Malignant Ascites
Conditions
Keywords
Ascites, Epithelial Cancer, Epithelial Carcinoma, Epithelial Ovarian Cancer, Epithelial Ovarian Carcinoma, Fallopian Tube Cancer, Fallopian Tube Carcinoma, Malignant Ascites, Ovarian Cancer, Ovarian Carcinoma, Ovarian Epithelial Cancer, Ovarian Epithelial Carcinoma, Peritoneal Cancer, Peritoneal Carcinoma, Recurrent Ascites, Recurrent Malignant Ascites, Recurrent Symptomatic Malignant Ascites, Symptomatic Malignant Ascites, Symptomatic Ascites, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Fallopian Tube Neoplasms, Peritoneal Neoplasms
Brief 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.
Detailed 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.
Interventions
DRUGcatumaxomab
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).
Sponsors
Fresenius Biotech North America
Neovii Biotech
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 6 months | 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. |
| Increase of Paracentesis/Puncture-free Interval (Ratio) | 180 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Puncture/Paracentesis-free Survival (PuFS) | ≥6 months | 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 |
| Overall Survival (OS) | ≥ 6 months | Overall survival is defined as the interval from the date of first dose to the date of death. |
| Ascites Signs and Symptoms | 6 months | 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. |
| Ascites Volume | 6 months | 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. |
Countries
United States
Participant flow
Recruitment details
40 patients were recruited and 32 patients were treated and evaluable. For analyses, there were 32 patients in the Full Analysis Set (FAS), 14 patients in the Per-Protocol (PP) population, and 32 patients in the Safety population.
Pre-assignment details
Eligible patients must have undergone at least 1 therapeutic paracentesis (the most recent paracentesis) within 4 weeks prior to the baseline paracentesis.
Participants by arm
| Arm | Count |
|---|---|
| Catumaxomab 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 4 days (10 μg, 20 μg, 50 μg, and 150 μg, respectively) | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Hospice withdrew consent | 2 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Catumaxomab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 14 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Age, Continuous | 60.3 years STANDARD_DEVIATION 10.84 |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 32 / 32 |
| serious Total, serious adverse events | 24 / 32 |
Outcome results
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.
Time frame: 180 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Catumaxomab | Increase of Paracentesis/Puncture-free Interval (Ratio) | 2 fold |
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Catumaxomab | 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. | 0.226 proportion of patients |
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.
Time frame: 6 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Catumaxomab | Ascites Signs and Symptoms | I have good appetite | 1.5 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I am sleeping well | 1.0 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I am able to get around by myself | 1.0 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I have been short of breath | 1.0 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I have nausea | 0.5 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I have been vomiting | 0.5 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I have pain in my stomach area | 1.0 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I have swelling in my stomach area | 1.0 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I have lack of energy | 2.0 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | When I eat, I seem to get full quickly | 2.0 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I urinate more frequently | 0.0 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I am bothered by constipation | 1.0 units on a scale |
| Catumaxomab | Ascites Signs and Symptoms | I have been emotionally distressed | 0 units on a scale |
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.
Time frame: 6 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Catumaxomab | Ascites Volume | prior to baseline (at screening) | 2800 mL |
| Catumaxomab | Ascites Volume | baseline (start of therapy) | 2050 mL |
| Catumaxomab | Ascites Volume | at puncture visit/ end of study (day 180) | 1500 mL |
Secondary
Overall Survival (OS)
Overall survival is defined as the interval from the date of first dose to the date of death.
Time frame: ≥ 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Catumaxomab | Overall Survival (OS) | 3.6 months |
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
Time frame: ≥6 months
Population: Full analysis set (FAS) Per protocol (PP)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Catumaxomab | Puncture/Paracentesis-free Survival (PuFS) | 4.2 weeks |