PRIMARY OBJECTIVE:To assess the safety and tolerability of MOR202 treatment in subjects with aMNKEY SECONDARY OBJECTIVE:To assess the effect of MOR202 on serum anti-PLA2R antibodies in subjects with aMNSECONDARY OBJECTIVES:1. To assess…
ID
Source
Brief title
Condition
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PRIMARY ENDPOINT:
Incidence and severity of treatment-emergent adverse events (TEAE)
Secondary outcome
KEY SECONDARY ENDPOINT:
Best Immunological Response: rate of sICR, ICR and IPR based on re-duction of
serum anti-PLA2R antibody titer
SECONDARY ENDPOINTS:
1. Number and antibody titers of subjects tested positive for anti-MOR202
antibodies
2. MOR202 serum concentrations after multiple i.v. administra-tions
3. Incidence and severity of adverse drug reactions (ADRs) in the follow-up
phase.
Background summary
The main treatment rationale is the reduction of membranous nephrop-athy (MN)
specific anti-PLA2R autoantibodies through MOR202 me-diated targeted depletion
of autoantibody producing plasma cells.
Autoantibodies binding to the PLA2R antigen are highly specific to pri-mary MN.
They are present in approximately 70% of patients diag-nosed with this
condition.
It is clinically observed that anti-PLA2R antibody titers correlate tightly
with disease activity. Taken together with the fact that the disease de-fining
glomerular basement changes contain both PLA2R protein as well as antibody
complex deposits, indirect evidence is provided that indeed anti-PLA2R
antibodies play a causative role in MN.
Patients diagnosed with MN and proteinuria >3.5 g per day initially re-ceive
supportive therapy with a combination of Angiotensin Converting Enzyme
Inhibitors (ACEI) or Angiotensin Receptor blockers (ARB), statins and diuretics
as per current clinical standard. If not responding with a significant decrease
of proteinuria within months, escalation to immunosuppressive therapy (IST) is
indicated with usage of cyclophos-phamide, CNIs or MMF, even though none of
these drugs is approved for use in MN. Recently introduced off-label use
therapy with anti-CD20 therapeutic antibody rituximab (RTX) allows for a more
targeted IST approach by depleting B cell populations involved in producing
autoantibodies. But in MN patients with high anti-PLA2R antibody ti-ters
response rates with RTX seem to be low. One reason could be that a substantial
amount of anti-PLA2R antibodies are produced by a ma-ture, long-lived plasma
cell pool with a CD20 negative, but CD38 pos-itive immuno-phenotype,
potentially limiting the efficacy of an anti-CD20 therapeutic approach.
Thus, an anti-CD38 directed specific plasma cell depletion approach employing
the monoclonal antibody MOR202 may provide a viable therapeutic option sparing
patients of significant toxicity of broader act-ing immunosuppressive agents,
possibly effective in patients with lim-ited benefit of anti-CD20 directed
therapy.
Study objective
PRIMARY OBJECTIVE:
To assess the safety and tolerability of MOR202 treatment in subjects with aMN
KEY SECONDARY OBJECTIVE:
To assess the effect of MOR202 on serum anti-PLA2R antibodies in subjects with
aMN
SECONDARY OBJECTIVES:
1. To assess immunogenicity of MOR202 (anti-MOR202 anti-body formation)
2. To assess the pharmacokinetic (PK) profile of MOR202
3. To assess safety in subjects with aMN after MOR202 treatment and during
follow-up phase
EXPLORATORY OBJECTIVES:
* To assess the clinical efficacy of MOR202
* To assess the effect of MOR202 on QoL
* To assess the kinetics of anti-PLA2R antibody titers
* Additional exploratory analyses may be performed to charac-terize further
potential biomarkers under MOR202 treatment
Study design
Phase Ib/IIa, Open-Label, Two-Cohort, Multicenter Clinical Trial to as-sess
Safety and Efficacy of MOR202 in aMN
Intervention
9 doses of MOR202 will be administered as an intravenous infusion at 16 mg/kg
over 6 treatment cycles at 28-days each. Dosing occurs QW in C1 and Q4W in C2-6
Study burden and risks
MOR202 may cause side effects/undesirable effects.
