INSIDE THE BLACK BOX is an occasional column providing insight into the FDA and its policies and procedures. In this installment, FDA hematologist/oncologist Albert Deisseroth, MD, PhD, discusses the recent approval of siltuximab for patients with multicentric Castleman’s disease who are human immunodeficiency virus (HIV)– and human herpesvirus-8 (HHV-8)–negative. Dr. Deisseroth is a Clinical Team Leader in the Division of Hematology Products, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research.
On April 22, 2014, the U.S. Food and Drug Administration (FDA) approved the interleukin-6 (IL-6) antagonist siltuximab (Sylvant) for the treatment of patients with multicentric Castleman’s disease who are HIV-negative and HHV-8–negative. The ASCO Post spoke to Dr. Deisseroth about this uncommon lymphoproliferative disorder and the trial that led to siltuximab’s approval.
Rare Disorder
What is Castleman’s disease, and what are its clinical manifestations?
Castleman’s disease, also known as angiofollicular lymph node hyperplasia, is a very rare disorder characterized by hyperplasia of lymphoid tissue that results in lymphadenopathy (unicentric or multicentric) and is often associated with HIV and HHV-8 infections. The lymphadenopathy is associated with symptoms of fatigue, fever, weakness, day or night sweats, anorexia, pruritus, pain, and/or dyspnea. In addition, patients with Castleman’s disease have physical findings of weight loss, fluid retention, edema, effusions, ascites, neuropathy, skin rashes, skin nodules, anemia, and/or splenomegaly and hepatomegaly.
There are three different histopathologic variants: the plasmacytic variant, the hyaline vascular variant, and the mixed subtype. Castleman’s disease, especially the hyaline vascular form, has been reported to progress into a clonal proliferation of lymphocytes and may evolve into non-Hodgkin lymphoma.
Treatment Options
What therapies are available to treat patients with multicentric Castleman’s disease?
Prior to siltuximab’s approval, there were no approved therapies in the United States for multicentric Castleman’s disease. Palliative treatment with chemotherapy and steroids has been tried. Rituximab (Rituxan) has been used in multicentric Castleman’s disease alone and in combination with chemotherapy (eg, liposomal doxorubicin). Initial responses occur but may be followed by relapse and progression of disease.
There have been case reports of responses to bortezomib (Velcade), thalidomide (Thalomid), and the thalidomide/rituximab combination. Autologous bone marrow transplantation following high-dose chemotherapy has also been tried.
Underlying Mechanism
What is the rationale for testing siltuximab in multicentric Castleman’s disease?
Excessive secretion of IL-6 is thought to play a role in the generation of the signs and symptoms of the disease. Transgenic mice with the human IL-6 gene have high levels of IL-6 from birth and develop a disease that resembles multicentric Castleman’s disease. Treatment of these mice with an antibody to the IL-6 receptor reduces the severity of the multicentric Castleman’s disease–like disease.
Siltuximab is a human-mouse chimeric IgG1 monoclonal antibody that binds human IL-6, thereby preventing its interaction with the IL-6 receptor. A phase I study of siltuximab in 37 patients with Castleman’s disease demonstrated one complete and eight partial responses in patients treated with the 11 mg/kg dose.
Study Design
What were the most important design features of the trial used to support marketing approval of siltuximab?
The randomized placebo-controlled trial of siltuximab enrolled patients with multicentric Castleman’s disease and excluded patients with known HIV or HHV-8 infections. A total of 79 men and women with symptomatic and measurable multicentric Castleman’s disease were allocated (2:1) to best supportive care with siltuximab (n = 53) or to best supportive care with placebo (n = 26).
Patients were treated with siltuximab at 11 mg/kg or placebo intravenously every 3 weeks until treatment failure, discontinuation of treatment, withdrawal from the study, or 48 weeks after the last subject started study treatment. Patients who met the criteria for treatment failure were allowed to cross over from the placebo arm to the siltuximab arm. The primary endpoint of the trial was the proportion of patients in each arm achieving a durable tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure.
One of the most interesting parts of the clinical trial design was the definition of the primary endpoint: a composite of tumor response (reduction of lymphadenopathy on computed tomgraphy [CT] scans by independent review), response as measured by clinician-reported severity of symptoms, and response as measured by physical signs of the disease as reported by the investigator.
Tumor response was defined as a complete or partial response of the lymph node masses as assessed by independent review of CT scans using the International Working Group response criteria for malignant lymphoma. Symptomatic response was defined as complete resolution or stabilization of 34 Castleman’s disease–related signs and symptoms as defined by the multicentric Castleman’s disease–related overall symptom score. This score was calculated as the sum of the investigator-determined severity (NCI-CTCAE) grades of the multicentric Castleman’s disease–related signs and symptoms. The percentage change from baseline was calculated at the beginning of each cycle of therapy.
