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Investigation of Safety and Tolerability of Catumaxomab in Patients With NMIBC

Primary Purpose

Urinary Bladder Neoplasms

Status
Recruiting
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
Catumaxomab
Sponsored by
Lindis Biotech GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Urinary Bladder Neoplasms focused on measuring Non Muscle Invasive Bladder Cancer, NMIBC, Catumaxomab, Intravesical

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Urologie PlaneggRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Catumaxomab

Arm Description

intravesical Catumaxomab instillation

Outcomes

Primary Outcome Measures

Dose escalation phase to evaluate DLT incidence
Dose Limited Toxicity
Incidence and severity of treatment related adverse events
Incidence and severity of treatment related adverse events during intravesical instillation with catumaxomab are observed according to NCI CTCAE, Version 5.0

Secondary Outcome Measures

Anti-drug antibodies (ng/ml)
the incidence of ADA (anti-drug antibodies to catumaxomab by intravesical instillation in serum
Cytokines (pg/mL)
cytokines (pg/mL)
Number of EpCAM-positive tumor cells in the urine
• number of EpCAM-positive tumor cells in the urine
Number of immune cells in the urine
• number of immune cells in the urine
Cmax (ng/ml)
PK parameter of Catumaxomab is Cmax (ng/ml)
Cmin (ng/ml)
PK parameters of Catumaxomab is Cmin (ng/ml)
Tmax (hours)
PK parameter of Catumaxomab is Tmax (hours)
AUC (day * ng/ml)
PK parameters of Catumaxomab AUC (day * ng/ml)
t1/2 (days)
PK parameter of Catumaxomab t1/2 (days)
Antitumor activity
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
Complete response
Complete response will be defined as no histological evidence of disease at 3-monthly evaluations
Recurrence-free interval
recurrence-free interval is evaluated following the catumaxomab treatment in the follow up phase 3 month to 2 years
Local progression free interval
local progression free interval is evaluated following the catumaxomab treatment in the follow up phase 3 month to 2 years
Identification and quantification of tumor cells in urine
this is evalulated at screening and in the course of the study
EpCAM expression
Evaluation of potential and predictive EpCAM expression and relative Lymphocytes count can be correlated with outcome

Full Information

First Posted
March 18, 2021
Last Updated
April 4, 2022
Sponsor
Lindis Biotech GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT04819399
Brief Title
Investigation of Safety and Tolerability of Catumaxomab in Patients With NMIBC
Official Title
Phase I, Open Label, Dose Escalating Study to Investigate Safety and Tolerability of Intravesical Application of Trifunctional Anti-EPCAM x Anti-CD3 Antibody Catumaxomab in Patients With Non-muscle Invasive Bladder Cancer (NMIBC)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
July 7, 2020 (Actual)
Primary Completion Date
December 30, 2022 (Anticipated)
Study Completion Date
December 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Lindis Biotech GmbH

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Urinary Bladder Neoplasms
Keywords
Non Muscle Invasive Bladder Cancer, NMIBC, Catumaxomab, Intravesical

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Catumaxomab
Arm Type
Experimental
Arm Description
intravesical Catumaxomab instillation
Intervention Type
Drug
Intervention Name(s)
Catumaxomab
Intervention Description
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
Primary Outcome Measure Information:
Title
Dose escalation phase to evaluate DLT incidence
Description
Dose Limited Toxicity
Time Frame
approximately 1 year after study start
Title
Incidence and severity of treatment related adverse events
Description
Incidence and severity of treatment related adverse events during intravesical instillation with catumaxomab are observed according to NCI CTCAE, Version 5.0
Time Frame
approximately 2.5 years after study start
Secondary Outcome Measure Information:
Title
Anti-drug antibodies (ng/ml)
Description
the incidence of ADA (anti-drug antibodies to catumaxomab by intravesical instillation in serum
Time Frame
approximately 2.5 years after study start
Title
Cytokines (pg/mL)
Description
cytokines (pg/mL)
Time Frame
approximately 2.5 years after study start
Title
Number of EpCAM-positive tumor cells in the urine
Description
• number of EpCAM-positive tumor cells in the urine
Time Frame
approximately 2.5 years after study start
Title
Number of immune cells in the urine
Description
• number of immune cells in the urine
Time Frame
approximately 2.5 years after study start
Title
Cmax (ng/ml)
Description
PK parameter of Catumaxomab is Cmax (ng/ml)
Time Frame
approximately 2.5 years after study start
Title
Cmin (ng/ml)
Description
PK parameters of Catumaxomab is Cmin (ng/ml)
Time Frame
approximately 2.5 years after study start
Title
Tmax (hours)
Description
PK parameter of Catumaxomab is Tmax (hours)
Time Frame
approximately 2.5 years after study start
Title
AUC (day * ng/ml)
Description
PK parameters of Catumaxomab AUC (day * ng/ml)
Time Frame
approximately 2.5 years after study start
Title
t1/2 (days)
Description
PK parameter of Catumaxomab t1/2 (days)
Time Frame
approximately 2.5 years after study start
Title
Antitumor activity
Description
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
Time Frame
approximately 2.5 years after study start
Title
Complete response
Description
Complete response will be defined as no histological evidence of disease at 3-monthly evaluations
Time Frame
approximately 2.5 years after study start
Title
Recurrence-free interval
Description
recurrence-free interval is evaluated following the catumaxomab treatment in the follow up phase 3 month to 2 years
Time Frame
approximately 2.5 years after study start
Title
Local progression free interval
Description
local progression free interval is evaluated following the catumaxomab treatment in the follow up phase 3 month to 2 years
Time Frame
approximately 2.5 years after study start
Title
Identification and quantification of tumor cells in urine
Description
this is evalulated at screening and in the course of the study
Time Frame
approximately 2.5 years after study start
Title
EpCAM expression
Description
Evaluation of potential and predictive EpCAM expression and relative Lymphocytes count can be correlated with outcome
Time Frame
approximately 2.5 years after study start

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Horst Lindhofer, Dr
Phone
498970076624
Email
horst.lindhofer@lindisbiotech.de
First Name & Middle Initial & Last Name or Official Title & Degree
Peter Ruf, Dr
Phone
4989452396020
Email
peter.ruf@lindisbiotech.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
R Oberneder, MD
Organizational Affiliation
Urologische Klinik München-Planegg
Official's Role
Principal Investigator
Facility Information:
Facility Name
Urologie Planegg
City
München
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ralph Oberneder, Dr

12. IPD Sharing Statement

Learn more about this trial

Investigation of Safety and Tolerability of Catumaxomab in Patients With NMIBC

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