Primary objective:Pharmacokinetics/-dynamics of 124I-F8IL10 Secondary objective:Dosimetric parameters of arthritic joints and internal organs.
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
- Autoimmune disorders
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetics and -dynamics of F8IL10 in RA (including uptake in joints)
Secondary outcome
Radiation dosimetry of 124-I-F8IL10 in joints and internal organs.
Background summary
Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint
disease that affects 0.5-1% of the population in the industrialized world and
commonly leads to significant disability and a consequent reduction in quality
of life.
Traditional therapy of RA included anti-inflammatory treatment with low-dose
systemic glucocorticoids as well as symptomatic treatment with non-steroidal
anti-inflammatory drugs (NSAIDs), which alleviate the disease but may induce
significant damage to the upper and lower gastrointestinal tract and do not
provide a complete control of the disease. Disease modifying drugs (DMARDs)
have been used since the beginning of the 20th century in order to avoid
disease progression; a number of molecules have been developed and used in RA
patients (gold salts, chloroquine and hydroxychloroquine, salazopyrine,
leflunomide, cyclosporine) Until today Methotrexate (MTX) is the most commonly
used DMARD and continues to be the gold standard of therapy of rheumatoid
arthritis.
More recently, biological compounds that target TNF-* and other inflammatory
cytokines, B-cells or T-cells have been used successfully to treat RA patients
with an inadequate response to MTX; however, approximately 30-40% of patients
do not respond to these treatments or had to stop treatment due to drug-related
adverse events, resulting in an unmet need for alternative therapies.
Inflammatory bowel diseases (IBD), which include Crohn*s disease (CD) and
ulcerative colitis (UC), are chronic inflammatory diseases of the intestinal
tract characterized by a succession of periods of clinical relapse and
remission. The pathogenesis of IBD likely involves multifactorial interactions
among genetic and immunological factors and environmental triggers. IBD causes
significant gastrointestinal symptoms, including diarrhea, abdominal pain,
bleeding, anemia and weight loss. Several score systems to measure disease
activity have been developed [3], the most widely adopted being Mayo score [4]
and CDAI [1] for UC and CD, respectively. Treatment is aimed at maintaining a
normal quality of life for the patient by rapidly inducing and sustaining
remission and avoiding complications of the disease itself and its treatment.
Corticosteroids, aminosalicylates, immunosuppressive drugs as well as TNF*
blockers are the mainstay of medical treatment.
Interleukin-10 (IL-10) is a cytokine produced by activated monocytes and T
cells which is deeply involved in the regulation of inflammatory responses and
immune reactions. IL-10 has been considered an attractive candidate for
therapeutic use based on its potent in vitro immunomodulating activities and
proven effects in animal models of acute and chronic inflammation,
autoimmunitiy, cancer and infectious disease. Schering-Plough developed
recombinant human IL-10 (ilodecakin, Tenovil®) for clinical trials in patients
suffering from inflammatory bowel disease, psoriasis or rheumatoid arthritis. A
combination of IL-10 and Methotrexate in a multicenter, placebo-controlled,
dose escalation study in RA patients was described where 8 or 20 µg / kg three
times weekly resulted in ACR 20 responses in 50-60 % of patients compared to 10
% for placebo. However, the development of recombinant IL-10 as a therapeutic
drug for chronic inflammation was discontinued in 2003 probably due to
insufficient response rates in the medium-high responder group and/or to
problems with manufacturing.
In the F8IL10 molecule, IL-10 is coupled to the antibody fragment F8 which
binds to the extra-domain A of fibronectin, selectively expressed at sites of
inflammation. Upon administration to a patient, F8IL10 is supposed to
accumulate at the site of arthritis and exhibit its biological function there.
Such antibody-mediated targeted delivery of cytokines to sites of disease is a
novel therapeutic concept which is largely unexplored for the treatment of
chronic inflammatory conditions but has been investigated successfully in the
cancer setting over the last few years.
In the frame of the preclinical analysis of the drug candidate, F8IL10
displayed an impressive ability to selectively localize at sites of arthritis
in the CIA mouse model upon intravenous and subcutaneous injection.
Furthermore, F8IL10 showed a therapeutic activity, which was superior to the
one of IL-10 fused to an antibody of irrelevant specificity in the mouse and
was highly synergistic when administered in combination with Methotrexate
(MTX).
Study objective
Primary objective:
Pharmacokinetics/-dynamics of 124I-F8IL10
Secondary objective:
Dosimetric parameters of arthritic joints and internal organs.
Study design
The presented trial is a phase 0 single dose study of the arthritic targeting
human monoclonal-antibody cytokine fusion protein 124I-F8IL10 in 5 patients
with active rheumatoid arthritis and 5 patients with active IBD.
It is a uncontrolled, open-label study in one clinical center.
5 patients with active rheumatoid arthritis and 5 with active IBD will be
enrolled.
