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Frits Van Rhee - One of the best experts on this subject based on the ideXlab platform.

  • long term safety of Siltuximab in patients with idiopathic multicentric castleman disease a prespecified open label extension analysis of two trials
    The Lancet Haematology, 2020
    Co-Authors: Frits Van Rhee, Peter M Voorhees, Corey Casper, Luis Fayad, Damilola Gibson, Karan Kanhai, Razelle Kurzrock
    Abstract:

    Background Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of Siltuximab over up to 6 years of treatment. Methods This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on Siltuximab. Patients received Siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of Siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27. Findings Patient enrolment into the phase 1 trial was from June 20, 2005, to Sept 15, 2009, and enrolment into the phase 2 trial was from Feb 9, 2010, to Feb 3, 2012. Patients were enrolled in this long-term extension from April 1, 2011, to Jan 15, 2014. Median follow-up was 6 years (IQR 5·11-7·76). Median treatment duration, from the beginning of the previous trials to the end of the present study, was 5·5 years (IQR 4·26-7·14). Siltuximab was well tolerated; however, adverse events of grade 3 or worse were reported in 36 (60%) of 60 patients with the most common being hypertension (eight [13%]), fatigue (five [8%]), nausea (four [7%]), neutropenia (four [7%]), and vomiting (three [5%]). 25 (42%) patients reported at least one serious adverse event, which most commonly was an infection (eight [13%]). Only two serious adverse events, polycythaemia and urinary retention, were considered related to Siltuximab treatment. 18 patients discontinued before study completion, either to receive Siltuximab locally (eight) or because of progressive disease (two), adverse events (two), or other reasons (six). No deaths were reported. Interpretation These results show that Siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients with idiopathic multicentric Castleman disease. Funding Janssen R&D and EUSA Pharma.

  • Predictors of response to anti-IL6 monoclonal antibody therapy (Siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phase II clinical trial data
    British Journal of Haematology, 2019
    Co-Authors: Deanna E. Morra, Sheila K. Pierson, Mary Guilfoyle, Craig Tendler, Frits Van Rhee, Dustin Shilling, Sepideh Nemat, Carlos Appiani, David C. Fajgenbaum
    Abstract:

    Siltuximab is the only US Food and Drug Administration-approved treatment for idiopathic multicentric Castleman disease (iMCD), a rare haematological disorder associated with substantial morbidity and mortality. Although Siltuximab induces a response in a significant proportion of iMCD patients via interleukin 6 (IL6) neutralization, it is not universally effective. To develop a predictive model of response, we performed an in-depth analysis of 38 baseline laboratory parameters in iMCD patients from the phase II Siltuximab trial who met criteria for treatment response or treatment failure. Univariate analyses identified eight baseline laboratory parameters that were significantly different between responders and treatment failures: albumin, immunoglobulin G (IgG), immunoglobulin A, C reactive protein (CRP), fibrinogen, haemoglobin, sodium and triglycerides. Stepwise logistic regression analysis of these candidate parameters identified a top performing model that included fibrinogen, IgG, haemoglobin and CRP. Based on cross-validation of the final multivariate logistic regression model, the model accurately discriminated responders from those who failed treatment (area under the receiver operator characteristic curve 0·86, 95% confidence interval: 0·73-0·95). All four laboratory parameters associated with response to Siltuximab have biological relationships with IL6 and acute inflammation. Our model suggests that iMCD patients with laboratory evidence of an inflammatory syndrome are the best candidates for Siltuximab therapy.

  • Predictors of response to anti‐IL6 monoclonal antibody therapy (Siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phase II clinical trial data
    British journal of haematology, 2018
    Co-Authors: Deanna E. Morra, Sheila K. Pierson, Mary Guilfoyle, Craig Tendler, Frits Van Rhee, Dustin Shilling, Sepideh Nemat, Carlos Appiani, David C. Fajgenbaum
    Abstract:

    Siltuximab is the only US Food and Drug Administration-approved treatment for idiopathic multicentric Castleman disease (iMCD), a rare haematological disorder associated with substantial morbidity and mortality. Although Siltuximab induces a response in a significant proportion of iMCD patients via interleukin 6 (IL6) neutralization, it is not universally effective. To develop a predictive model of response, we performed an in-depth analysis of 38 baseline laboratory parameters in iMCD patients from the phase II Siltuximab trial who met criteria for treatment response or treatment failure. Univariate analyses identified eight baseline laboratory parameters that were significantly different between responders and treatment failures: albumin, immunoglobulin G (IgG), immunoglobulin A, C reactive protein (CRP), fibrinogen, haemoglobin, sodium and triglycerides. Stepwise logistic regression analysis of these candidate parameters identified a top performing model that included fibrinogen, IgG, haemoglobin and CRP. Based on cross-validation of the final multivariate logistic regression model, the model accurately discriminated responders from those who failed treatment (area under the receiver operator characteristic curve 0·86, 95% confidence interval: 0·73-0·95). All four laboratory parameters associated with response to Siltuximab have biological relationships with IL6 and acute inflammation. Our model suggests that iMCD patients with laboratory evidence of an inflammatory syndrome are the best candidates for Siltuximab therapy.

