E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Multicentric Castleman's disease |
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E.1.1.1 | Medical condition in easily understood language |
Multicentric Castleman's disease |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10050251 |
E.1.2 | Term | Castleman's disease |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to demonstrate that CNTO 328 in combination with BSC is superior to BSC in terms of durable tumor and symtomatic response among subjects with multicentric Castleman’s disease (MCD). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To demonstrate additional measures of efficacy (tumor response; duration of response; time to treatment failure; change in hemoglobin levels; ability to discontinue corticosteroids; and improvement in fatigue, physical function, and other disease-related symptoms)
• To study the safety of prolonged dosing
• To determine the pharmacokinetics of CNTO 328 among subjects with MCD
• To determine a baseline hepcidin value predictive of a ≥ 2 g/dL increase in hemoglobin |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Measurable and symptomatic MCD proven by biopsy and confirmed by central pathology review. Symptomatic disease is defined clinically by the presence of symptoms with NCI-CTCAE grading ≥ 1 that are attributable to the disease, and for which treatment is indicated. Subjects are required to have measurable disease, which may not be limited to cutaneous lesions. Laboratory abnormalities (eg, elevations in acute-phase proteins [CRP, fibrinogen] and increased ESR) in the absence of clinical symptoms do not qualify as symptomatic disease.
2. ≥ 18 years of age
3. Pretreatment clinical laboratory values meeting these criteria within 4 weeks before treatment:
a. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
b. Platelets ≥ 75 x 109/L
c. ALT within 2.5 xx ULN; total bilirubin within 2.5 x ULN; unfractionated alkaline phosphatase within 2.5 x ULN; if unfractionated alkaline phosphatase is above 2.5 x ULN, subjects will be eligible if alkaline phosphatase liver fraction is within 2.5 x ULN
d. Serum creatinine ≤ 3.0 mg/dL
4. ECOG Performance Status of 0, 1, or 2
5. Corticosteroids dose that does not exceed 1 mg/kg/day of prednisone (or equivalent) and has remained stable or decreased over the 4 weeks before randomization
6. Women of childbearing potential must agree to use adequate birth control measures during the study and for 3 months after receiving the last dose of study agent, and must have a negative pregnancy test (serum or urine beta human chorionic gonadotropin [β-HCG]) at screening. Men must agree to use adequate birth control measures and to not donate sperm during the study and for 3 months after receiving the last dose of study agent.
7. Subjects (or their legally-acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. Informed consent must be obtained before performing any study-specific procedures. |
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E.4 | Principal exclusion criteria |
1. HIV or HHV-8 positive
2. Skin lesions as sole measurable manifestation of MCD
3. Previous lymphoma
4. Malignancies, except for adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or cancer other than lymphoma, from which the subject has been disease-free for ≥ 3 years.
5. Concurrent medical condition or disease (eg, autoimmune disease, active systemic
infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is
likely to interfere with study procedures or results, or that in the opinion of the
investigator would constitute a hazard for participating in this study
6. Prior exposure to agents targeting IL 6 or the IL 6 receptor
7. Use of disallowed therapies: other concomitant anti-tumor therapies for Castleman’s disease (eg, anti-CD20 antibodies, IL-6- or IL-6 receptor-targeted therapies, chemotherapy), biologic treatments such as anti-tumor necrosis factor α (TNFα) antibodies, immunosuppressive agents (except stable doses of corticosteroids), and erythropoietin stimulating agents (ESAs)
8. Received an investigational drug (including vaccines), ESAs, or any systemic
treatment for Castleman’s disease within 4 weeks (or in the case of rituximab, within
8 weeks) before the planned start of treatment
9. Major surgery within 4 weeks of treatment
10. History of uncontrolled heart disease such as unstable angina, congestive heart
failure, myocardial infarction within preceding 12 months, hemodynamic instability
or known left ventricular ejection fraction (LVEF) < 30%, or clinically significant
rhythm or conduction abnormality
11. Clinically significant infections, including known hepatitis C infection or known to be hepatitis B surface antigen (HBsAg) positive
12. History of allogeneic transplant (except corneal transplants)
13. Known, unmanageable severe infusion related reactions to monoclonal antibodies or to murine, chimeric, or human proteins or their excipients
14. Pregnant or nursing
15. Vaccination with live, attenuated vaccines within 4 weeks of first administration of
study agent
16. Paraneoplastic pemphigus or bronchiolitis obliterans
17. Any condition that, in the opinion of the investigator, would compromise the wellbeing of the subject or the study or prevent the subject from meeting or performing study requirements |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be durable tumor and symptomatic response. For definitions, see Section 9.2.2 of the protocol. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Treatment failure, discontinuation of treatment, withdrawal from the study, or until 48 weeks after the last subject starts study treatment, whichever occurs earlier. |
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E.5.2 | Secondary end point(s) |
- Duration of tumor and symptomatic response (whenever possible, treatment failure documented by the appearance of new lesions should be confirmed by histologic examination of the new lesions)
- Tumor response
- Duration of tumor response (whenever possible, tumor progression documented by the appearance of new lesions should be confirmed by histologic examination of the new lesions)
- Time to treatment failure
- Maximum change from baseline in hemoglobin in the absence of transfusion
- Proportion of subjects who are able to discontinue corticosteroids |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Treatment failure, discontinuation of treatment, withdrawal from the study, or until 48 weeks after the last subject starts study treatment, whichever occurs earlier. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Brazil |
Canada |
China |
Egypt |
France |
Germany |
Hong Kong |
Hungary |
India |
Israel |
Korea, Republic of |
Malaysia |
Netherlands |
New Zealand |
Norway |
Russian Federation |
Singapore |
Spain |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study is defined as 48 weeks after the last subject starts study treatment, to increase the power of the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 8 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 25 |