These side effects are very common (occur in 1 in 10 people or more):
- Leukopenia (decrease in white blood cells)
- Lymphopenia (decrease in certain white blood cells with important function in
the immune system),
- Neutropenia (decrease in certain types of white blood cells),
- Thrombocytopenia (reduction in blood platelets which increases risk of
bleeding and bruising),
- Anemia (reduction in red blood cells which can make the skin pale and cause
weakness and breathlessness),
- Fatigue (tiredness),
- Infusion related reaction* (can occur during or following infusion of the
drug. The reaction may include fever, chills, rash, low blood pressure, and
difficulty swallowing or breathing, swollen face, lips, mouth, tongue or
throat), Respiratory tract infection, - Diarrhea.
These side effects occur, but not as often:
- Nausea (feel sick to the stomach)
- Hypokalemia (low blood potassium level)
- Upper respiratory tract infection (infection of the upper respiratory tract
namely nose, sinuses, throat, windpipe, and voice box)
- C-reactive protein increased (increase of a protein that is mainly used as a
marker for inflammation)
- Constipation
- Lung infection/pneumonia
- Cough
- Nasopharyngitis (infection of the lining of the nose and in the throat)
- Urinary tract infection
- Oral herpes (cold sore)
- Pyrexia (fever)
- Hypophosphatemia (low blood phosphate level)
MOR202 is an investigational study medication being tested and thus, not all
possible side effects that may occur from taking the medication are known at
this time. So far, approximately 90 patients have been treated with MOR202, but
these were not patients with membranous nephropathy.
Possible risks for a percutaneous kidney biopsy include:
- Bleeding (occurrence of blood in the urine), it usually stops within a few
days. Bleeding that is serious enough to require a blood transfusion affects a
very small percentage of people who have a kidney biopsy. Rarely, surgery is
needed to control bleeding.
- Pain at the biopsy site is common after a kidney biopsy, but it usually lasts
only a few hours.
- Arteriovenous fistula (an abnormal connection between the two blood vessels),
occurs if the biopsy needle accidentally damages the walls of a nearby artery
and vein. This type of fistula usually causes no symptoms and closes on its own.
- Hematoma formation (a collection of blood around the kidney) which also might
become infected, occurs rarely and is treated with antibiotics and surgical
drainage.
- High blood pressure related to a large hematoma, uncommon risk
Semmelweisstrasse 7
Planegg D-82152
DE
Semmelweisstrasse 7
Planegg D-82152
DE
Listed location countries
Age
Inclusion criteria
1. *18 to *80 years (at date of signing ICF)
2. Urine protein to creatinine ratio (UPCR) of * 3.0000 g/g OR proteinuria *
3.500 g/24 h from 24-hr urine at screening
3. Active and anti-PLA2R antibody positive MN in need for IST according to
investigator judgement and with diagnostic biopsy, archival biopsy
acquired within 5 years prior to screening is acceptable
4. Estimated glomerular filtration rate (eGFR) *50 ml/min/1.73m² or >30 and <50
ml/min/1.73m², and IFTA (interstitial fibrosis and tub-ular
atrophy) score of less than 25% on a renal biopsy obtained within the last 6
months prior to start of screening. If a subject falls into the latter
range without availability of an adequate biopsy, a biopsy at screening should
be performed for IFTA assessment.
5. Not in spontaneous remission despite proper treatment with ACEIs, ARBs
(sufficient dose and treatment duration) as per clinical practice
and guidelines. If the PI determines that a subject is intolerant to an ACEI or
ARB, the reason must be documented and approval obtained
from the Medical Monitor prior to enrolment.
6. Systolic BP * 150 mmHg and diastolic BP * 100 mmHg after a period of 5
minutes of rest as measured at screening
7. Subject vaccinated against Pneumococcus within the last 5 years prior to
date of signing ICF (subjects may be vaccinated during screening to meet this
criterion; interval to first dose of MOR202 must be at least 14days (1)).
8. Cohort 1 comprises newly or relapsed subjects: Serum anti-PLA2R antibodies
*50.0 RU/ml determined by Euroimmun ELISA at central
laboratory.
9. Cohort 2 comprises therapy refractory subjects:
a. subject did not achieve immunological remission after prior IST(s) as
documented by the investigator AND
b. subject is without promising standard therapeutic options as documented by
the investigator(i.e. investigator expects efficacy or safety issues with
remaining IST options AND
c. serum anti-PLA2R antibodies *20RU/mL measured at screening by the Euroimmun
ELISA at central laboratory
10. Female of non-childbearing potential fulfilling one of the criteria:
a. post-menopausal: after 12 months of natural (spontaneous)
amenorrhea with an appropriate clinical profile (e.g. age appropriate, history
of vasomotor symptoms)
b. surgically sterile: tubal ligation at least 6 weeks before taking trial
treatment, hysterectomy, or bilateral oophorectomy
c. genetically sterile: e. g. Turner syndrome, uterine agenesis.
