Investigation of Safety and Tolerability of Catumaxomab in Patients With NMIBC
Indikation (Clinical Trials):
Urinary Bladder Neoplasms
Lindis Biotech GmbH
Urologische Klinik München-Planegg
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The present Phase I dose escalation study (CATUNIBLA) in patients with non-muscle invasive
bladder cancer (NMIBC) of high and intermediate risk for progression aims at investigating
the therapeutic potential of Catumaxomab applied as intravesical instillation. Catumaxomab is
an intact trifunctional bispecific monoclonal antibody and has the molecular targets EpCAM
and CD3. It mediates antibody-dependent cellular cytotoxicity against human epithelial tumor
cells including bladder cancer.
The study consists of two parts: Part I is dose finding and will investigate 3 sequential
cohorts consisting of 3 patients to be enrolled at the specified dose levels. After
determination of the dose for Part II an additional number (n=X) of patients will be included
at this dose level. Part I and part II have a screening period, 6 week treatment phase and a
Patients will be enrolled in this Phase I study only if they meet all of the following
- Male or non-pregnant, non-breastfeeding female, age 18 years or older at date of
- Any of the following histologically confirmed non-muscle invasive urothelial carcinoma
of the bladder:
High-risk tumors according to EAU guidelines:
- G3 HG tumors
- Multiple, recurrent and large (>3cm) pTa G1-G2 LG tumors (all features must be
- Patients of the subgroup of highest risk tumours (T1G3/HG associated with
concurrent bladder CIS, multiple- and/or large T1G3/HG and/or recurrent T1G3/HG,
T1G3/HG with CIS in the prostatic urethra, some forms of variant histology of
urothelial carcinoma, lymphovascular invasion) will be only enrolled if they have
already failed BCG-treatment or they cannot tolerate it and are ineligible or
refuse cystectomy. In the Part II of the study a minimal expression of EpCAM in
the tumor tissue may be required, based on preliminary evidence from the Part I
of the study
- Previous therapies must be discontinued at least 2 weeks prior to administration
of Catumaxomab and all treatment related toxicities must have resolved or
decreased to common toxicity criteria (CTCAE) grade 1.
- Time period from primary resection to antibody treatment start must be at least
one week and should not exceed 2 weeks.
- Any investigational agent must be discontinued at least 4 weeks or 5 half-lives,
whichever is longer, prior to antibody treatment start.
- Female patients of child-bearing potential (for definition refer to section
- have negative serum pregnancy test prior to study treatment to rule out pregnancy.
- Use at least one method of birth control that results in a low failure rate (i.e.,
less than 1% per year) when used consistently and correctly such as implants,
injectables, combined oral contraceptives, some intrauterine devices (IUDs), true
sexual abstinence or vasectomized partner from the time of signing the informed
consent through 2 weeks after the last study drug treatment.
- All sexually active patients agree to use barrier contraception (i.e., condoms)
while receiving study treatment and for 2 weeks following their last dose of
- Adequate organ function, as defined by the following criteria:
- Aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST/SGOT) and
alanine aminotransferase / serum glutamic pyruvate transaminase (ALT/SGPT) ≤ 3.0 x
upper limit of normal (ULN);
- Total serum bilirubin ≤ 1.5 x ULN (CTCAE Grade ≤ 1);
- Serum creatinine ≤ 1.5 x ULN; or a creatinine clearance ≥40 ml/min
- Alkaline phosphatase < 2.5 x ULN
• Adequate hematological, liver and kidney function:
- Hemoglobin ≥8.0 g/dL;
- Absolute neutrophil count ≥1500/mm3;
- Platelets ≥75,000mm3(= 75 G/l)
- Activated Partial thromboplastin time (aPTT) within limits of normal • Signed and
dated informed consent/assent form
Patients will not be enrolled in this Phase I study if they meet any of the following
- The female patient is pregnant, lactating or breastfeeding or has a positive serum
pregnancy test during the screening period.
- Low risk or intermediate risk tumors according to EAU guidelines
- History or signs (obstruction of upper urinary tract or cross hematuria in the
ureteral orifice) of urethral or upper tract transitional cell carcinoma (TCC).
Patients with T1 disease of the bladder must have no evidence of upper or lower tract
disease or a more advanced stage of disease by either computed tomography (CT)
urography or magnetic resonance imaging (MRI) urography of the abdomen and pelvis
performed within 8 weeks before the first application of study treatment. If
intravenous contrast medium for CT and MRI is contraindicated, retrograde
ureteropyelography, or CT or MRI without intravenous contras tmedia may be performed.
- Patients with hydronephrosis.
- Any intravesicular or other chemotherapy treatment within 2 weeks or any
investigational agent within 4 weeks or 5 half-lives of the agent whatever is longer
prior to the initial dose of study drug
- History of recurrent severe urinary tract infections (UTIs) per investigator judgment.
- Active, uncontrolled impairment of the urogenital, renal, hepatobiliary,
cardiovascular, gastrointestinal, neurologic or hematopoietic systems which, in the
opinion of the investigator, would predispose the patient to the development of
complications from the administration of intravesical therapy.