  • a phase 2 open label multicenter study of the long term safety of Siltuximab an anti interleukin 6 monoclonal antibody in patients with multicentric castleman disease
    Oncotarget, 2015
    Co-Authors: Frits Van Rhee, Peter M Voorhees, Corey Casper, Luis Fayad, Jessica Vermeulen, Helgi Van De Velde, Xiang Qin, Brenda Tromp, Razelle Kurzrock
    Abstract:

    // Frits van Rhee 1 , Corey Casper 2 , Peter M. Voorhees 3 , Luis E. Fayad 4 , Helgi van de Velde 5 , Jessica Vermeulen 6 , Xiang Qin 7 , Ming Qi 7 , Brenda Tromp 6 , Razelle Kurzrock 4 1 Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA 3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA 4 MD Anderson Cancer Center, The University of Texas, Houston, TX, USA 5 Janssen Research & Development LLC, Beerse, Belgium 6 Janssen Research & Development LLC, Leiden, Netherlands 7 Janssen Research & Development LLC, Spring House, PA, USA Correspondence to: Frits van Rhee, e-mail: vanrheefrits@uams.edu Keywords: multi-centric Castleman's disease, interleukin-6, Siltuximab, clinical trial Received: February 26, 2015      Accepted: July 23, 2015      Published: August 03, 2015 ABSTRACT Background: Multicentric Castleman disease (MCD) is a rare, systemic lymphoproliferative disorder driven by interleukin (IL)-6 overproduction. Siltuximab, an anti-IL-6 monoclonal antibody, has demonstrated durable tumor and symptomatic responses in a multinational, randomized, placebo-controlled study of MCD. Methods: This preplanned safety analysis was conducted to evaluate the long-term safety of Siltuximab treatment among 19 patients with MCD who had stable disease or better and were enrolled in a phase-1 study and subsequent ongoing, open-label, phase-2 extension study. Dosing was 11 mg/kg administered intravenously every 3 weeks, per protocol, or every 6 weeks at the investigator's discretion. Safety monitoring focused on potential risks associated with the anti-IL-6 mechanism of action. Investigator-assessed disease control status was also documented. Results: Median treatment duration for the 19 patients was 5.1 (range 3.4, 7.2) years, with 14 (74%) patients treated for >4 years. Grade-≥3 adverse events (AEs) reported in >1 patient included hypertension ( n = 3) and nausea, cellulitis, and fatigue ( n = 2 each). Grade-≥3 AEs at least possibly attributed to Siltuximab were leukopenia, lymphopenia, and a serious AE of polycythemia ( n = 1 each). Hypertriglyceridemia and hypercholesterolemia (total cholesterol) were reported in 8 and 9 patients, respectively. No disease relapses were observed, and 8 of 19 patients were able to switch to an every-6-week dosing schedule. Conclusions: All MCD patients in this extension study have received Siltuximab for a prolonged duration (up to 7 years) without evidence of cumulative toxicity or treatment discontinuations and with few serious infections. All patients are alive, demonstrate sustained disease control, and continue to receive Siltuximab.

  • Patient-reported Outcomes for Multicentric Castleman’s Disease in a Randomized, Placebo-controlled Study of Siltuximab
    The patient, 2015
    Co-Authors: Frits Van Rhee, Nikhil C Munshi, Raymond Sm Wong, Alexander Fossa, Angela Dispenzieri, Margaret Rothman, James Cavet, Sarah Fleming, Jessica Vermeulen
    Abstract:

    Background Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder driven by dysregulated interleukin-6 production. MCD has a poor prognosis, and treatment is generally noncurative and aimed at symptom relief. Siltuximab is a novel, monoclonal interleukin-6 antibody recently shown to be effective in a registration clinical trial. MCD symptoms, such as fatigue, pain, and weakness, are most appropriately quantified using patient-reported outcome (PRO) measures. We assessed the effect of Siltuximab on patient perception of symptoms, functional status, and wellbeing using PRO instruments.

Peter M Voorhees - One of the best experts on this subject based on the ideXlab platform.

  • long term safety of Siltuximab in patients with idiopathic multicentric castleman disease a prespecified open label extension analysis of two trials
    The Lancet Haematology, 2020
    Co-Authors: Frits Van Rhee, Peter M Voorhees, Corey Casper, Luis Fayad, Damilola Gibson, Karan Kanhai, Razelle Kurzrock
    Abstract:

    Background Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of Siltuximab over up to 6 years of treatment. Methods This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on Siltuximab. Patients received Siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of Siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27. Findings Patient enrolment into the phase 1 trial was from June 20, 2005, to Sept 15, 2009, and enrolment into the phase 2 trial was from Feb 9, 2010, to Feb 3, 2012. Patients were enrolled in this long-term extension from April 1, 2011, to Jan 15, 2014. Median follow-up was 6 years (IQR 5·11-7·76). Median treatment duration, from the beginning of the previous trials to the end of the present study, was 5·5 years (IQR 4·26-7·14). Siltuximab was well tolerated; however, adverse events of grade 3 or worse were reported in 36 (60%) of 60 patients with the most common being hypertension (eight [13%]), fatigue (five [8%]), nausea (four [7%]), neutropenia (four [7%]), and vomiting (three [5%]). 25 (42%) patients reported at least one serious adverse event, which most commonly was an infection (eight [13%]). Only two serious adverse events, polycythaemia and urinary retention, were considered related to Siltuximab treatment. 18 patients discontinued before study completion, either to receive Siltuximab locally (eight) or because of progressive disease (two), adverse events (two), or other reasons (six). No deaths were reported. Interpretation These results show that Siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients with idiopathic multicentric Castleman disease. Funding Janssen R&D and EUSA Pharma.

  • a phase 2 open label multicenter study of the long term safety of Siltuximab an anti interleukin 6 monoclonal antibody in patients with multicentric castleman disease
    Oncotarget, 2015
    Co-Authors: Frits Van Rhee, Peter M Voorhees, Corey Casper, Luis Fayad, Jessica Vermeulen, Helgi Van De Velde, Xiang Qin, Brenda Tromp, Razelle Kurzrock
    Abstract:

    // Frits van Rhee 1 , Corey Casper 2 , Peter M. Voorhees 3 , Luis E. Fayad 4 , Helgi van de Velde 5 , Jessica Vermeulen 6 , Xiang Qin 7 , Ming Qi 7 , Brenda Tromp 6 , Razelle Kurzrock 4 1 Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA 3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA 4 MD Anderson Cancer Center, The University of Texas, Houston, TX, USA 5 Janssen Research & Development LLC, Beerse, Belgium 6 Janssen Research & Development LLC, Leiden, Netherlands 7 Janssen Research & Development LLC, Spring House, PA, USA Correspondence to: Frits van Rhee, e-mail: vanrheefrits@uams.edu Keywords: multi-centric Castleman's disease, interleukin-6, Siltuximab, clinical trial Received: February 26, 2015      Accepted: July 23, 2015      Published: August 03, 2015 ABSTRACT Background: Multicentric Castleman disease (MCD) is a rare, systemic lymphoproliferative disorder driven by interleukin (IL)-6 overproduction. Siltuximab, an anti-IL-6 monoclonal antibody, has demonstrated durable tumor and symptomatic responses in a multinational, randomized, placebo-controlled study of MCD. Methods: This preplanned safety analysis was conducted to evaluate the long-term safety of Siltuximab treatment among 19 patients with MCD who had stable disease or better and were enrolled in a phase-1 study and subsequent ongoing, open-label, phase-2 extension study. Dosing was 11 mg/kg administered intravenously every 3 weeks, per protocol, or every 6 weeks at the investigator's discretion. Safety monitoring focused on potential risks associated with the anti-IL-6 mechanism of action. Investigator-assessed disease control status was also documented. Results: Median treatment duration for the 19 patients was 5.1 (range 3.4, 7.2) years, with 14 (74%) patients treated for >4 years. Grade-≥3 adverse events (AEs) reported in >1 patient included hypertension ( n = 3) and nausea, cellulitis, and fatigue ( n = 2 each). Grade-≥3 AEs at least possibly attributed to Siltuximab were leukopenia, lymphopenia, and a serious AE of polycythemia ( n = 1 each). Hypertriglyceridemia and hypercholesterolemia (total cholesterol) were reported in 8 and 9 patients, respectively. No disease relapses were observed, and 8 of 19 patients were able to switch to an every-6-week dosing schedule. Conclusions: All MCD patients in this extension study have received Siltuximab for a prolonged duration (up to 7 years) without evidence of cumulative toxicity or treatment discontinuations and with few serious infections. All patients are alive, demonstrate sustained disease control, and continue to receive Siltuximab.

  • An Open-Label, Phase 2, Multicenter Study Of The Safety Of Long-Term Treatment With Siltuximab (an Anti-Interleukin-6 Monoclonal Antibody) In Patients With Multicentric Castleman’s Disease
    Blood, 2013
    Co-Authors: Frits Van Rhee, Peter M Voorhees, Corey Casper, Jessica Vermeulen, Helgi Van De Velde, Xiang Qin, Brenda Tromp, Luis E Fayad, Razelle Kurzrock
    Abstract:

    ![Graphic][1] Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disease driven by interleukin (IL)-6 overproduction. There is no established standard of care for MCD, and patients are usually managed by a variety of strategies with only modest success. Treatment with Siltuximab, an anti-IL-6 mAb, demonstrated clinical and radiologic responses in MCD patients in a phase 1 study (Kurzrock et al. Clin Cancer Res 2013;19:3659-70). A phase 2 extension study to assess the safety of long-term treatment with Siltuximab in MCD patients is currently ongoing. We report the interim analysis results based on 19 patients who had sustained disease control on Siltuximab in the phase 1 study and continued to receive Siltuximab 11 mg/kg q3w IV in the phase 2 extension study. Safety monitoring focused on infections, hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, and liver function based on the potential risks from the mechanism of action of IL-6 blockade. Investigator assessed disease control and survival status were also collected. When these 19 patients started the phase 1 study, median age was 44 (range 18, 76) yrs, 63% were male, median disease duration was 4.8 mos (37% newly diagnosed), 53% had hyaline vascular and 47% had plasmacytic histological type, all were HIV- and HHV-8-negative, 32% were therapy-naive, and 68% had prior therapy (including 21% with prior cancer-related surgery and 63% with prior systemic therapy for MCD). At the data cutoff for this interim analysis of the extension study (January 2013), patients had received in total a median of 81 doses (maximum 129) of Siltuximab during a median treatment duration of 5.1 (range 3.4, 7.2) yrs, with 74% of patients treated >4 yrs. All 19 patients are alive and continuing Siltuximab treatment. Over the entire treatment duration (ie, both studies), upper respiratory tract infection (89%); nausea (63%); vomiting (58%); diarrhea (53%); hypercholesterolemia (47%); hypertriglyceridemia, pain in extremities, headache, rash, and hepatic function abnormal (each 42%) were most commonly reported. The incidence of AEs reported in the different system-organ classes was similar or lower in the treatment periods of 2 to 4 yrs and more than 4 yrs compared with the treatment period of 0 to 2 yrs. 63% of patients reported at least one grade ≥3 AE (mostly grade 3, none grade 5) during the entire treatment period, most commonly in the following system-organ classes: gastrointestinal (32%); infections (26%); and blood/lymphatic system disorders or general disorders/administration-site conditions (each 21%). Grade ≥3 hypertension was reported in 3 patients; grade ≥3 nausea, cellulitis, and fatigue in 2 patients each; other grade ≥3 AEs were reported in single patients. Two patients had at least one serious infection during phase 1, and none were reported during phase 2 extension study (overall incidence 0.0226 per pt-yr). Eight patients had low-grade hypertriglyceridemia in phase 1, with no additional cases reported during extension study (overall incidence 0.1250 per pt-yr). No patient had grade ≥3 thrombocytopenia, and only 1 patient had grade ≥3 neutropenia during the entire treatment period (overall incidence 0.0103 per pt-yr). Only 1 case of grade ≥3 abnormal hepatic function was reported (in phase 1). No GI perforations occurred. No patient developed infusion-related reactions during the extension study. Only 3 patients had SAEs during the extension study, including unrelated syncope and dyspnea. One patient developed grade 3 polycythemia (Hb 18.8 g/dL), which was controlled without complications. Based on independent radiologic review of images from the phase 1 study, 1 patient had CR, 11 had PR, and 7 had SD at initiation of extension study. All 19 patients have sustained disease control (SD or better) by investigator assessment, including 8 patients who had their dosing interval increased to q6w after established prolonged PR/CR (median q6w treatment duration 11 mos). After a median follow-up of 5.1 yrs, the OS rate in these 19 patients is 100%. In conclusion, the 19 patients with MCD in this extension study have received Siltuximab for a prolonged period of time (median 5.1 yrs, up to 7.2 yrs). All patients are alive and maintain disease control. Prolonged Siltuximab treatment is well tolerated, with no evidence of new or cumulative toxicity or treatment discontinuations and with a low rate of serious adverse events including serious infections. Disclosures: Van Rhee: Janssen Research & Development: Research Funding. Casper: Janssen Research & Development: Research Funding. Voorhees: Janssen Research & Development: Research Funding; Abbott: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Membership on an entity’s Board of Directors or advisory committees; MedImmune: Membership on an entity’s Board of Directors or advisory committees. van de Velde: Johnson & Johnson: Equity Ownership; Janssen Research & Development: Employment. Vermeulen: Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qin: Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qi: Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Tromp: Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Kurzrock: Janssen Research & Development: Research Funding. [1]: /embed/inline-graphic-2.gif