11. Sexually active females of reproductive potential should use one of the
following contraception options until 3 months after the last dose of
MOR202:
a. One method of contraception that has a typical use failure rate of <1%
(i.e., less than 1 pregnancy expected per 100 women), which would include
sterilization surgery for women, sterilization implant for women, sterilization
surgery for men, Copper IUD, IUD with progestin, or implantable rod
b. A hormonal method of contraception (i.e., shot/injection, oral
contraceptive, contraceptive patch, vaginal contraceptive ring, having
typical use failure rate * 9%) plus a barrier method (i.e., diaphragm with
spermicide, sponge with spermicide, cervical cap with spermicide,
male condom, female condom, spermicide alone).
Note: France will only enroll patients in Cohort 2.
Exclusion criteria
1. Hemoglobin < 80 g/L
2. Thrombocytopenia: Platelets < 100.0x10^9/L
3. Neutropenia: Neutrophils < 1.5x10^9/L
4. Leukopenia: Leukocytes < 3.0x10^9/L
5. Hypogammaglobulinemia: Serum immunoglobulins *4.0 g/L
6. B-cells < 5 x 106/L
7. Secondary cause of MN (e.g. SLE, medications, malignancies) as determined by
the investigator
8. Concomitant renal disease other than MN (e.g., diabetic renal disease, lupus
nephritis, IgA nephropathy)
9. Diabetes mellitus type 1
10. Diabetes mellitus type 2: Subjects with type 2 diabetes mellitus may only
enter the clinical trial if a kidney biopsy performed within 6 months
prior to screening shows membranous nephropathy without histological signs of
diabetic nephropathy and their disease is controlled, such as:
o Hba1c <8.0 % or 64 mmol/mol,
o No diabetic retinopathy known
o No peripheral neuropathy known
11. Previous treatment with an anti-CD38 antibody
12. Subject received treatment with:
a.Mycophenolate mofetil (MMF) or high dose corticosteroids (> 20 mg
prednisone/day), within 30 days prior to screening OR
b.Alkylating agents (e.g. cyclophosphamide [CYC]) or CNIs (e.g. tacrolimus,
cyclosporine A [CSA]) within 90 days OR
c.Biologic drugs including RTX within 180 days
d.Any other oral/parenteral IST within 180 days.
13. Significant uncontrolled cardiovascular disease or cardiac insufficiency
(New York Heart Association [NYHA] class IV) as judged by the investigator
14. Clinically relevant findings on a 12 lead ECG as determined by the
investigator at screening
15. History of significant cerebrovascular disease or sensory or motor
neuropathy of tox-icity * grade 3
16. Total bilirubin, aspartate aminotransferase and alanine aminotransferase
>1.5 x ULN, alkaline phosphatase >2.0 x ULN
17. Treatment within five terminal half-lives (if known) or within the last 30
days prior to baseline (whatever is longer) with investigational drugs.
18. Known or suspected hypersensitivity to MOR202 and its excipients
(L-histidine, su-crose, polysorbate 20)
19. Serologic or virologic markers positive for HIV, hepatitis C (subjects with
positive anti hepatitis C virus [anti-HCV] antibody but negative HCV
RNA polymerase chain reaction [PCR] may enroll) or active or latent hepatitis B
(subjects with positive hepatitis B surface antigen [HBsAg]
are excluded, subjects with isolated positive hepatitis B core antibody
[anti-HBc] but non-detectable hepatitis B virus (HBV) DNA by PCR may
be enrolled).
20. For any other preexisting symptoms and impairments of health classified or
any re-sidual toxicity from prior therapy * grade 3 (NCICTCAE,
see 3.2): these subjects may be included upon confirmation by the medical
department of the sponsor
21. Pregnancy or breast feeding
22.Any active infection (viral, fungal, bacterial) requiring systemic therapy.
23.Any malignancy within 5 years prior to date of screening, with the exception
of adequately treated in situ carcinoma of the cervix, uteri,
basal or squamous cell carcinoma or non-melanomatous skin cancer.
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 | EUCTR2019-000780-24-NL |
| CCMO | NL70007.091.19 |