Ovarian Cancer
Conditions
Keywords
recurrent ovarian epithelial cancer, stage III ovarian epithelial cancer
Brief summary
RATIONALE: Radiolabeled monoclonal antibodies can locate tumor cells and deliver radioactive tumor-killing substances to them without harming normal cells. Giving radiolabeled monoclonal antibody directly into the abdominal cavity may kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of giving radiolabeled monoclonal antibody therapy directly into the abdominal cavity in treating patients who have advanced ovarian epithelial cancer.
Detailed description
OBJECTIVES: Primary * Determine the safety and maximum tolerated dose of intraperitoneally (IP) administered yttrium-90 (90Y) radiolabeled monoclonal antibody (mAB) hu3S193 (90Y-hu3S193) in patients with advanced ovarian epithelial cancer. Secondary * Determine the localization and whole body and abdominal clearance of 90Y-hu3S193 using indium-111 (111In) radiolabeled hu3S193 and gamma camera imaging. * Determine the serum pharmacokinetics of hu3S193 using gamma well counting. * Determine the antibody response as measured by human anti-human antibody response (HAHA). OUTLINE: This is a dose-escalation study of the yttrium-90 radiolabeled monoclonal antibody, 90Y-hu3S193. Patients received technetium (99mTc-sulfur colloid) IP and underwent abdominal imaging on day 1. Provided the distribution of the 99mTC-sulfur colloid was deemed adequate, patients then received 90Y-hu3S193 IP. 111In-hu3S193 was also administered IP over 30 minutes on day 1 to enable gamma camera imaging. Within 3-5 hours after antibody administration, patients underwent whole body imaging and single-photon emission-computed tomography (SPECT) imaging of the abdomen and pelvis. Cohorts of 3-6 patients were to receive escalating doses of 90Y-hu3S193 until the maximum tolerated dose (MTD) was determined. The MTD was defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients were to be followed every 3 months for at least 2 years and then every 6 months for up to 5 years.
Interventions
BIOLOGICAL90Y-hu3S193
Patients received a single dose of 10 mg of hu3S193 radiolabeled with the intended dose (mCi) of 90Y.
BIOLOGICAL111In-hu3S193
Patients received a single dose of 5 mCi 111In-hu3S193 together with the 90Y-hu3S193.
Sponsors
National Cancer Institute (NCI)
Ludwig Institute for Cancer Research
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed non-mucinous ovarian adenocarcinoma. 2. Persistent or recurrent intraperitoneal cancer following platinum/taxane-based therapy for Stage 3 ovarian cancer. 3. Patients with residual disease \< 2cm will be candidates for this study. 4. The following laboratory and clinical results within the last 2 weeks prior to study day 1: Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L; Platelet count ≥ 100 x 10\^9/L; Serum bilirubin ≤ 2.0 mg/dL; Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN); Alanine aminotransferase (ALT) ≤ 2.5 x ULN; Serum creatinine ≤2.0 mg/dL; Forced expiratory volume (FEV1) ≥60% of predicted; Forced vital capacity (FVC) ≥60% of predicted; Diffusion capacity ≥55% of predicted; Left ventricular ejection fraction (LVEF) ≥50%; 5. Karnofsky performance status ≥ 70. 6. Before any trial-specific procedures or treatment can be performed, the patient or legally authorized guardian or representative must give witnessed written informed consent for participation in the trial. 7. Placement of an intra-abdominal catheter at the time of surgery.