  • a phase i open label study of Siltuximab an anti il 6 monoclonal antibody in patients with b cell non hodgkin lymphoma multiple myeloma or castleman disease
    Clinical Cancer Research, 2013
    Co-Authors: Razelle Kurzrock, Peter M Voorhees, Corey Casper, Richard R Furman, Luis Fayad, Sagar Lonial, Hossein Borghaei, Sundar Jagannath, Lubomir Sokol, Saad Z Usmani
    Abstract:

    Purpose: To evaluate the safety and pharmacokinetics of Siltuximab, an anti–interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease. Experimental Design: In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received Siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease. Results: Sixty-seven patients received a median of 16 Siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to Siltuximab, or apparent dose–toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia ( n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of Siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR. Conclusion: No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma. Clin Cancer Res; 19(13); 3659–70. ©2013 AACR .

  • a phase i open label study of Siltuximab an anti il 6 monoclonal antibody in patients with b cell non hodgkin lymphoma multiple myeloma or castleman disease
    Clinical Cancer Research, 2013
    Co-Authors: Razelle Kurzrock, Peter M Voorhees, Corey Casper, Richard R Furman, Luis Fayad, Sagar Lonial, Hossein Borghaei, Sundar Jagannath, Lubomir Sokol, Saad Z Usmani
    Abstract:

    Purpose: To evaluate the safety and pharmacokinetics of Siltuximab, an anti–interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease. Experimental Design: In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received Siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease. Results: Sixty-seven patients received a median of 16 Siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to Siltuximab, or apparent dose–toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia ( n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of Siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR. Conclusion: No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma. Clin Cancer Res; 19(13); 3659–70. ©2013 AACR .

Razelle Kurzrock - One of the best experts on this subject based on the ideXlab platform.

  • afebrile pneumonia in a patient with multicentric castleman disease on Siltuximab infection without fever on anti interleukin 6 therapy
    Cureus, 2020
    Co-Authors: Philip R Cohen, Mina Nikanjam, Shumei Kato, Aaron M Goodman, Razelle Kurzrock
    Abstract:

    Castleman disease is a lymphoproliferative disorder characterized by atypical lymph node hyperplasia and systemic symptoms; it can also affect the skin and blood counts. The condition is categorized by the extent of involvement (unicentric or multicentric) and the observed lymph node pathology (hyaline-vascular, plasma cell or mixed cellularity). Pathogenesis also has a role in the classification and treatment of multicentric Castleman disease; this variant can either be related to the presence of human herpesvirus-8 (HHV-8) infection or associated with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins and skin changes) syndrome, or idiopathic. The principal cytokine responsible for causing idiopathic multicentric Castleman disease (IMCD) is interleukin-6 (IL-6). Therefore, treatment with agents that bind to IL-6 (such as Siltuximab) or block the IL-6 receptor (such as tocilizumab) has been used. We report a woman with IMCD who was successfully being treated with Siltuximab; her cutaneous manifestations and systemic disease (lung and lymph nodes) improved within three months. However, nine months after starting Siltuximab, she developed a worsening cough and new infiltrates in the right lung on positron emission tomography/computed tomography (PET/CT) scan; there were no other constitutional symptoms such as fever, night sweats or fatigue. Differential diagnosis included Castleman disease recurrence, lung neoplasm and infection. Her pulmonary symptoms and infiltrates on scan resolved after treatment with systemic levofloxacin, indicating that she had an antibiotic-sensitive afebrile pneumonia. We postulate that her Siltuximab therapy blocked the IL-6-associated fever and constitutional symptoms that normally are a hallmark of pneumonia. Therefore, patients who are receiving medications such as Siltuximab and tocilizumab that block the IL-6 pathway and impair the acute phase inflammatory response may fail to manifest constitutional symptoms such as fever when infected.

  • long term safety of Siltuximab in patients with idiopathic multicentric castleman disease a prespecified open label extension analysis of two trials
    The Lancet Haematology, 2020
    Co-Authors: Frits Van Rhee, Peter M Voorhees, Corey Casper, Luis Fayad, Damilola Gibson, Karan Kanhai, Razelle Kurzrock
    Abstract:

    Background Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of Siltuximab over up to 6 years of treatment. Methods This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on Siltuximab. Patients received Siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of Siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27. Findings Patient enrolment into the phase 1 trial was from June 20, 2005, to Sept 15, 2009, and enrolment into the phase 2 trial was from Feb 9, 2010, to Feb 3, 2012. Patients were enrolled in this long-term extension from April 1, 2011, to Jan 15, 2014. Median follow-up was 6 years (IQR 5·11-7·76). Median treatment duration, from the beginning of the previous trials to the end of the present study, was 5·5 years (IQR 4·26-7·14). Siltuximab was well tolerated; however, adverse events of grade 3 or worse were reported in 36 (60%) of 60 patients with the most common being hypertension (eight [13%]), fatigue (five [8%]), nausea (four [7%]), neutropenia (four [7%]), and vomiting (three [5%]). 25 (42%) patients reported at least one serious adverse event, which most commonly was an infection (eight [13%]). Only two serious adverse events, polycythaemia and urinary retention, were considered related to Siltuximab treatment. 18 patients discontinued before study completion, either to receive Siltuximab locally (eight) or because of progressive disease (two), adverse events (two), or other reasons (six). No deaths were reported. Interpretation These results show that Siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients with idiopathic multicentric Castleman disease. Funding Janssen R&D and EUSA Pharma.

