Fallopian Tube Cancer, Ovarian Cancer, Primary Peritoneal Cancer
Conditions
Keywords
recurrent ovarian epithelial cancer, recurrent fallopian tube cancer, recurrent primary peritoneal cancer
Brief summary
RATIONALE: Monoclonal antibodies, such as Hu3S193, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. PURPOSE: This phase II trial is studying how well Hu3S193 works in treating patients with ovarian epithelial cancer, fallopian tube cancer, or peritoneal cavity cancer.
Detailed description
OBJECTIVES: Primary * To evaluate the efficacy of monoclonal antibody Hu3S193 in women with platinum-resistant/refractory ovarian, fallopian tube, or primary peritoneal cancer, based on RECIST criteria (Response Evaluation Criteria in Solid Tumors). Secondary * To determine the safety of the study drug. * To determine the drug pharmacokinetics when administered in multiple weekly injections. Exploratory analysis * Clinical Benefit (objective response rate + tumor stabilization). * Progression Free Survival (PFS). * Duration of Response. * Overall Survival. * 12-month survival rate. OUTLINE: This is a multicenter study. Patients receive monoclonal antibody Hu3S193 IV over 1 hour once weekly in weeks 1-8. Treatment repeats every 8 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed monthly.
Interventions
BIOLOGICALhu3S193
20 mg/m2, intravenous, weekly for a maximum of 3 cycles (of 8 weeks each)
Sponsors
Recepta Biopharma
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
DISEASE CHARACTERISTICS: * Histologically confirmed ovarian epithelial, fallopian tube, or primary peritoneal carcinoma * Progressive disease * Disease must express Lewis-Y antigen documented by immunohistochemistry in archived or fresh primary or metastatic tumor biopsies * Measurable disease, including at least one measurable lesion, according to RECIST criteria or CA-125 (Cancer Antigen-125) \> 2 times upper normal limit * Pleural effusion, ascites, bone metastases, and lesions located in previously irradiated areas are not considered measurable * Disease must be considered platinum-refractory or resistant, meeting any of the following criteria: * Platinum-refractory defined as progression during the initial platinum-based chemotherapy regimen or failure to achieve a complete response (e.g., stable disease or partial response) with evidence of progressive disease (by physical examination, radiological exams, or CA-125) during the initial platinum-based chemotherapy * Platinum-resistant defined as recurrence within six months of completion of the initial platinum-based regimen (primary platinum-resistance) or recurrence after six months of completion of the initial platinum-based regimen (still considered platinum-sensitive, but incurable by any approach, that will progress to a secondary platinum-resistance scenario) and failure to ≥ 1 re-induction with a platinum-based regimen (secondary platinum-resistance) * No high tumor burden, as assessed by the investigator * No rapidly progressing disease, as assessed by clinical evaluation * No known CNS (Central Nervous System) involvement by tumor PATIENT CHARACTERISTICS: Inclusion criteria: * Karnofsky performance status \> 70% * Life expectancy ≥ 12 weeks * ANC (absolute neutrophil count) ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Serum bilirubin ≤ 2.0 mg/dL * AST (aspartate aminotransferase) and ALT (alanine aminotransferase) ≤ 2.5 times upper limit of normal (ULN) (≤ 5 times ULN if with liver metastases) * Creatinine ≤ 2.0 mg/dL * Prothrombin time \< 1.3 times control * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception
Exclusion criteria
* NYHA (New York Heart Association) class III or IV heart disease * Clinically significant arrhythmias by ECG * Myocardial infarction within the past 6 months * Any other serious illness, including any of the following: * Severe ascites * Severe active infections requiring antibiotics * Bleeding disorders * Chronic inflammatory bowel disease * Diseases that might interfere with the collection of accurate results from this study * Positive for human anti-human antibodies * Prior history of tumor (excluding adequately treated nonmelanoma skin cancer or carcinoma in situ of the uterine cervix) * Uncontrolled hypercalcemia (i.e., \> 11.5 mg/dL) PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Recovered from the toxic effects of any prior therapy * No concurrent systemic steroids or immunosuppressant agents * No more than 1 prior non-platinum-containing regimen for the treatment of platinum-resistant/refractory disease * Patients who receive 2 or more different non-platinum-containing chemotherapy regimens for platinum-resistant/refractory disease are not eligible * More than 4 weeks since prior and no other concurrent