Ovarian Cancer
Conditions
Keywords
Ovarian cancer, Abagovomab
Brief summary
The purpose of this study is to evaluate the benefit of vaccination with Abagovomab, an experimental immunotherapy in ovarian cancer patients. The benefit will be evaluated in terms of time the remission status is kept as well as prolongation of life expectancy.
Detailed description
Standard initial treatment of ovarian cancer patients includes both surgery and chemotherapy which in the vast majority of cases achieves the disappearance of ovarian cancer lesions. This status, called clinical remission which means having no evidence of cancer on CT scan or physical examination needs to be carefully follow up in order to confirm the maintenance of the remission status or to early detect if the cancer grows again and then start a new chemotherapy. At present, no approved therapies exist for the maintenance treatment of patients who achieved the clinical remission. This trial aims to evaluate if the repeated vaccination with Abagovomab creates an immunoresponse which is able to fight the cancer cells thus keeping the remission status as long as possible and help patients live disease-free and longer. Patients who achieve the remission status after chemotherapy will be screened for study participation and if they meet the criteria for inclusion they will start to receive a single subcutaneous injection every 2 weeks (for the first 4 doses - induction phase) and then every 4 weeks (maintenance phase). The duration of treatment is up to approximately 4 years or it will be stopped in case relapse occurs. In order to evaluate the real benefit of vaccination, the experimental treatment includes Abagovomab (the active drug) or placebo (the vehicle only, without drug), with a double chance to receive Abagovomab. Assignment of Abagovomab or placebo will be done by a computerised system and nobody in the study will know which treatment has been allocated until study end. Patients will be visited every 4 weeks and will undergo CT scan of pelvis and abdomen every 12 weeks in order to confirm the remission status or to early detect if relapse eventually occurs. This will be done in blind condition (i.e. without being aware which treatment the patient is going to receive) for the first part of the study which is expected to last four years. After then the overall status of patient will continue to be monitored by phone contact for additional five years.
Interventions
BIOLOGICALAbagovomab
2 mg/ml SC (subcutaneously)
BIOLOGICALPlacebo
2 mg/ml SC (subcutaneously)
Sponsors
Menarini Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
At a maximum of 12 weeks after the last cycle of first line standard platinum/taxane intravenous (IV) or intraperitoneal (IP) chemotherapy, patients must fulfill all the following inclusion criteria: * Age \>/= 18 years; * Properly executed written informed consent; * History of histological and CA125 (\> 35 U/ml) confirmed diagnosis of stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer; * History of debulking surgery and 6-8 cycles of standard platinum/taxane based non-investigational IV-IP chemotherapy; * Complete clinical response defined as: * Normal physical examination; * No symptoms suggestive of persistent cancer; * No definite evidence of disease by computed tomography (CT) of the abdomen and pelvis within the previous 4 weeks; * Negative chest x-ray (or chest CT scan) within the previous 4 weeks; * Serum CA125 within the normal laboratory range. * Adequate hematologic, renal and hepatic function: * Absolute Neutrophil Count (ANC) \>/=1.5 \* 109/l; * Platelets \>/= 75 \* 109/l; * Haemoglobin \>/= 6.2 mmol/l (\>9.9 g/dl); * Serum creatinine \</= 1.5 \* ULN (Upper Limit of Normal); * Bilirubin \</= 1.5 \* ULN; AST, ALT, AP \</= 2.5 \* ULN. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) \</= 2.
