Study of the Trifunctional Antibody Catumaxomab to Treat Recurrent Symptomatic Malignant Ascites

Malignant Ascites Clinical Trial

Official title:

A Single-Arm, Open-Label, Phase II Study to Assess the Safety and Efficacy of the Trifunctional Antibody Catumaxomab (Anti-EpCAM x Anti-CD3) Administered Intraperitoneally in Ovarian Cancer Patients With Recurrent Symptomatic Malignant Ascites

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00326885
• Other study ID #: IP-REM-AC-02-US
• Status: Completed
• Phase: Phase 2
• Start date: June 2006
• Est. completion date: August 2010

Study information

• Verified date: September 2018
• Source: Neovii Biotech
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether the investigational drug catumaxomab is a safe and effective treatment for recurrent symptomatic malignant ascites.

Description:

A multi-center, phase II study of catumaxomab in ovarian cancer patients with recurrent symptomatic malignant ascites requiring therapeutic paracentesis. Each eligible patient will receive four ascending doses of catumaxomab, administered intraperitoneally via an indwelling catheter. Catumaxomab will be administered as a 3-hour constant rate infusion with a dosing interval of 3-4 days. Each patient will participate in this study for up to 7 months (includes the baseline therapeutic paracentesis and screening period, 11 to 21 days treatment period, and up to 180 days/6 months follow-up), with monthly post-study follow-up for the lifetime of the patient.

Catumaxomab is a trifunctional antibody targeting EpCAM on tumor cells and CD3 on T cells. Trifunctional antibodies represent a new concept for targeted anticancer therapy. This new antibody class has the capability to redirect T cells and accessory cells (e.g. macrophages, dendritic cells (DCs) and natural killer (NK) cells) to the tumor site. According to preclinical data, trifunctional antibodies activate these different immune effector cells, which can trigger a complex anti-tumor immune response.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: August 2010
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Signed and dated informed consent

• Histologically confirmed diagnosis of epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer; any stage at diagnosis [International Federation of Gynecology and Obstetrics (FIGO) Stages I through IV].

• Progression on or = 12 months after primary platinum-based systemic or intraperitoneal (IP) chemotherapy OR relapse following reinduction = 12 months after primary chemotherapy.

• Have refused, failed, or have been deemed not suitable candidates for gemcitabine or liposomal doxorubicin.

• Recurrent symptomatic malignant ascites requiring therapeutic paracentesis

• At least 1 therapeutic paracentesis within 4 weeks prior to baseline paracentesis

• Age = 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Life expectancy = 16 weeks

• Serum creatinine = 1.5 x upper limit of normal (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 x ULN, and total bilirubin = 1.5 x ULN

• Absolute neutrophil count (ANC) = 1,500/mm3 and platelet count = 75,000/mm3

• Negative serum pregnancy test result at screening in women of childbearing potential (applies to patients without documented menopause or sterility).

• Willingness of patients of childbearing potential to use an effective contraceptive method (i.e., oral contraceptive, cervical cap, diaphragm with spermicide, condom with spermicide, or intrauterine device) during the study and for at least 6 months after the last infusion.

Exclusion Criteria:

• Acute or chronic systemic infection

• Exposure to investigational drugs, chemotherapy or radiotherapy 21 days prior to the first dose of catumaxomab

• Major surgery 2 weeks prior to first dose

• Previous treatment with mouse or rat antibodies

• Known or suspected hypersensitivity to catumaxomab or other monoclonal antibodies

• Body mass index (BMI) < 19 (body weight after paracentesis to be used for calculation of BMI)

• Serum albumin level < 2.0 g/dL

• Reduced nutritional status requiring predominantly parenteral nutrition (> 50% of energy intake). Permanent naso-gastric (NG) feeding tube.

• Ileus in a location that precludes paracentesis

• Extensive liver metastases (> 70% organ volume comprises malignancy)

• Documented brain metastases

• History of myocardial infarction, congestive heart failure or relevant cardiac arrhythmia 3 months prior to the first dose of catumaxomab

• Portal vein obstruction or portal vein thrombosis diagnosed by computed tomography (CT) scan at screening

• Persistent massive pleural effusion or inadequate respiratory function of any other etiology (except if related to ascites symptoms) in the opinion of the investigator

• Any other condition which, according to the investigator, results in an undue risk to the patient by participating in the study

• Prior exposure to catumaxomab

Related Conditions & MeSH terms

• Ascites
• Malignant Ascites

Intervention

Drug:
• catumaxomab
Catumaxomab is administered intraperitoneally via an indwelling catheter (or port) as a 3-hour infusion 4 times (Days 0, 3, 7, and 10) in ascending doses (10 mcg, 20 mcg, 50 mcg, and 150 mcg, respectively).

Locations

Country	Name	City	State
United States	Johns Hopkins Medical Institute	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Wayne State University	Detroit	Michigan
United States	The Methodist Hospital	Houston	Texas
United States	University of San Diego	La Jolla	California
United States	Dartmouth-Hitchock Medical Center	Lebanon	New Hampshire
United States	University of Louisville Cancer Center	Louisville	Kentucky
United States	University of Miami	Miami	Florida
United States	Columbia University Cancer center	New York	New York
United States	University of Oklahoma Health Science Center	Oklahoma City	Oklahoma
United States	Florida Hospital Cancer Center	Orlando	Florida
United States	Magee Women's Hospital, University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	Northern Indiana Cancer Research Consortium	South Bend	Indiana
United States	Stanford University Hospital and Clinics	Stanford	California
United States	University of Arizona Cancer Center	Tucson	Arizona
United States	Wake-Forest University	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Neovii Biotech	Fresenius Biotech North America

Country where clinical trial is conducted

United States, 

References & Publications (7)

Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, Ivanchenko VV, Dudnichenko AS, Aleknaviciene B, Razbadauskas A, Gore M, Ganea-Motan E, Ciuleanu T, Wimberger P, Schmittel A, Schmalfeldt B, Burges A, Bokemeyer C, Lindhofer H, Lahr A, Parsons SL. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int J Cancer. 2010 Nov 1;127(9):2209-21. doi: 10.1002/ijc.25423. — View Citation

Heiss MM, Ströhlein MA, Jäger M, Kimmig R, Burges A, Schoberth A, Jauch KW, Schildberg FW, Lindhofer H. Immunotherapy of malignant ascites with trifunctional antibodies. Int J Cancer. 2005 Nov 10;117(3):435-43. — View Citation

Riesenberg R, Buchner A, Pohla H, Lindhofer H. Lysis of prostate carcinoma cells by trifunctional bispecific antibodies (alpha EpCAM x alpha CD3). J Histochem Cytochem. 2001 Jul;49(7):911-7. — View Citation

Ruf P, Kluge M, Jäger M, Burges A, Volovat C, Heiss MM, Hess J, Wimberger P, Brandt B, Lindhofer H. Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients. Br J Clin Pharmacol. 2010 Jun;69(6):617-25. doi: 10.1111/j.1365-2125.2010.03635.x. — View Citation

Ruf P, Lindhofer H. Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody. Blood. 2001 Oct 15;98(8):2526-34. — View Citation

Zeidler R, Mysliwietz J, Csánady M, Walz A, Ziegler I, Schmitt B, Wollenberg B, Lindhofer H. The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Br J Cancer. 2000 Jul;83(2):261-6. — View Citation

Zeidler R, Reisbach G, Wollenberg B, Lang S, Chaubal S, Schmitt B, Lindhofer H. Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing. J Immunol. 1999 Aug 1;163(3):1246-52. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Proportion of Patients Who Achieved at Least a 4-fold Increase of Puncture/Paracentesis-free Interval Following Catumaxomab Relative to Their Pre-treatment Interval.	The parameter to be estimated is the proportion of patients who achieve at least a 4-fold increase in their puncture/paracentesis-free interval. The pretreatment interval is defined as the length of time between the patient's most recent paracentesis (baseline) and the subsequent paracentesis necessitated by her increasing ascites-related symptoms. The post-treatment interval is defined as the time between the last dose of catumaxomab plus 1 day to the time of recurrence of ascites requiring therapeutic paracentesis or death, whichever occurred sooner.	6 months
Primary	Increase of Paracentesis/Puncture-free Interval (Ratio)	The parameter to be tested is the ratio of the post-treatment puncture/paracentesis-free interval divided by the pre-treatment puncture/paracentesis-free interval. The pre-treatment interval is defined as the length of time between the patient`s most recent paracentesis (baseline) and the subsequent paracentesis necessitated by her increasing ascites-related symptoms. The post-treatment interval is defined as the time between the last dose of catumaxomab plus 1 day to the time of recurrence of ascites requiring therapeutic paracentesis or death, whichever occurred sooner.	180 days
Secondary	Puncture/Paracentesis-free Survival (PuFS)	Puncture/Paracentesis-free Survival (PuFS), Defined as the Number of Days Between the Date of Last Dose and the Date of Documented End of Study (EoS) Paracentesis or Death, Whichever Occurred First	=6 months
Secondary	Overall Survival (OS)	Overall survival is defined as the interval from the date of first dose to the date of death.	= 6 months
Secondary	Ascites Signs and Symptoms	Patient-reported ascites symptoms were to be assessed using the patient questionnaire, Functional Assessment of Chronic Illness Therapy - Ascites Index (FACIT-AI). At 6 months following catumaxomab administration, the patient was requested to assess the severity of the following parameters during the past week using a 5-point scale with scores from "0 = not at all" to "4 = very much": anorexia, insomnia, decreased mobility, dyspnea, nausea, vomiting, abdominal pain, abdominal distention, fatigue, early satiety, urinary frequency, constipation, and emotional distress. For the parameters anorexia, insomnia, and decreased mobility, high scores mean good response, for the other parameters low scores mean good response.	6 months
Secondary	Ascites Volume	Ascites volume measurement were to be performed at screening (= prior to baseline), at baseline (= before start of therapy with catumaxomab) and during the 6-month follow-up period when the patient had recurrence of symptomatic ascites requiring therapeutic paracentesis. At each paracentesis, drainage to dryness was to be achieved and the exact volume was to be measured and documented.	6 months