A single dose of 0.4 mg F8IL10 labeled with Iodine-124 (with a maximum
radiation burden of the scanning procedure of 13 mSv )will be administered to
consenting patients with arthritis. Target localization will be analyzed by
PET/CT scans.
Scheme:
Visit 1: screening visit, thyroid prophylaxis is provided for day -1 and day -2
for start of the study.
Visit 2:
- thyroid prophylaxis
- infusion 124-I-F8IL10
- PET-CT at 0.5-1h after infusion
- blood sampling for laboratory parameters, pharmacokinetics and
pharmacodynamics
Visit 3:
- thyroid prophylaxis
- PET-CT at 24h after infusion
- blood sampling for pharmacokinetics and pharmacodynamics
Visit 4: (This PET-CT will be cancelled if the burden for the patient is too
large)
- thyroid prophylaxis
- PET-CT at 72h after infusion
- blood sampling for laboratory parameters, pharmacokinetics and
pharmacodynamics
Study burden and risks
Burden and risks
- Collection of blood; can cause local bruises
- Drip (2x); can cause local bruises
- 3x PET-CT scan; radiation burden of in total 13 mSv
- Very small chance of allergic reaction to F8IL10
Localita Bellaria 35
Sovicille (SI) 53018
NL
Localita Bellaria 35
Sovicille (SI) 53018
NL
Listed location countries
Age
Inclusion criteria
For patients with Rheumatoid Arthritis:;1. Diagnosis of RA according to ACR criteria;2. Active RA (Disease Activity Score 28 * 3.2);3. Treatment with disease modifying anti-rheumatic drugs (DMARDS), biologicals and in addition, corticosteroids up to 10 mg daily and non-steroidal anti-inflammatory drugs (NSAIDs) is permitted, provided that there is a stable dose for at least 2 weeks.;For patients with Inflammatory Bowel Disease:;1. diagnosis of IBD to clicinico -pathologic criteria;2. clinically active IBD:
a. Crohn*s disease: active Crohn*s disease, with a CDAI (Crohn*s Disease Activity index) > 220 [Best et al. Gastroenterology 1976] with CDEIS (Crohn*s disease endoscopic index of severety) > 15 [Mary et al. Gut, 1989] assessed via colonoscopy or MRI enteroclysis within 4 weeks of dosing.;b. Ulcerative Colitis: active ulcerative colitis, Mayo score > assessed via colposcopy within 4 weeks of dosing.;3. Treatment with aminosalacylates, immunomodulators, biological and corticosteroids up to 20 mg. dialy is permitted, provided that there is a stable dose for at least 2 weeks.;For ALL patients;1. Patients aged *18 years;2. All acute toxic effects of any prior therapy returned to classification mild according to MedDRA;3. Sufficient hematologic, liver and renal function: total white cell count as well as ANC should be normal prior to start the treatment, as well as liver function tests:;a. Absolute neutrophil count (ANC) * 1.5 x 109/L, platelets * 100 x 109/L, haemoglobin (Hb) * 9.5 g/dl;b. Alkaline phosphatase (AP), alanine aminotransferase (ALT) and/or aspartate aminotransferase < 3 x upper limit of reference range (ULN), and total bilirubin < 2.0 mg/gL;c. Creatinine < 1.5 ULN or 24 h creatinine clearance > 50 mL/min;4. Negative serum pregnancy test for females of childbearing age prior to starting treatment;5. Male patients, who are potentially fertile, must agree to use adequate contraceptive methods at the beginning of the screening visit and continue until 3 months following the last treatment with the study drug.;6. Evidence of a personally signed and dated Ethics Committee-approved Informed Consent form indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the study;7. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study
Exclusion criteria
Patients must not be enrolled in the study if, at the time of enrollment, they have any of the following. ;1. Presence of active infections (e.g. requiring antibiotic therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study;2. Chronic active hepatitis (hepatitis B/C) or active autoimmune diseases other than RA;3. Known primary or secondary immonodeficiency;4. HIV positive patient;5. Evidence of active malignant disease, malignancies diagnosed within the previous 5 years;6. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris;7. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria);8. Irreversible cardiac arrhythmias requiring permanent medication;9. Uncontrolled hypertension;10. Ischemic peripheral vascular disease (Grade IIb-IV);11. Severe diabetic retinopathy;12. Recovery from major trauma including surgery within 4 weeks of administration of study treatment;13. Known history of allergy to IL-10 or other intravenously administered human proteins/peptides/antibodies;14. Pregnancy or breast feeding;15. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol;16. Previous exposure to radioactivity with a yearly cumulative dose of * 5 mSv. ing:;17. For patient undergoing MRI:
a. electronically, magnetically and mechanically activated implants.
b. cardiac pacemakers
c. ferromagnetic haemostatic clips in the central nervous system (CNS) or in the body.
d. cochlear implants or stapedial implants.
e. insulin pumps and nerve stimulators.
f. prosthetic heart valves
g. ferromagnetic or electrically operated active devices like automatic cardioverter defebrillators.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023114-32-NL |
| CCMO | NL33778.029.10 |