The primary objective is to assess the clinical efficacy of siltuximab (a chimeric (murine-human) IgG1* mAb that specifically binds human IL-6 with high affinity and prevents its interaction with the IL-6 receptor, glycoprotein (GP) 80),…
ID
Source
Brief title
Condition
- Other condition
- Red blood cell disorders
Synonym
Health condition
myelodysplastic syndrome (MDS)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the trial (page 10 of protocol) is *to assess the
clinical efficacy of siltuximab, demonstrated by a reduction in RBC
transfusions to treat the anemia of MDS*
Secondary outcome
-To demonstrate symptomatic improvement of subjects treated with siltuximab
compared with the
placebo group
-To compare the number of RBC units transfused to treat the anemia of MDS, and
the proportion of
subjects treated with siltuximab who do not require a RBC transfusion to treat
the anemia of MDS,
from Week 5 to Week 12, compared with the placebo group
-To assess the change in hemoglobin among MDS subjects treated with siltuximab
compared with the
placebo group
-To compare disease progression (proportion of bone marrow blasts and
cytogenetic change) for
subjects treated with siltuximab compared with the placebo group
-To assess the safety profile of siltuximab and RBC transfusions among subjects
with Low- or
Intermediate-1 (INT-1)-risk MDS
-To assess the pharmacodynamics, pharmacokinetics, and antibodies to siltuximab
(immunogenicity) in
MDS subjects
-To investigate a biomarker profile that predicts response to siltuximab in
this MDS population
-To perform an initial validation of a new patient-reported outcome (PRO)
instrument (Non-
Chemotherapy Anemia Symptom Scale [NCA-SS])
-To assess medical resource utilization (MRU), workforce behavior, and global
productivity associated
with health status in MDS subjects
Background summary
- Serum levels of IL-6 are known to be elevated in MDS, raising the possibility
that inflammation may play an important role in the anemia associated with this
disease. Dysregulated hepcidin is the principal mechanism underlying the anemia
of inflammation, and increases in IL-6 have been shown toinduce the synthesis
of hepcidin.
- The role of the bone marrow microenvironment in MDS has been investigated.
Fibroblasts derived from MDS marrow produced significantly higher levels of
IL-6 and tumor necrosis factor-*, (TNF-*), and MDS macrophages produce
significantly higher levels of TNF-* than do their normal counterparts.8 In
addition, a common morphological change within MDS marrow cells is the presence
of abnormal mitochondrial iron accumulation, which is not confined to the
refractory anemia with ringed sideroblast subtype of MDS and may contribute to
numerous MDS pathophysiologic processes.11 Hepcidin, through its effect on
ferroportin, is profoundly involved in control of intracellular iron, raising
the possibility that IL-6 may be a mediator of disease
progression in MDS
Study objective
The primary objective is to assess the clinical efficacy of siltuximab (a
chimeric (murine-human) IgG1* mAb that specifically binds human IL-6 with high
affinity and prevents its interaction with the IL-6 receptor, glycoprotein (GP)
80), demonstrated by a reduction in RBC transfusions to treat the anemia of
MDS.
Study design
The hypothesis for this study is that a higher proportion of siltuximab-treated
subjects will achieve a reduction in RBC transfusions to treat the anemia of
Low- and INT-1-risk MDS patients, compared with the placebo group.
Approximately 75 subjects will be randomized in a 2:1 ratio to receive
siltuximab (15 mg/kg) administered as a 1 hour infusion every 4 weeks + Best
Standard Care (BSA) (Group A) (n=50) or placebo administered as a 1-hour
infusion every 4 weeks + BSC (Group B) (n=25). BSC includes RBC transfusion,
antimicrobials, white blood cell (WBC) growth factors, platelet transfusions,
and thrombopoietic agents, as indicated by institutional guidelines and the
clinical status of the subject. The treatment for each subject will be
unblinded after 12 weeks of treatment, or at the time of treatment
discontinuation, if prior to Week 13. Subjects who complete 12 weeks of
treatment may qualify to receive open-label siltuximab as follows:
* Subjects receiving siltuximab who experience treatment failure will
discontinue treatment and enter the Posttreatment Period.
* Subjects receiving siltuximab who have not experienced treatment failure may
continue to receive open-label siltuximab.
* Subjects receiving placebo who experience treatment failure will have the
option to cross-over to open-label siltuximab. Subjects who do not cross-over
to treatment with siltuximab will discontinue treatment and enter the
Posttreatment Period.
* Subjects receiving placebo who have not experienced treatment failure are to
discontinue treatment and enter the Posttreatment Period. However, at the
investigator*s discretion, and after sponsor approval, subjects may cross-over
to receive open-label siltuximab.