If the difference of the primary endpoint (proportion of patients achieving a durable tumor and symptomatic response) on each arm achieved statistical significance, the following secondary endpoints were analyzed in a fixed order: tumor response by central review, time to treatment failure, the percentage of patients on each arm in whom the hemoglobin level increased ≥ 1.5 g/dL over baseline at week 13, the median time to improvement in the Multicentric Castleman’s Disease Symptom Scale (as reported by patients), the median time to improvement in the Functional Assessment of Chronic Illness Therapy–Fatigue score, and the proportion of patients who were corticosteroid-free for at least 9 consecutive weeks during the blinded treatment period.
Baseline Data
What were the disease and demographic characteristics of patients enrolled on the trial?
Only patients with multicentric Castleman’s disease were eligible. Of all patients enrolled, 33% had the hyaline vascular subtype, 23% had the plasmacytic subtype, and 44% had the mixed subtype. About 19% had one to three symptoms of multicentric Castleman’s disease prior to initiation of therapy, 81% had four or more symptoms, and 58% had received at least one prior treatment. As mentioned before, patients positive for HIV or HHV-8 infection were excluded.
Why were patients with HIV or HHV-8 infections excluded from the trial?
Siltuximab was not studied in this patient population because the drug did not bind to virally produced IL-6 in a nonclinical study.
Key Findings
What were the results of the trial?
The durable tumor and symptom response rate was 34% on the siltuximab arm compared to no response on the placebo arm, a result that was statistically and clinically significant. This difference was seen across all subsets except for subsets defined by histopathology. There were no responses among 18 patients in the hyaline vascular subset, 8 responses among 13 patients in the plasmacytic subset, and 10 responses among 22 patients in the mixed subsets. The median duration of response was 383 days.
The results of three of the six secondary endpoints were statistically significant. The percentage of patients on the siltuximab and placebo arms with a partial response or better was 38% and 4%, respectively. With 424 days of follow-up, the time to treatment failure was not reached on the siltuximab arm and was 134 days on the placebo arm. For the hyaline vascular subset, the time to treatment failure was 206 days on the siltuximab arm and 70 days on the placebo arm.
Approximately 61% of patients treated with siltuximab experienced an increase in hemoglobin ≥ 1.5g/dL at 13 weeks, whereas no patient on the placebo arm did. Additionally, 17% of patients in the hyaline vascular subset experienced an increase in hemoglobin level ≥ 1.5 g/dL at 13 weeks of treatment with siltuximab, compared to none on the placebo arm.
Adverse Events
What were the safety issues?
The most common adverse reactions (> 10% compared to placebo) with siltuximab in the randomized trial were pruritis, increased weight, rash, hyperuricemia, and upper respiratory tract infection.
Overall, about 750 patients have been treated with siltuximab. One patient was reported to have experienced an anaphylactic reaction. Among 249 patients treated with siltuximab monotherapy, infusion reactions were reported in 4.8%.
The median number of completed infusions was more than double in the siltuximab group (19 infusions) compared with the placebo group (8 infusions). The median duration of treatment was 375 days in the siltuximab arm and 152 days in the placebo arm. There were no adverse events leading to death, and the percentage of patients who discontinued treatment due to adverse events was 23% on the siltuximab arm and 39% on the placebo arm.
Risk-Benefit Assessment
How would you characterize the risks and potential benefits of siltuximab for multicentric Castleman’s disease?
Multicentric Castleman’s disease is a disease of lymphadenopathy accompanied by signs and symptoms associated with elevated levels of IL-6. Infusions of siltuximab are well tolerated, and many patients remain on therapy for years. There is no other FDA-approved therapy for patients with multicentric Castleman’s disease, and for patients with multicentric Castleman’s disease and no HIV or HHV-8 infection, siltuximab provides symptomatic relief to a substantial number of patients with acceptable toxicity.
Closing Thoughts
What are your concluding thoughts about the approval of siltuximab for multicentric Castleman’s disease?
There are several notable features of the FDA approval of siltuximab for multicentric Castleman’s disease. This is the first treatment FDA-approved for this very rare disease and the first approval of an anti-IL-6 antibody in the U. S. In addition, the treatment targets the basic pathophysiologic mechanism of the disease. Despite the rarity of the disease and the many hurdles that had to be overcome in launching this global randomized trial, sufficient numbers of patients were enrolled and the trial met its prespecified primary endpoint as well as three secondary
endpoints. ■
Disclosure: Dr. Deisseroth reported no potential conflicts of interest.
Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of
Hematology and Oncology Products.