chemotherapy, radiotherapy, radiopharmaceuticals (e.g., \^32P), biological therapy, anti-estrogen therapy (including tamoxifen), immunotherapy, or surgery * More than12 weeks since prior investigational agent * No prior treatment with a murine or humanized antibody and/or antibody fragment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response | From start of study treatment until the end of Cycle 1 (8 weeks), Cycle 2 (16 weeks) or Cycle 3 (24 weeks). | Best response recorded from the start of treatment until disease progression/recurrence. Includes all patients evaluable for efficacy, regardless of used criteria: RECIST or CA-125 (Cancer Antigen 125). Evaluation of target lesions: Complete Response (CR), resolution of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter (LD sum) of target lesions, taking as reference the baseline LD sum; Progressive Disease (PD), a 20% increase in LD sum of target lesions or the appearance of new lesion(s); Stable Disease (SD), no sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. Evaluation of non-target lesions: CR, resolution of all non-target lesions and normalization of CA-125 level; SD, persistence of one or more non-target lesions and/or maintenance of CA-125 level above the normal limits; PD, appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events and Serious Adverse Events | From the first dose of investigational product up to 30 days after the last dose of investigational product | A listing of all adverse events is located in the Reported Adverse Event module. |
| Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | From the first dose of investigational product up to 30 days after the last dose of investigational product | Adverse events with possible, probable or definite relationship to the investigational product were considered to be reasonably related. |
| Mean Cmax and Cmin of Hu3S193 Relating to the First 4 Doses. | Pre-dose (within 10 minutes) and Post-dose (5 minutes after completion of infusion) on weeks 1, 2, 3, and 4 of Cycle 1. | Cmax = Peak (post-dosing) IP (Investigational Product) plasma concentration. Cmin = Trough (pre-dosing) IP plasma concentration (Cmin). Plasma concentration of Hu3S193 expressed in µg/mL. |
| Mean Cmax and Cmin of Hu3S193 Relating to the First 8 Doses | Pre-dose (within 10 minutes) and Post-dose (5 minutes after completion of infusion) on weeks 1, 2, 3, 4, 5, 6, 7 and 8 of Cycle 1. | Cmax = Peak (post-dosing) IP plasma concentration. Cmin = Trough (pre-dosing) IP plasma concentration (Cmin). Plasma concentration of Hu3S193 expressed in µg/mL. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From the first day of the investigational product administration until documentation of disease progression or death due to any cause (whichever occurred first). An average of 16.5549 weeks. | Progression free survival (PFS) is defined as the duration of time from start of treatment to time of disease progression. |
| Overall Survival | From start of study treatment until death or the date that patients were last known to be alive. An average of 56.126 weeks. | Measured from the beginning of therapy until the date of death or for patients without a known date of death, they will be censored at the date they were last known to be alive. |
| 12-Month Survival Rate | 12 months from the start of study treatment. | Rate of patients alive 12 months after starting therapy with the investigational product. |
| Clinical Benefit | From start of study treatment until the end of Cycle 3 (24 weeks). | The clinical benefit was calculated considering all patients with objective response rate (CR + PR) or stable disease (SD) for at least 24 weeks according RECIST or CA-125 if patients were non-assessable or when assessment by RECIST was unknown. Clinical benefit = 100% x (Number of patients with objective response + Number of patients with stable disease for at least 24 weeks) / Number of patients included in the efficacy population. The evaluation of target and non-target lesions is described at the Outcome Measure titled Best Overall Response. CR: Complete Response; PR: Partial Response; SD: Stable Disease. |
Countries
Brazil
Participant flow
Recruitment details
This was a brazilian, multicentric clinical trial. From June 20, 2008 to July 13, 2010 (recruitment period of 24 months) a total of 51 patients were screened for this study, of whom 31 were considered eligible and received at least one dose of the investigational product and 20 were considered non-eligible.
Pre-assignment details
Patients were considered included in the study on the day of the first investigational product administration after investigator assured that patients met all the inclusion criterions and none of the exclusion criterions.