Exclusion criteria
Patients are ineligible to participate in the study, if any of the following criteria are present: * any other invasive malignancies, with the exception of non-melanoma skin cancer or cervical carcinoma in situ, within the last 5 years or whose previous cancer treatment contraindicates this protocol therapy; * known active autoimmune disease requiring chronic treatment with immunosuppressive agents (e.g., rheumatoid arthritis, ulcerative colitis, etc.); * known immune deficiency (e.g. HIV, hypogammaglobulinemia, etc.); * known infection with hepatitis B, or hepatitis C; * history of recent myocardial infarction (\</= 6 months) or decompensated heart failure (New York Heart Association - NYHA class \>/= III); * previous or concomitant use of any anti-cancer therapy other than the platinum-taxane based 1st line chemotherapy for ovarian cancer; any maintenance or consolidation therapy is not permitted after completion of standard front line chemotherapy. * concomitant use of any other investigational agent; * any prior investigational anti-cancer vaccine or monoclonal antibody; * known allergy to murine proteins; * any significant medical or psychiatric condition, drug or alcohol abuse that might prevent the patient from complying with all study procedures; * clinically significant active infection; * concomitant use of any immunosuppressive agent (e.g., steroids, cyclosporin, etc.); * major surgery within the previous 2 weeks; * radiotherapy within the previous 4 weeks; * any significant toxicity from prior chemotherapy; * unreliability or inability to follow protocol requirements; * potentially childbearing and not willing to use adequate contraceptive methods throughout the entire study period; * pregnancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence Free Survival Evaluated by Clinical Event Adjudication Committee (CEAC) | Every 12 weeks up to recurrence or up to 3 months after last administered dose | The Recurrence free survival correspond to the time from date of randomization to documented disease recurrence or death. Disease recurrence is defined as the appearance of any lesion or development of tumor-related symptoms evaluated by medical examination and must be confirmed by a documented CT scan. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 2 years | 2 years survival rate |
| Safety | Along treatment administration and up to double blind observation period. i.e. for each patient after the first dose administration till the f inal study visit, or within 12 weeks of the last dose | Safety was analyzed in all patients who received at least 1 dose administration. Adverse event (AE) are defined as events which started on or after the first dose of study medication and on or before the date of the final study visit, or within 12 weeks of the last dose if the final study visit was not performed. |
| Time Course of Immunoresponse | at baseline, at week 10 after first dose administration and at final study visit (at week 4 or week 12 after the last administered dose, as appropriate) | Time course of immunologic parameters (anti-anti-idiotypic antibody - Ab3) will be assessed in all patients, by comparing levels at baseline (week 0), at week 10 after first dose administration and at end of treatment (at week 4 or week 12 after the last administered dose, as appropriate). |
Countries
Belgium, Czechia, France, Germany, Hungary, Italy, Poland, Spain, United States
Participant flow
Recruitment details
Study population was recruited in 139 sites (Hospitals/University Clinics) distributed in Europe (Belgium, Czech Republic, France, Germany, Hungary, Italy, Poland and Spain) and US. Date of first patient randomised: 08 December 2006 Date of last patient randomised: 26 December 2008
Participants by arm
| Arm | Count |
|---|---|
| Abagovomab 2 mg/ml SC, every 2 weeks (for the first 4 doses - induction phase) and then every 4 weeks (maintenance phase) | 593 |
| Placebo 2 mg/ml SC, every 2 weeks (for the first 4 doses - induction phase) and then every 4 weeks (maintenance phase) | 295 |
| Total | 888 |
Baseline characteristics
| Characteristic | Placebo | Abagovomab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 68 Participants | 145 Participants | 213 Participants |
| Age, Categorical Between 18 and 65 years | 227 Participants | 447 Participants | 674 Participants |
| Age Continuous | 56.0 years STANDARD_DEVIATION 10.47 | 56.4 years STANDARD_DEVIATION 10.57 | 56.3 years STANDARD_DEVIATION 10.53 |
| Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 0 | 240 participants | 460 participants | 700 participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 1 | 55 participants | 131 participants | 186 participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 2 | 0 participants | 2 participants | 2 participants |
| Grade of histologic differentiation G1-G2 | 82 participants | 160 participants | 242 participants |
| Grade of histologic differentiation G3-G4 | 185 participants | 365 participants | 550 participants |
| Grade of histologic differentiation GX | 4 participants | 12 participants | 16 participants |
| Grade of histologic differentiation not done | 24 participants | 56 participants | 80 participants |
| Histology of ovarian tumor Endometrioid | 21 participants | 38 participants | 59 participants |
| Histology of ovarian tumor missing | 0 participants | 3 participants | 3 participants |
| Histology of ovarian tumor Mixed tumor | 7 participants | 18 participants | 25 participants |
| Histology of ovarian tumor Mucinous | 3 participants | 6 participants | 9 participants |
| Histology of ovarian tumor Others | 12 participants | 33 participants | 45 participants |
| Histology of ovarian tumor Serous/papillary | 245 participants | 481 participants | 726 participants |
| Histology of ovarian tumor Undifferentiated | 7 participants | 14 participants | 21 participants |
| International Federation of Gynecology and Obstetrics (FIGO) stage III | 252 participants | 513 participants | 765 participants |
| International Federation of Gynecology and Obstetrics (FIGO) stage IV | 42 participants | 80 participants | 122 participants |
| International Federation of Gynecology and Obstetrics (FIGO) stage missing | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Belgium | 4 participants | 19 participants | 23 participants |
| Region of Enrollment Czech Republic | 28 participants | 54 participants | 82 participants |
| Region of Enrollment France | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Germany | 93 participants | 206 participants | 299 participants |
| Region of Enrollment Hungary | 8 participants | 17 participants | 25 participants |
| Region of Enrollment Italy | 40 participants | 97 participants | 137 participants |
| Region of Enrollment Poland | 25 participants | 53 participants | 78 participants |
| Region of Enrollment Spain | 48 participants | 55 participants | 103 participants |
| Region of Enrollment United States | 47 participants | 91 participants | 138 participants |
| Serum CA-125 after 3rd chemotherapy cycle <= 35 U/ml | 239 participants | 479 participants | 718 participants |
| Serum CA-125 after 3rd chemotherapy cycle > 35 U/ml | 55 participants | 114 participants | 169 participants |
| Serum CA-125 after 3rd chemotherapy cycle missing | 1 participants | 0 participants | 1 participants |
| Sex/Gender, Customized Female | 295 participants | 593 participants | 888 participants |
| Tumor size after debulking surgery <= 1 cm | 232 participants | 479 participants | 711 participants |
| Tumor size after debulking surgery > 1 cm | 63 participants | 114 participants | 177 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 532 / 592 | 261 / 294 |
| serious Total, serious adverse events | 141 / 592 | 72 / 294 |
Outcome results
Primary
Recurrence Free Survival Evaluated by Clinical Event Adjudication Committee (CEAC)
The Recurrence free survival correspond to the time from date of randomization to documented disease recurrence or death. Disease recurrence is defined as the appearance of any lesion or development of tumor-related symptoms evaluated by medical examination and must be confirmed by a documented CT scan.