  • JAK1 Genomic Alteration Associated With Exceptional Response to Siltuximab in Cutaneous Castleman Disease
    JAMA dermatology, 2017
    Co-Authors: Maulik Patel, Sadakatsu Ikeda, Susan R. Pilat, Razelle Kurzrock
    Abstract:

    Importance Castleman disease (CD) is an ultrarare, interleukin-6 (IL-6)–driven lymphoproliferative disorder whose underlying molecular alterations are unknown. Siltuximab (anti–IL-6 antibody) is approved for treatment of this disease. To our knowledge, genomic sequencing of CD has not been reported. Objective To investigate and identify molecular aberration(s) that help explain the exceptional response to Siltuximab in a patient with cutaneous CD. Design, Setting, and Participants This case study examines data from comprehensive genomic profiling (using targeted next-generation sequencing) of tissue from a patient with cutaneous CD who demonstrated an exceptional response to Siltuximab treated at a National Cancer Institute–designated Comprehensive Cancer Center. Interventions Intravenous Siltuximab 12 mg/kg every 3 weeks. Tissue from the patient was interrogated by next-generation sequencing (405 genes). Serum was evaluated for IL-6 levels by enzyme-linked immunoassay. Main Outcomes and Measures Identification of pretreatment serum IL-6 levels and somatic variants that may explain the exceptional response to Siltuximab in this patient with cutaneous CD. Results Patient pretreatment serum IL-6 levels were normal. Treatment with Siltuximab resulted in a complete response lasting 7 years. Next-generation sequencing demonstrated a JAK1 V310I missense mutation. Janus Kinase 1 (JAK1) is a crucial signaling component of the IL-6/IL-6 receptor/gp130 machinery. JAK1 V310I may induce a conformation change with functional activation effect leading to enhanced sensitivity to the IL-6 ligand. Conclusions and Relevance Our observations suggest that a JAK1 alteration may explain the underlying biology of a patient’s cutaneous CD, as well as the patient’s exceptional response to Siltuximab.

  • Siltuximab: a targeted therapy for idiopathic multicentric Castleman disease
    Immunotherapy, 2015
    Co-Authors: David C. Fajgenbaum, Razelle Kurzrock
    Abstract:

    Human herpes virus-8 (HHV-8)-negative or idiopathic multicentric Castleman disease (iMCD) is a rare and deadly disorder that sits at the nexus of hematology/oncology, virology and immunology. Management of iMCD has been challenging due to limited understanding of etiology and pathogenesis and few treatment options. The recent approvals in North America, Europe and Brazil of Siltuximab, a monoclonal antibody against IL-6, for iMCD now provide a safe and effective therapy that targets a key aspect of pathogenesis. In the first ever randomized, placebo-controlled trial in iMCD, Siltuximab significantly reduced disease burden and symptoms in a large portion (34%) of patients. The optimal dose is 11 mg/kg intravenously every 3 weeks. At this time, duration of treatment is often life-long or until treatment failure. Additional research is needed to identify biomarkers that may assist with predicting treatment effectiveness in iMCD and to investigate the role of Siltuximab in HHV-8-positive MCD and pediatric iMCD patients.

  • a phase 2 open label multicenter study of the long term safety of Siltuximab an anti interleukin 6 monoclonal antibody in patients with multicentric castleman disease
    Oncotarget, 2015
    Co-Authors: Frits Van Rhee, Peter M Voorhees, Corey Casper, Luis Fayad, Jessica Vermeulen, Helgi Van De Velde, Xiang Qin, Brenda Tromp, Razelle Kurzrock
    Abstract:

    // Frits van Rhee 1 , Corey Casper 2 , Peter M. Voorhees 3 , Luis E. Fayad 4 , Helgi van de Velde 5 , Jessica Vermeulen 6 , Xiang Qin 7 , Ming Qi 7 , Brenda Tromp 6 , Razelle Kurzrock 4 1 Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA 3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA 4 MD Anderson Cancer Center, The University of Texas, Houston, TX, USA 5 Janssen Research & Development LLC, Beerse, Belgium 6 Janssen Research & Development LLC, Leiden, Netherlands 7 Janssen Research & Development LLC, Spring House, PA, USA Correspondence to: Frits van Rhee, e-mail: vanrheefrits@uams.edu Keywords: multi-centric Castleman's disease, interleukin-6, Siltuximab, clinical trial Received: February 26, 2015      Accepted: July 23, 2015      Published: August 03, 2015 ABSTRACT Background: Multicentric Castleman disease (MCD) is a rare, systemic lymphoproliferative disorder driven by interleukin (IL)-6 overproduction. Siltuximab, an anti-IL-6 monoclonal antibody, has demonstrated durable tumor and symptomatic responses in a multinational, randomized, placebo-controlled study of MCD. Methods: This preplanned safety analysis was conducted to evaluate the long-term safety of Siltuximab treatment among 19 patients with MCD who had stable disease or better and were enrolled in a phase-1 study and subsequent ongoing, open-label, phase-2 extension study. Dosing was 11 mg/kg administered intravenously every 3 weeks, per protocol, or every 6 weeks at the investigator's discretion. Safety monitoring focused on potential risks associated with the anti-IL-6 mechanism of action. Investigator-assessed disease control status was also documented. Results: Median treatment duration for the 19 patients was 5.1 (range 3.4, 7.2) years, with 14 (74%) patients treated for >4 years. Grade-≥3 adverse events (AEs) reported in >1 patient included hypertension ( n = 3) and nausea, cellulitis, and fatigue ( n = 2 each). Grade-≥3 AEs at least possibly attributed to Siltuximab were leukopenia, lymphopenia, and a serious AE of polycythemia ( n = 1 each). Hypertriglyceridemia and hypercholesterolemia (total cholesterol) were reported in 8 and 9 patients, respectively. No disease relapses were observed, and 8 of 19 patients were able to switch to an every-6-week dosing schedule. Conclusions: All MCD patients in this extension study have received Siltuximab for a prolonged duration (up to 7 years) without evidence of cumulative toxicity or treatment discontinuations and with few serious infections. All patients are alive, demonstrate sustained disease control, and continue to receive Siltuximab.

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  • insufficient evidence exists to use histopathologic subtype to guide treatment of idiopathic multicentric castleman disease
    American Journal of Hematology, 2020
    Co-Authors: David C. Fajgenbaum, Raymond Sm Wong, Aaron M Goodman, Amy Chadburn, Sunita D Nasta, Gordan Srkalovic, Sudipto Mukherjee, Heather A Leitch, Raj Jayanthan, Simone Ferrero
    Abstract:

    Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular (HyperV) more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with Siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends Siltuximab first-line for iMCD except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide Siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18/79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate Siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype. This article is protected by copyright. All rights reserved.

  • analysis of inflammatory and anemia related biomarkers in a randomized double blind placebo controlled study of Siltuximab anti il6 monoclonal antibody in patients with multicentric castleman disease
    Clinical Cancer Research, 2015
    Co-Authors: Corey Casper, Jessica Vermeulen, Shalini Chaturvedi, Nikhil C Munshi, Raymond Sm Wong, Michael Schaffer, Rajesh Bandekar, Brett Hall, Helgi Van De Velde, Manjula Reddy
    Abstract:

    Background: Siltuximab (interleukin-6 [IL-6] antibody) is approved for the treatment of multicentric Castleman9s disease (MCD). Effects of IL-6 inhibition on the inflammatory milieu accompanying MCD have not been characterized. Methods: Trends in inflammatory- and anemia-associated markers measured over the course of a placebo-controlled study of Siltuximab (11 mg/kg q3w) in MCD patients (N = 79) were characterized. Results: Baseline IL-6 and C-reactive protein (CRP) levels were significantly correlated (r = 0.708; P less than 0.0001). CRP levels decreased (median 92%) by Cycle 1 Day 8 (C1D8), remaining suppressed during Siltuximab treatment, while remaining stable in the placebo group. There were no associations between baseline CRP or IL-6 and MCD symptom burden, histologic subtype, ethnicity, maximum CRP decrease, and response parameters. A hemoglobin response (change greater than or equal to 15 g/L at Week 13) was observed with Siltuximab (61%; P = 0.0002). Median hepcidin decrease from baseline at C1D8 with Siltuximab was 47% versus median 11% increase with placebo. Maximum post-baseline changes in hepcidin levels among Siltuximab recipients were correlated with maximum changes for hemoglobin (r = −0.395; P = 0.00607), total iron binding capacity (TIBC; r = −0.354; P = 0.01694), and ferritin (r = 0.599, P = 0.0001). Greater median changes from baseline in ferritin, hemoglobin, and TIBC were observed in anemic Siltuximab-treated patients. Conclusion: IL-6 neutralization with Siltuximab resulted in sustained CRP suppression and improvement of anemia in part by hepcidin pathway inhibition.

  • patient reported outcomes for multicentric castleman s disease in a randomized placebo controlled study of Siltuximab
    The Patient: Patient-Centered Outcomes Research, 2015
    Co-Authors: Frits Van Rhee, Jessica Vermeulen, Nikhil C Munshi, Raymond Sm Wong, Alexander Fossa, Angela Dispenzieri, Margaret Rothman, James Cavet, Sarah Fleming, Corey Casper
    Abstract:

    Background Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder driven by dysregulated interleukin-6 production. MCD has a poor prognosis, and treatment is generally noncurative and aimed at symptom relief. Siltuximab is a novel, monoclonal interleukin-6 antibody recently shown to be effective in a registration clinical trial. MCD symptoms, such as fatigue, pain, and weakness, are most appropriately quantified using patient-reported outcome (PRO) measures. We assessed the effect of Siltuximab on patient perception of symptoms, functional status, and wellbeing using PRO instruments.

  • Patient-reported Outcomes for Multicentric Castleman’s Disease in a Randomized, Placebo-controlled Study of Siltuximab
    The patient, 2015
    Co-Authors: Frits Van Rhee, Nikhil C Munshi, Raymond Sm Wong, Alexander Fossa, Angela Dispenzieri, Margaret Rothman, James Cavet, Sarah Fleming, Jessica Vermeulen
    Abstract:

    Background Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder driven by dysregulated interleukin-6 production. MCD has a poor prognosis, and treatment is generally noncurative and aimed at symptom relief. Siltuximab is a novel, monoclonal interleukin-6 antibody recently shown to be effective in a registration clinical trial. MCD symptoms, such as fatigue, pain, and weakness, are most appropriately quantified using patient-reported outcome (PRO) measures. We assessed the effect of Siltuximab on patient perception of symptoms, functional status, and wellbeing using PRO instruments.