Participants by arm
| Arm | Count |
|---|---|
| hu3S193 hu3S193 : 20 mg/m2, intravenous, weekly for a maximum of 3 cycles (of 8 weeks each) | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Lack of compliance with the protocol | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progressive disease | 19 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | hu3S193 |
|---|---|
| ABO blood type Type A | 11 participants |
| ABO blood type Type AB | 2 participants |
| ABO blood type Type B | 1 participants |
| ABO blood type Type O | 17 participants |
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Expression of the Lewis Y antigen in tumor tissue Positive (+1) | 14 participants |
| Expression of the Lewis Y antigen in tumor tissue Positive (+2) | 6 participants |
| Expression of the Lewis Y antigen in tumor tissue Positive (+3) | 8 participants |
| Expression of the Lewis Y antigen in tumor tissue Positive (+4) | 3 participants |
| Region of Enrollment Brazil | 31 participants |
| Sex: Female, Male Female | 31 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 | 31 / 31 |
| serious Total, serious adverse events | 9 / 31 |
Outcome results
Primary
Best Overall Response
Best response recorded from the start of treatment until disease progression/recurrence. Includes all patients evaluable for efficacy, regardless of used criteria: RECIST or CA-125 (Cancer Antigen 125). Evaluation of target lesions: Complete Response (CR), resolution of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter (LD sum) of target lesions, taking as reference the baseline LD sum; Progressive Disease (PD), a 20% increase in LD sum of target lesions or the appearance of new lesion(s); Stable Disease (SD), no sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. Evaluation of non-target lesions: CR, resolution of all non-target lesions and normalization of CA-125 level; SD, persistence of one or more non-target lesions and/or maintenance of CA-125 level above the normal limits; PD, appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: From start of study treatment until the end of Cycle 1 (8 weeks), Cycle 2 (16 weeks) or Cycle 3 (24 weeks).
Population: All patients enrolled in the study that received at least 4 doses of investigational product were considered to the efficacy evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| hu3S193 | Best Overall Response | Complete response | 0 participants |
| hu3S193 | Best Overall Response | Partial response | 0 participants |
| hu3S193 | Best Overall Response | Stable disease | 13 participants |
| hu3S193 | Best Overall Response | Disease progression | 11 participants |
| hu3S193 | Best Overall Response | Unknown | 2 participants |
Secondary
Mean Cmax and Cmin of Hu3S193 Relating to the First 4 Doses.
Cmax = Peak (post-dosing) IP (Investigational Product) plasma concentration. Cmin = Trough (pre-dosing) IP plasma concentration (Cmin). Plasma concentration of Hu3S193 expressed in µg/mL.
Time frame: Pre-dose (within 10 minutes) and Post-dose (5 minutes after completion of infusion) on weeks 1, 2, 3, and 4 of Cycle 1.
Population: All patients enrolled in the study that received at least 4 doses of investigational product were considered to this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| hu3S193 | Mean Cmax and Cmin of Hu3S193 Relating to the First 4 Doses. | Mean Cmax of Hu3S193 | 16.7 µg/mL | Standard Deviation 3.7 |
| hu3S193 | Mean Cmax and Cmin of Hu3S193 Relating to the First 4 Doses. | Mean Cmin of Hu3S193 | 2.1 µg/mL | Standard Deviation 1 |
Secondary
Mean Cmax and Cmin of Hu3S193 Relating to the First 8 Doses
Cmax = Peak (post-dosing) IP plasma concentration. Cmin = Trough (pre-dosing) IP plasma concentration (Cmin). Plasma concentration of Hu3S193 expressed in µg/mL.
Time frame: Pre-dose (within 10 minutes) and Post-dose (5 minutes after completion of infusion) on weeks 1, 2, 3, 4, 5, 6, 7 and 8 of Cycle 1.
Population: All patients enrolled in the study that received at least 8 doses of investigational product were considered to this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| hu3S193 | Mean Cmax and Cmin of Hu3S193 Relating to the First 8 Doses | Mean Cmax of Hu3S193 | 10.9 µg/mL | Standard Deviation 4.7 |
| hu3S193 | Mean Cmax and Cmin of Hu3S193 Relating to the First 8 Doses | Mean Cmin of Hu3S193 | 2.3 µg/mL | Standard Deviation 0.8 |
Secondary
Number of Participants With Adverse Events and Serious Adverse Events
A listing of all adverse events is located in the Reported Adverse Event module.
Time frame: From the first dose of investigational product up to 30 days after the last dose of investigational product
Population: All patients enrolled in the study that received at least 1 dose of investigational product were considered for safety evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| hu3S193 | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Events | 31 participants |
| hu3S193 | Number of Participants With Adverse Events and Serious Adverse Events | Serious Adverse Events | 9 participants |
Secondary
Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%).
Adverse events with possible, probable or definite relationship to the investigational product were considered to be reasonably related.
Time frame: From the first dose of investigational product up to 30 days after the last dose of investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Nausea | 5 participants |
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Fatigue | 4 participants |
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Diarrhoea | 3 participants |
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Hypersensitivity | 3 participants |
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Hypertension | 3 participants |
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Pyrexia | 3 participants |
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Constipation | 2 participants |
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Dry mouth | 2 participants |
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Haemoglobin abnormal | 2 participants |
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Tremor | 2 participants |
| hu3S193 | Number of Participants With Adverse Events Reasonably Related to the Investigational Product (Incidence Greater Than 5%). | Adverse event: Urticaria | 2 participants |
Other Pre-specified
12-Month Survival Rate
Rate of patients alive 12 months after starting therapy with the investigational product.
Time frame: 12 months from the start of study treatment.
Population: All patients enrolled in the study that received at least 4 doses of investigational product were considered to this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| hu3S193 | 12-Month Survival Rate | 57.7 percentage of participants |
Other Pre-specified
Clinical Benefit
The clinical benefit was calculated considering all patients with objective response rate (CR + PR) or stable disease (SD) for at least 24 weeks according RECIST or CA-125 if patients were non-assessable or when assessment by RECIST was unknown. Clinical benefit = 100% x (Number of patients with objective response + Number of patients with stable disease for at least 24 weeks) / Number of patients included in the efficacy population. The evaluation of target and non-target lesions is described at the Outcome Measure titled Best Overall Response. CR: Complete Response; PR: Partial Response; SD: Stable Disease.
Time frame: From start of study treatment until the end of Cycle 3 (24 weeks).
Population: All patients enrolled in the study that received at least 4 doses of investigational product and that were evaluable for response were considered to this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| hu3S193 | Clinical Benefit | 25.0 percentage of participants |
Other Pre-specified
Overall Survival
Measured from the beginning of therapy until the date of death or for patients without a known date of death, they will be censored at the date they were last known to be alive.
Time frame: From start of study treatment until death or the date that patients were last known to be alive. An average of 56.126 weeks.
Population: All patients enrolled in the study that received at least 4 doses of investigational product were considered to this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| hu3S193 | Overall Survival | 67.214 weeks |
Post Hoc
Progression Free Survival in Patients With and Without Ascites at Baseline
Progression free survival (PFS) is defined as the duration of time from start of treatment to time of disease progression.
Time frame: From the first day of the investigational product administration until documentation of disease progression or death due to any cause (whichever occurred first) while the patient was on treatment, non-treatment period, or during the long-term follow-up.
Population: All patients enrolled in the study that received at least 4 doses of investigational product were considered to this analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| hu3S193 | Progression Free Survival in Patients With and Without Ascites at Baseline | PFS in patients with ascites at baseline (n=9) | 6.0000 weeks |
| hu3S193 | Progression Free Survival in Patients With and Without Ascites at Baseline | PFS in patients without ascites at baseline (n=17) | 16.1429 weeks |
Post Hoc
Progression Free Survival in Patients With and Without Visceral Disease at Baseline
Progression free survival (PFS) is defined as the duration of time from start of treatment to time of disease progression
Time frame: From the first day of the investigational product administration until documentation of disease progression or death due to any cause (whichever occurred first) while the patient was on treatment, non-treatment period, or during the long-term follow-up.
Population: All patients enrolled in the study that received at least 4 doses of investigational product and that were assessed for visceral disease at baseline were considered for this analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| hu3S193 | Progression Free Survival in Patients With and Without Visceral Disease at Baseline | PFS in patients with visceral disease (n=5) | 6.1429 weeks |
| hu3S193 | Progression Free Survival in Patients With and Without Visceral Disease at Baseline | PFS in patients without visceral disease (n=20) | 8.9286 weeks |
Post Hoc
Progression Free Survival in Patients Without Ascites and no Visceral Disease at Baseline Versus Patients With Ascites and/or Visceral Disease at Baseline
Progression free survival (PFS) is defined as the duration of time from start of treatment to time of disease progression.
Time frame: From the first day of the investigational product administration until documentation of disease progression or death due to any cause (whichever occurred first) while the patient was on treatment, non-treatment period, or during the long-term follow-up.
Population: All patients enrolled in the study that received at least 4 doses of investigational product and that were assessed for visceral disease and ascites at baseline were considered for this analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| hu3S193 | Progression Free Survival in Patients Without Ascites and no Visceral Disease at Baseline Versus Patients With Ascites and/or Visceral Disease at Baseline | Without ascites and no visceral disease (n=13) | 16.1429 weeks |
| hu3S193 | Progression Free Survival in Patients Without Ascites and no Visceral Disease at Baseline Versus Patients With Ascites and/or Visceral Disease at Baseline | With ascites and/or visceral disease (n=12) | 6.0714 weeks |
Other Pre-specified
Progression Free Survival (PFS)
Progression free survival (PFS) is defined as the duration of time from start of treatment to time of disease progression.
Time frame: From the first day of the investigational product administration until documentation of disease progression or death due to any cause (whichever occurred first). An average of 16.5549 weeks.
Population: All patients enrolled in the study that received at least 4 doses of investigational product and that were evaluable for response were considered to this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| hu3S193 | Progression Free Survival (PFS) | 8.4286 weeks |