Investigation of Safety and Tolerability of Catumaxomab in Patients With NMIBC
Investigation of Safety and Tolerability of Catumaxomab in Patients With NMIBC
The purpose of the study is to investigate the safety, tolerability, and preliminary efficacy
 of the monoclonal bispecific trifunctional antibody Catumaxomab in patients with non-muscle
 invasive bladder cancer (NMIBC).
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
 follow-up phase.
Inclusion Criteria:

 Patients will be enrolled in this Phase I study only if they meet all of the following
 criteria:

 -  Male or non-pregnant, non-breastfeeding female, age 18 years or older at date of
 consent.

 -  Any of the following histologically confirmed non-muscle invasive urothelial carcinoma
 of the bladder:

 High-risk tumors according to EAU guidelines:

 -  pT1

 -  G3 HG tumors

 -  CIS

 -  Multiple, recurrent and large (>3cm) pTa G1-G2 LG tumors (all features must be
 present)

 -  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
 14.3)must:

 -  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
 study treatment.

 -  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

 Exclusion Criteria:

 Patients will not be enrolled in this Phase I study if they meet any of the following
 criteria:

 -  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)