  • Superior Restoration of Health with Siltuximab Among Multicentric Castleman’s Disease Patients When Measured By SF-36
    Blood, 2014
    Co-Authors: Frits Van Rhee, Corey Casper, Jessica Vermeulen, Helgi Van De Velde, Margaret K Vernon, Dylan Trundell, Don Robinson, Raymond Sm Wong
    Abstract:

    INTRODUCTION Siltuximab (SylvantTM), a monoclonal antibody against interleukin-6, was recently approved in both US and EU for treatment of adult patients with Multicentric Castleman's Disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. Information on MCD symptoms, functioning and well-being was gathered in a pivotal global registration study (MCD2001, Van Rhee 2014) with a general patient reported outcome (PRO) questionnaire: the Short Form-36 (SF-36, acute version 2), and other PRO measures. OBJECTIVES Evaluate the longitudinal impact of Siltuximab on symptoms, functioning and well-being as measured by SF-36 when compared to placebo. METHODS MCD2001 was a randomized (2:1), double-blind, placebo-controlled, multicenter study to determine the safety and efficacy of Siltuximab in patients with symptomatic MCD. Patients received Siltuximab 11 mg/kg or placebo by intravenous infusion every 3 weeks in combination with best supportive care (BSC). Subjects (N = 79) completed the SF-36 at baseline and every three weeks throughout the treatment period; 1998 scoring weights were applied. Patients, whose baseline SF-36 domain scores were below the general population norm for their age group (n = 46) were included in an analysis to compare by treatment arm the proportion of patients achieving an SF-36 domain score equal to, or greater than, the population norm at final visit. This analysis, hereafter referred to as a return to general population health norms (RTN), was conducted separately for each SF-36 domain. It is regarded as clinically-relevant improvement (CRI) since disease control is the current treatment goal. Referent norms were based on the US general population SF-36 cohort from the Medical Outcomes Study (Ware et al 1998). An intent-to-treat analysis was applied where missing data were not imputed; data were censored at treatment discontinuation, including crossover. Odds ratio was calculated between the two treatment arms and statistically compared with the Fisher’s Exact test. RESULTS At baseline the population demonstrated inferior health compared to general population across all SF-36 domains ([Figure 1][1]). The odds of Siltuximab-treated patients for reaching RTN vs. placebo patients in the Vitality, Role-emotional and Social functioning domains are significant, with odds ratios of 5.3 (p=0.049), 5.5 (p=0.011) and 11.4 (p=0.014), respectively. A positive health trend was observed for patients who received Siltuximab compared with placebo across all other domains, particularly Role-physical (5.5, p=0.067; [Figure 2][2]). Sensitivity analysis using a literature-based CRI supported the robustness of the results. CONCLUSION Overall MCD patients reported notably inferior health compared to the general population at baseline; Siltuximab significantly improved the odds for RTN versus placebo in the Role-emotional, Vitality and Social function domains, as well as demonstrated a trend to improve health across all other SF-36 domains among MCD patients who were below the norms at baseline. A clinically-relevant PRO benefit for physical and mental health was observed with Siltuximab therapy, as measured with the SF-36, which supports the “disease control” treatment goal. References Van Rhee et al. Siltuximab for multicentric Castleman’s disease:a randomised, double-blind, placebo-controlled trial, Lancet Oncol, 2014, 15(9):966-74 Teschendorf B et al. Development and Content Validation of a Multicentric Castleman’s Disease Symptom Scale; Value in Health, 2010, 13(7): A470 Ware et al. SF-36v2 health survey: manual and interpretation guide. 1998 ![Figure][3] ![Figure][3] Disclosures van Rhee: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Casper: Janssen: Consultancy, Research Funding. Robinson: Johnson & Johnson: Employment, Stocks Other. He: Janssen: Employment, Equity Ownership. Vermeulen: Janssen Biologics: Employment, Equity Ownership, Honoraria. van de Velde: Janssen Research & Development: Employment, Equity Ownership. Wong: Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Biogen-Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. [1]: #F1 [2]: #F2 [3]: pending:yes

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  • long term safety of Siltuximab in patients with idiopathic multicentric castleman disease a prespecified open label extension analysis of two trials
    The Lancet Haematology, 2020
    Co-Authors: Frits Van Rhee, Peter M Voorhees, Corey Casper, Luis Fayad, Damilola Gibson, Karan Kanhai, Razelle Kurzrock
    Abstract:

    Background Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of Siltuximab over up to 6 years of treatment. Methods This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on Siltuximab. Patients received Siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of Siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27. Findings Patient enrolment into the phase 1 trial was from June 20, 2005, to Sept 15, 2009, and enrolment into the phase 2 trial was from Feb 9, 2010, to Feb 3, 2012. Patients were enrolled in this long-term extension from April 1, 2011, to Jan 15, 2014. Median follow-up was 6 years (IQR 5·11-7·76). Median treatment duration, from the beginning of the previous trials to the end of the present study, was 5·5 years (IQR 4·26-7·14). Siltuximab was well tolerated; however, adverse events of grade 3 or worse were reported in 36 (60%) of 60 patients with the most common being hypertension (eight [13%]), fatigue (five [8%]), nausea (four [7%]), neutropenia (four [7%]), and vomiting (three [5%]). 25 (42%) patients reported at least one serious adverse event, which most commonly was an infection (eight [13%]). Only two serious adverse events, polycythaemia and urinary retention, were considered related to Siltuximab treatment. 18 patients discontinued before study completion, either to receive Siltuximab locally (eight) or because of progressive disease (two), adverse events (two), or other reasons (six). No deaths were reported. Interpretation These results show that Siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients with idiopathic multicentric Castleman disease. Funding Janssen R&D and EUSA Pharma.

  • a phase 2 open label multicenter study of the long term safety of Siltuximab an anti interleukin 6 monoclonal antibody in patients with multicentric castleman disease
    Oncotarget, 2015
    Co-Authors: Frits Van Rhee, Peter M Voorhees, Corey Casper, Luis Fayad, Jessica Vermeulen, Helgi Van De Velde, Xiang Qin, Brenda Tromp, Razelle Kurzrock
    Abstract:

    // Frits van Rhee 1 , Corey Casper 2 , Peter M. Voorhees 3 , Luis E. Fayad 4 , Helgi van de Velde 5 , Jessica Vermeulen 6 , Xiang Qin 7 , Ming Qi 7 , Brenda Tromp 6 , Razelle Kurzrock 4 1 Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA 3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA 4 MD Anderson Cancer Center, The University of Texas, Houston, TX, USA 5 Janssen Research & Development LLC, Beerse, Belgium 6 Janssen Research & Development LLC, Leiden, Netherlands 7 Janssen Research & Development LLC, Spring House, PA, USA Correspondence to: Frits van Rhee, e-mail: vanrheefrits@uams.edu Keywords: multi-centric Castleman's disease, interleukin-6, Siltuximab, clinical trial Received: February 26, 2015      Accepted: July 23, 2015      Published: August 03, 2015 ABSTRACT Background: Multicentric Castleman disease (MCD) is a rare, systemic lymphoproliferative disorder driven by interleukin (IL)-6 overproduction. Siltuximab, an anti-IL-6 monoclonal antibody, has demonstrated durable tumor and symptomatic responses in a multinational, randomized, placebo-controlled study of MCD. Methods: This preplanned safety analysis was conducted to evaluate the long-term safety of Siltuximab treatment among 19 patients with MCD who had stable disease or better and were enrolled in a phase-1 study and subsequent ongoing, open-label, phase-2 extension study. Dosing was 11 mg/kg administered intravenously every 3 weeks, per protocol, or every 6 weeks at the investigator's discretion. Safety monitoring focused on potential risks associated with the anti-IL-6 mechanism of action. Investigator-assessed disease control status was also documented. Results: Median treatment duration for the 19 patients was 5.1 (range 3.4, 7.2) years, with 14 (74%) patients treated for >4 years. Grade-≥3 adverse events (AEs) reported in >1 patient included hypertension ( n = 3) and nausea, cellulitis, and fatigue ( n = 2 each). Grade-≥3 AEs at least possibly attributed to Siltuximab were leukopenia, lymphopenia, and a serious AE of polycythemia ( n = 1 each). Hypertriglyceridemia and hypercholesterolemia (total cholesterol) were reported in 8 and 9 patients, respectively. No disease relapses were observed, and 8 of 19 patients were able to switch to an every-6-week dosing schedule. Conclusions: All MCD patients in this extension study have received Siltuximab for a prolonged duration (up to 7 years) without evidence of cumulative toxicity or treatment discontinuations and with few serious infections. All patients are alive, demonstrate sustained disease control, and continue to receive Siltuximab.

  • analysis of inflammatory and anemia related biomarkers in a randomized double blind placebo controlled study of Siltuximab anti il6 monoclonal antibody in patients with multicentric castleman disease
    Clinical Cancer Research, 2015
    Co-Authors: Corey Casper, Jessica Vermeulen, Shalini Chaturvedi, Nikhil C Munshi, Raymond Sm Wong, Michael Schaffer, Rajesh Bandekar, Brett Hall, Helgi Van De Velde, Manjula Reddy
    Abstract:

    Background: Siltuximab (interleukin-6 [IL-6] antibody) is approved for the treatment of multicentric Castleman9s disease (MCD). Effects of IL-6 inhibition on the inflammatory milieu accompanying MCD have not been characterized. Methods: Trends in inflammatory- and anemia-associated markers measured over the course of a placebo-controlled study of Siltuximab (11 mg/kg q3w) in MCD patients (N = 79) were characterized. Results: Baseline IL-6 and C-reactive protein (CRP) levels were significantly correlated (r = 0.708; P less than 0.0001). CRP levels decreased (median 92%) by Cycle 1 Day 8 (C1D8), remaining suppressed during Siltuximab treatment, while remaining stable in the placebo group. There were no associations between baseline CRP or IL-6 and MCD symptom burden, histologic subtype, ethnicity, maximum CRP decrease, and response parameters. A hemoglobin response (change greater than or equal to 15 g/L at Week 13) was observed with Siltuximab (61%; P = 0.0002). Median hepcidin decrease from baseline at C1D8 with Siltuximab was 47% versus median 11% increase with placebo. Maximum post-baseline changes in hepcidin levels among Siltuximab recipients were correlated with maximum changes for hemoglobin (r = −0.395; P = 0.00607), total iron binding capacity (TIBC; r = −0.354; P = 0.01694), and ferritin (r = 0.599, P = 0.0001). Greater median changes from baseline in ferritin, hemoglobin, and TIBC were observed in anemic Siltuximab-treated patients. Conclusion: IL-6 neutralization with Siltuximab resulted in sustained CRP suppression and improvement of anemia in part by hepcidin pathway inhibition.

  • patient reported outcomes for multicentric castleman s disease in a randomized placebo controlled study of Siltuximab
    The Patient: Patient-Centered Outcomes Research, 2015
    Co-Authors: Frits Van Rhee, Jessica Vermeulen, Nikhil C Munshi, Raymond Sm Wong, Alexander Fossa, Angela Dispenzieri, Margaret Rothman, James Cavet, Sarah Fleming, Corey Casper
    Abstract:

    Background Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder driven by dysregulated interleukin-6 production. MCD has a poor prognosis, and treatment is generally noncurative and aimed at symptom relief. Siltuximab is a novel, monoclonal interleukin-6 antibody recently shown to be effective in a registration clinical trial. MCD symptoms, such as fatigue, pain, and weakness, are most appropriately quantified using patient-reported outcome (PRO) measures. We assessed the effect of Siltuximab on patient perception of symptoms, functional status, and wellbeing using PRO instruments.

  • ORIGINAL RESEARCH ARTICLE Patient-reported Outcomes for Multicentric Castleman’s Disease in a Randomized, Placebo-controlled Study of Siltuximab
    2015
    Co-Authors: Frits Rhee, Corey Casper, Jessica Vermeulen, Margaret Rothman, Kai Fai, Ho Sarah Fleming, Raymond Wong S. Alex, James Cavet, Nikhil Munshi
    Abstract:

    The Author(s) 2015. This article is published with open access at Springerlink.com Background Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder driven by dysregulated interleukin-6 production. MCD has a poor prognosis, and treatment is generally noncurative and aimed at symptom relief. Siltuximab is a novel, monoclonal interleukin-6 antibody recently shown to be effective in a registration clinical trial. MCD symptoms, such as fatigue, pain, and weakness, are most appropriately quantified using patient-reported outcome (PRO) measures. We assessed the effect of Siltuximab on patient perception of symptoms, func-tional status, and wellbeing using PRO instruments. Methods We analyzed results of a randomized, double-blind trial comparing Siltuximab 11 mg/kg every 3 week