Time frame: Every 12 weeks up to recurrence or up to 3 months after last administered dose
Population: intention to treat (ITT) population (i.e. all randomized patients)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abagovomab | Recurrence Free Survival Evaluated by Clinical Event Adjudication Committee (CEAC) | 403 days |
| Placebo | Recurrence Free Survival Evaluated by Clinical Event Adjudication Committee (CEAC) | 402 days |
p-value: 0.30195% CI: [0.919, 1.315]Regression, Cox
Secondary
Overall Survival
2 years survival rate
Time frame: 2 years
Population: intention to treat (ITT) population (i.e. all randomized patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Abagovomab | Overall Survival | 80 Percentage of participants |
| Placebo | Overall Survival | 79 Percentage of participants |
Secondary
Safety
Safety was analyzed in all patients who received at least 1 dose administration. Adverse event (AE) are defined as events which started on or after the first dose of study medication and on or before the date of the final study visit, or within 12 weeks of the last dose if the final study visit was not performed.
Time frame: Along treatment administration and up to double blind observation period. i.e. for each patient after the first dose administration till the f inal study visit, or within 12 weeks of the last dose
Population: Safety population (i.e. All randomized patients who received at least one dose treatment administration)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Abagovomab | Safety | Patients with at least 1 Adverse Drug Reaction ADR | 507 participants |
| Abagovomab | Safety | Patients with at least 1 Serious ADR (SADR) | 10 participants |
| Abagovomab | Safety | Patients with at least 1 Adverse Event (AE) | 564 participants |
| Abagovomab | Safety | Patients with at least 1 AE leading to withdrawal | 93 participants |
| Abagovomab | Safety | Patients with at least 1 AE resulted in death | 8 participants |
| Abagovomab | Safety | Patients with at least 1 Serious Adverse Event SAE | 141 participants |
| Placebo | Safety | Patients with at least 1 AE resulted in death | 4 participants |
| Placebo | Safety | Patients with at least 1 Adverse Event (AE) | 278 participants |
| Placebo | Safety | Patients with at least 1 Adverse Drug Reaction ADR | 246 participants |
| Placebo | Safety | Patients with at least 1 Serious Adverse Event SAE | 72 participants |
| Placebo | Safety | Patients with at least 1 Serious ADR (SADR) | 3 participants |
| Placebo | Safety | Patients with at least 1 AE leading to withdrawal | 57 participants |
Secondary
Time Course of Immunoresponse
Time course of immunologic parameters (anti-anti-idiotypic antibody - Ab3) will be assessed in all patients, by comparing levels at baseline (week 0), at week 10 after first dose administration and at end of treatment (at week 4 or week 12 after the last administered dose, as appropriate).
Time frame: at baseline, at week 10 after first dose administration and at final study visit (at week 4 or week 12 after the last administered dose, as appropriate)
Population: Participants who received abagovomab (evaluable population)and have baseline serum sample: 576 at baseline; 538 at week 10 after first dose intake; 449 at the final study visit
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Abagovomab | Time Course of Immunoresponse | Ab3 (baseline) | 0 ng/ml |
| Abagovomab | Time Course of Immunoresponse | Ab3 (week 10) | 63550 ng/ml |
| Abagovomab | Time Course of Immunoresponse | Ab3 (end of treatment) | 493000 ng/ml |