Exclusion criteria
1. Active parenchymal disease (i.e., Stage IV International Federation of Gynecology and Obstetrics (FIGO) classification). 2. Presence of symptomatic extra abdominal metastases. 3. Known central nervous system (CNS) tumor involvement. 4. Clinically significant heart disease (New York Heart Association Class III or IV). 5. ECG demonstrating clinically significant arrhythmias or evidence of prior myocardial infarction. 6. Other serious illnesses, eg, serious infections requiring antibiotics, bleeding disorders that may limit the amount of antibody they can tolerate or render them ineligible for surgery. 7. Chronic inflammatory bowel disease. 8. Chemotherapy, biologic therapy, or immunotherapy within 4 weeks prior to enrollment. 9. Pregnancy or lactation. 10. Patients who are positive for human anti-human antibodies (HAHA) and/or who have received a murine monoclonal antibody.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose-limiting Toxicities (DLTs) | Up to day 56 | All adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (CTC) Scale (Version 2.0, published April 30, 1999). DLT was defined as: * Any Grade 3 or greater non-hematological toxicity (except for alopecia, nausea, and vomiting, defined separately below) * Any Grade alopecia * Grade 4 nausea or vomiting ≥ 5 days duration. * Any Grade 4 hematological toxicity (except for toxicity of ≤ 5 days duration without growth factor, platelet, or transfusion support). To be dose limiting, an adverse event must be definitely, probably, or possibly related to the administration of the investigational agent. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clearance as Measured by the Half-life (T1/2) of the Elimination Phase | Up to 22 days | Serum samples were taken 5 min, 1 hour, and 2 hours after end of infusion, twice on study day 2, and daily on study days 3 to 7, 8, 15 and 22. Serum samples were analyzed in a gamma well counter. Elimination half-life (T1/2) was generated by fitting effective clearance to a monoexponential curve. |
| Number of Patients With Human Anti-human Antibodies (HAHA) After Treatment | Up to day 56 | Blood samples were taken at baseline and on days15, 28 and 56. HAHA was measured by BIACORE. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Patients received a single intraperitoneal (IP) dose of 10 mg of hu3S193 radiolabeled with 10 millicuries (mCi) 90Y and 5 mCi 111In-hu3S193 to enable imaging after dosing.
90Y-hu3S193: Patients received a single dose of 10 mg of hu3S193 radiolabeled with the intended dose (mCi) of 90Y.
111In-hu3S193: Patients received a single dose of 5 mCi 111In-hu3S193 together with the 90Y-hu3S193. | 3 |
| Cohort 2 Patients received a single intraperitoneal (IP) dose of 10 mg of hu3S193 radiolabeled with 15 millicuries (mCi) 90Y and 5 mCi 111In-hu3S193 to enable imaging after dosing.
90Y-hu3S193: Patients received a single dose of 10 mg of hu3S193 radiolabeled with the intended dose (mCi) of 90Y.
111In-hu3S193: Patients received a single dose of 5 mCi 111In-hu3S193 together with the 90Y-hu3S193. | 4 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Progressive disease | 0 | 3 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment United States | 3 participants | 4 participants | 7 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 2 / 3 | 3 / 4 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 |
Outcome results
Primary
Number of Patients With Dose-limiting Toxicities (DLTs)
All adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (CTC) Scale (Version 2.0, published April 30, 1999). DLT was defined as: * Any Grade 3 or greater non-hematological toxicity (except for alopecia, nausea, and vomiting, defined separately below) * Any Grade alopecia * Grade 4 nausea or vomiting ≥ 5 days duration. * Any Grade 4 hematological toxicity (except for toxicity of ≤ 5 days duration without growth factor, platelet, or transfusion support). To be dose limiting, an adverse event must be definitely, probably, or possibly related to the administration of the investigational agent.
Time frame: Up to day 56
Population: All patients who entered the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Patients With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Cohort 2 | Number of Patients With Dose-limiting Toxicities (DLTs) | 0 Participants |
Secondary
Clearance as Measured by the Half-life (T1/2) of the Elimination Phase
Serum samples were taken 5 min, 1 hour, and 2 hours after end of infusion, twice on study day 2, and daily on study days 3 to 7, 8, 15 and 22. Serum samples were analyzed in a gamma well counter. Elimination half-life (T1/2) was generated by fitting effective clearance to a monoexponential curve.
Time frame: Up to 22 days
Population: All patients who entered the study and had serum samples taken at the specified times. Patient No. 5 in Cohort 2 did not have Day 22 blood drawn and was not included in the mean value.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 | Clearance as Measured by the Half-life (T1/2) of the Elimination Phase | 2.43 days |
| Cohort 2 | Clearance as Measured by the Half-life (T1/2) of the Elimination Phase | 2.28 days |
Secondary
Number of Patients With Human Anti-human Antibodies (HAHA) After Treatment
Blood samples were taken at baseline and on days15, 28 and 56. HAHA was measured by BIACORE.
Time frame: Up to day 56
Population: All patients who entered the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Patients With Human Anti-human Antibodies (HAHA) After Treatment | 0 Participants |
| Cohort 2 | Number of Patients With Human Anti-human Antibodies (HAHA) After Treatment | 0 Participants |