria [ Time Frame: 3, 6, 9, and 12 months ± 2 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 80 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: David C Fajgenbaum, MD, MBA, MS; 215-614-0935; davidfa@pennmedicine.upenn.edu

Contact: Tracey Sikora; 215-614-0199; CDtrial@pennmedicine.upenn.edu

Locations

United States, Arkansas

University of Arkansas for Medical Sciences; Recruiting

Little Rock, Arkansas, United States, 72205

Contact: Brooke Carter 501-214-2499 ext 25871 JBCarter@uams.edu

Principal Investigator: Frits van Rhee, MD, PHD

United States, California

University of California - San Diego; Not yet recruiting

La Jolla, California, United States, 92093

Contact: Aaron Goodman

United States, Pennsylvania

Children's Hospital of Philadelphia; Not yet recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: David Teachey

University of Pennsylvania; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: David C Fajgenbaum, MD, MBA, MSc 215-614-0935 davidfa@pennmedicine.upenn.edu

Contact: Tracey Sikora 215-614-0199 CDtrial@pennmedicine.upenn.edu

Principal Investigator: David C Fajgenbaum, MD, MBA, MSc

Sponsors and Collaborators

University of Pennsylvania

Investigators

• Principal Investigator: David C Fajgenbaum, MD, MBA, MS; University of Pennsylvania

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT03933904
• Other Study ID Numbers: 832465
• First Posted: May 1, 2019
• Last Update Posted: January 9, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: There is no current plan to share IPD.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Pennsylvania:

Castleman; iMCD; Castleman's Disease; multicentric Castleman's disease; multicentric Castleman disease; idiopathic Castleman disease; idiopathic Castleman's disease; CD; MCD; Castleman Disease

Additional relevant MeSH terms:

Castleman Disease; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Sirolimus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs