The primary objective of the study is the functional improvement with one point or more on the modified Rankin scale after the 12th week of natalizumab (compared to baseline).
ID
Source
Brief title
Condition
- Autoimmune disorders
- Central nervous system infections and inflammations
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Functional improvement with one point or more on the modified Rankin scale
after the 12th week of natalizumab (compared to baseline).
Secondary outcome
Secondary endpoints include neurological improvement and safety. Neurological
improvement is defined as a positive score (>0) in the EFIT overall evaluation
and improvement on the AMC linear disability scale, Barthel index and PNS
neurological scale after three natalizumab infusions (the 12th week of
natalizumab), compared to baseline. Safety is assessed by CTC AE 4.0 criteria,
from date of registration until 12 weeks after last study drug administration.
Background summary
Paraneoplastic neurological syndromes (PNS) are *remote effects* of cancer. It
is thought that expression of Hu antigens by the tumor provokes an autoimmune
response not only directed against the tumor but also against nervous tissues.
PNS disorders are rapidly progressive over weeks to months leaving the patient
severely debilitated. At the time of neurological presentation, 70% is not yet
known with cancer which often makes the diagnosis difficult. The most frequent
PNS is associated with anti-Hu autoantibodies (Hu-PNS). Hu-PNS is a monophasic,
severe, Th1 mediated organ specific autoimmune disease. Plasma exchange,
corticosteroids, cyclophosphamide and intravenous immunoglobulins (IVIG) are
generally considered not effective in the treatment of Hu-PNS and
immunosuppressive or immunomodulating treatment is at present not recommended.
Other than anti-tumor therapy after the detection of the tumor, no effective
treatment for Hu-PNS is available. Functional improvement rarely occurs (<10%)
and most of the patients ultimately die from the severe neurological disorder
and not from the underlying malignancy. Better treatment modalities for PNS are
a highly unmet medical need. Natalizumab may contribute to reduced activation
of T cells already present in the CNS, leading to apoptosis and strongly
inhibits migration of activated T cells to the CNS and consequently lowers
damage done to the CNS by these cells during Hu-PNS.
Study objective
The primary objective of the study is the functional improvement with one point
or more on the modified Rankin scale after the 12th week of natalizumab
(compared to baseline).
Study design
This is an uncontrolled single center phase II study testing 3 monthly
infusions of natalizumab in 20 Hu-PNS patients.
Intervention
Natalizumab 300 mg, intravenous infusions q 4 weeks for a maximum of 3
infusions over 12 weeks.
Study burden and risks
The main burden for the patients are a short admission (1-2 nights); 3
natalizumab infusions (1 during admission; 2 in daycare); 2 additional
outpatient visits, all at Erasmus MC Cancer Institute, location Daniel den Hoed
Clinic. In addition, 2 lumbar punctures and 4 venapunctures are performed. The
direct side effects of the 3 (maximum) natalizumab infusions are mild and
manageable. During all 5 (maximum) visits, general physical and neurological
examinations will be performed; 2 questionnaires (Barthel and AMC linear
disability scale), nine hole peg test, ten metre walking test, Williams delayed
recall test and Boston aphasia severity scale will be taken. Potential serious
side effects include PML and induction of tumor growth. However, the risk of
these serious side effects is considered low.
'sGravendijkwal 230
Rotterdam 3015 CE
NL
'sGravendijkwal 230
Rotterdam 3015 CE
NL
Listed location countries
Age
Inclusion criteria
- PEM/PSN associated with high titer (>=400) anti-Hu antibodies in serum or plasma
- The neurological symptoms must still be progressing defined as neurological deterioration over the last 4 weeks
- Score mRS >= 2
- Absolute CD4+ cell count >=400 x 109 cells per liter
- Patients aged >=18 years
- Patients who receive or will receive anti-tumor therapy are allowed to participate
- Patients who have given written informed consent
Exclusion criteria
- Patients who are unwilling to undergo lumbar puncture
- Known hypersensitivity to natalizumab or one of the additives
- Progressive multifocal leukoencephalopathy (PML)
- Immune compromised patients (patients using immunosuppressive medications other than short course (<2 weeks) of steroids)
- Liver enzymes (ASAT, ALAT, g-GT, Alk. Phosphatase) higher than 5x upper limit of normal value (ULN)
- Chronic HBV infection (positive HBsAg)
- Renal failure (GFR < 30 ml/min)
- Active infection for which antibiotics are indicated
- Active viral infection for which antiviral medication is indicated
- Known current pregnancy or lactating (NB: women of childbearing potential should take adequate contraceptive precautions).
- No history of active melanoma in the past 5 years; no history of T cell lymphoma or primary CNS lymphoma
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000675-13-NL |
| CCMO | NL48712.078.14 |
| OMON | NL-OMON28171 |