- A diagnosis of another malignancy within 2 years before the first dose of study
treatment, except for superficial skin cancer or localized solid tumors deemed cured
by surgery and not treated with systemic anticancer therapy and not expected to
require anticancer therapy within the next 2 years i.e., while the patient may be
taking study treatment or is in the follow up period of this study.
- Patients with a history of cancer who have completed treatment and are free from
disease since at least 5 years can be enrolled.
- Patients with low-risk prostate cancer, e.g.:
- Clinically localized disease (≤T2a) and
- Gleason score ≤6 (3+3) and
- Serum PSA <10 ng/ml undergoing active surveillance may be enrolled with agreement
of the sponsor.
- Patients who cannot tolerate intravesical administration or intravesical surgical
manipulation (cystoscopy, biopsy) due to the presence of serious comorbid condition(s)
(e.g., uncontrolled cardiac or respiratory disorders).
- Known hypersensitivity to Catumaxomab and its analogues in general, or to any other
component of the study drug formulation.
- Documented acute or chronic infection including known hepatitis B or C or HIV
infection or other concurrent non-malignant co morbidities such as unstable or
uncontrolled pectoral angina, myocardial infarction during the last 6 months, valvular
heart disease that requires treatment, acute myocarditis or congestive heart failure
(CHF) (New York Heart Association (NYHA) III or IV).
- Any concurrent chemotherapy, radiotherapy (except for local radiation therapy for bone
metastasis), immunotherapy or corticoid therapy.
Any other concurrent disease or medical conditions that are deemed to interfere with the
conduct of the study as judged by the investigator.
- Participation in any of the following types of clinical studies either concurrently or
within the previous 28 days or within 5 half-lives of any investigational
pharmacologic agents, whichever is longer: pharmacologic agents or imaging materials,
including dyes, investigational surgical techniques or devices. Participation in
studies of psychology, or socioeconomic issues is allowed.
- Unwilling or unable to follow protocol requirements.
- Legal incompetence or limited legal competence, or detainment in an institution due to
official or legal reasons
- Involvement in the conduct and/or the design of the study (applies to sponsor's staff
or staff in treating centres)
1. Dose escalation phase to evaluate DLT incidence (Time Frame - approximately 1 year after study start):
Dose Limited Toxicity
2. Incidence and severity of treatment related adverse events (Time Frame - approximately 2.5 years after study start):
Incidence and severity of treatment related adverse events during intravesical instillation with catumaxomab are observed according to NCI CTCAE, Version 5.0
1. Anti-drug antibodies (ng/ml) (Time Frame - approximately 2.5 years after study start):
the incidence of ADA (anti-drug antibodies to catumaxomab by intravesical instillation in serum
2. Cytokines (pg/mL) (Time Frame - approximately 2.5 years after study start):
3. Number of EpCAM-positive tumor cells in the urine (Time Frame - approximately 2.5 years after study start):
• number of EpCAM-positive tumor cells in the urine
4. Number of immune cells in the urine (Time Frame - approximately 2.5 years after study start):
• number of immune cells in the urine
5. Cmax (ng/ml) (Time Frame - approximately 2.5 years after study start):
PK parameter of Catumaxomab is Cmax (ng/ml)
6. Cmin (ng/ml) (Time Frame - approximately 2.5 years after study start):
PK parameters of Catumaxomab is Cmin (ng/ml)
7. Tmax (hours) (Time Frame - approximately 2.5 years after study start):
PK parameter of Catumaxomab is Tmax (hours)
8. AUC (day * ng/ml) (Time Frame - approximately 2.5 years after study start):
PK parameters of Catumaxomab AUC (day * ng/ml)
9. t1/2 (days) (Time Frame - approximately 2.5 years after study start):
PK parameter of Catumaxomab t1/2 (days)
10. Antitumor activity (Time Frame - approximately 2.5 years after study start):
antitumor activities is assessed by cystoscopy and biopsy/or resection at EoT (day 43) and all follow up visits and measures and documents tumor size, tumor localization, tumor numbers and morphological criteria
11. Complete response (Time Frame - approximately 2.5 years after study start):
Complete response will be defined as no histological evidence of disease at 3-monthly evaluations
12. Recurrence-free interval (Time Frame - approximately 2.5 years after study start):
recurrence-free interval is evaluated following the catumaxomab treatment in the follow up phase 3 month to 2 years
13. Local progression free interval (Time Frame - approximately 2.5 years after study start):
local progression free interval is evaluated following the catumaxomab treatment in the follow up phase 3 month to 2 years
14. Identification and quantification of tumor cells in urine (Time Frame - approximately 2.5 years after study start):
this is evalulated at screening and in the course of the study
15. EpCAM expression (Time Frame - approximately 2.5 years after study start):
Evaluation of potential and predictive EpCAM expression and relative Lymphocytes count can be correlated with outcome
Procedure: 6 weekly intravesical administration at each dose level; 3 sequential cohorts consisting of 3 patients (part I) cohort 50 µg cohort 70 µg cohort 100 µg Part II will be treated at recommended dose
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