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JOURNAL ONKOLOGIE – STUDIE

Investigation of Safety and Tolerability of Catumaxomab in Patients With NMIBC

Rekrutierend

NCT-Nummer:
NCT04819399

Studienbeginn:
Juli 2020

Letztes Update:
29.03.2021

Wirkstoff:
Catumaxomab

Indikation (Clinical Trials):
Urinary Bladder Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
Lindis Biotech GmbH

Collaborator:
-

Studienleiter

R Oberneder, MD
Principal Investigator
Urologische Klinik München-Planegg

Kontakt

Studienlocations
(1 von 1)

Studien-Informationen

Detailed Description:

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.

Ein-/Ausschlusskriterien

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)

Studien-Rationale

Primary outcome:

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

Secondary outcome:

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):
cytokines (pg/mL)

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

Geprüfte Regime

  • Catumaxomab:
    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

Quelle: ClinicalTrials.gov


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