In addition, treatment may continue until death, unacceptable toxicity,
withdrawal of consent, or the clinical cutoff (defined as 24 weeks after the
last subject is randomized), whichever occurs first. All subjects who
discontinue treatment and who have not withdrawn consent for study
participation will have an End of Treatment Visit (4 weeks after the last study
agent administration) as well as posttreatment visits at 8 and 12 weeks after
the last study agent administration. The study will end approximately 36 weeks
after the last subject is randomized. Periodical unblinded data will be
reviewed by a Data Monitoring Committee (DMC). An interim analysis for
futility only will be conducted after approximately 40 subjects complete 12
weeks of treatment.
Intervention
see study design
Study burden and risks
Regarding the study, the patients will have up to 16 visits, when they
participate in the blinded phase and then follow-up phase only. If the patient
and doctor choose for the open-label phase, then there is an extra monthly
visit for the injection. During these visits the usual physical tests will be
performed and a blood sample will be taken by the patient, also the patient
will be asked to complete 4 questionnaires. These visits will take the patient
maximal 4 hours.
Taking blood may cause bruising at the place where the needle goes into the
skin. The patient may experience discomfort or pain from the bone marrow
bioptsy / puncture. And the patient may have a reaction to the injection.
It is estimated that the overall safety profile will be similar to the
experience to date. All details regarding the product Siltuximab are
documentated in the Investigator Brochure.
Antwerpseweg 15-17
2340 Beerse
BE
Antwerpseweg 15-17
2340 Beerse
BE
Listed location countries
Age
Inclusion criteria
1. At least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place)
2. Confirmed diagnosis of MDS, according to WHO or FAB pathologic classification, with an IPSS score 0, 0.5, or 1.0, indicating Low- or INT-1- risk disease. Subjects with 5q- or PDGFR gene mutations are eligible if they are intolerant to or have failed prior specific therapy (eg, lenalidomide and imatinib mesylate).
3. Documented RBC transfusion of at least 2 units of RBC for the treatment of the anemia of MDS in the 8 weeks preceding the start of the Screening Period.
4. Adequate iron stores, demonstrated by either the presence of stainable iron in the bone marrow or a serum ferritin of > 100 ng/mL
5. ECOG performance status score of 0 to 2
6. Symptomatic anemia (defined by a score > 0 on the NCA-SS).
7. 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 have a negative serum or urine beta human chorionic gonadotropin (beta hCG) pregnancy test at screening. Men must agree to use a double barrier method of birth control and to not donate sperm during the study and for 3 months after receiving the last dose of study agent
8.Be willing and able to adhere to the prohibitions and restrictions specified in this protocol 9.Sign 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
Exclusion criteria
1.Had treatment with ESAs, androgens, hypomethylating agents, immunomodulatory drugs (IMiDs), or other agents targeting IL-6 or its receptor within 4 weeks of randomization
2.Any condition that, in the opinion of the investigator, would make participation not be in the best interest (eg, compromise the well-being) of the subject or that could prevent, limit, or confound the protocolspecified assessments (eg, has a history of clinically significant, uncontrolled disease of the pulmonary, cardiovascular, endocrine, neurologic, gastrointestinal, or genitourinary systems that is not attributable to MDS). Subjects with Chronic Myelomonocytic Leukemia (CMML) are to be excluded from the study.
3.Causes other than MDS contributing to anemia, such as Vitamin B12 or folate deficiency, bleeding, hemolysis, hemoglobinopathy, or chronic renal failure
4.Known unmanageable allergies, hypersensitivity, or intolerance to monoclonal antibodies or to murine, chimeric, or human proteins or their excipients
5.A history of seropositivity for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) (Note: HBV antibodypositivity is not a reason for exclusion from the study) 6.Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 30 days or 5 half lives before randomization or is currently enrolled in an investigational study
7.Had a modification of an effective preexisting therapy for the explicit purpose of entering the study.
8.Is a woman who is pregnant, or breast-feeding, or planning to become pregnant or is a man who plans to father a child while enrolled in this study or within 12 weeks after the last dose of study agent
9.Had hospitalization for infection or major surgery, (eg, requiring general anesthesia) within 2 weeks before randomization or will not have fully recovered from surgery. Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate
10.Been vaccinated with live, attenuated vaccines within 4 weeks of randomization
11.Has clinically significant laboratory abnormalities: *Platelets < 20 x 109/L *Estimated glomerular filtration rate (eGFR) <=20 mL/min *Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) * 2.5 x upper limit of normal (ULN) *Bilirubin > 2.5 x ULN *Alkaline phosphatase * 3 x ULN
12.Is an employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a subject's status (including laboratory results) changes after screening but before the first dose of study agent is given such that they now meet an exclusion criterion, then they should be excluded from participation in the study
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-000261-12-NL |
| CCMO | NL37687.098.11 |