Ovarian Cancer
Conditions
Brief summary
This open-label, non-comparative, multi-center study will assess the safety profile and efficacy of Avastin (bevacizumab) when added to carboplatin and paclitaxel therapy in participants with epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma. Participants will receive 15 milligrams/kilogram (mg/kg) Avastin intravenously (IV) on Day 1 of every cycle for up to 36 cycles of 3 weeks each, carboplatin (area under the plasma concentration-time curve \[AUC\] 5-6 mg/ml/min) on Day 1 every 3 weeks for a maximum of 8 cycles and paclitaxel 175 milligram per square meter (mg/m\^2) on Day 1 every 3 weeks or 80 mg/m\^2 every week for a maximum of 8 cycles. The anticipated time on study drug will be 108 weeks or until disease progression or unacceptable toxicity.
Interventions
DRUGPaclitaxel
175 mg/m\^2 on Day 1 every 3 weeks or at a dose of 80 mg/m\^2 every week for a minimum of 4 cycles and not more than 8 cycles or until disease progression or unacceptable toxicity, whichever occurs first
DRUGBevacizumab
15 mg/kg intravenously on Day 1 of every cycle for up to 36 cycles of 3 weeks each or until disease progression or unacceptable toxicity, whichever occurs first
DRUGCarboplatin
AUC 5-6 mg/ml/min on Day 1 every 3 weeks for a minimum of 4 cycles and not more than 8 cycles or until disease progression or unacceptable toxicity, whichever occurs first
Sponsors
Hoffmann-La Roche
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
* Histologically confirmed epithelial ovarian carcinoma, fallopian tube carcinoma, primary peritoneal carcinoma or clear cell carcinoma or carcinosarcoma. Participants with recurrent ovarian cancer who have been previously treated with surgery alone for their early stage disease are eligible. * Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1 or 2 * Life expectancy greater than or equal to (\>=3) months
Exclusion criteria
* Participants with non-epithelial ovarian cancer, ovarian tumors with low malignant potential (i.e., borderline tumors), or synchronous primary endometrial carcinoma * Previous systemic therapy for ovarian cancer. Prior neo-adjuvant chemotherapy is allowed * Planned intraperitoneal cytotoxic chemotherapy * Radiotherapy within 28 days of Day 1, Cycle 1 * Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to first dose of Avastin * History or evidence of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade \>=1 arterial thromboembolic event or Grade \>=3 venous thromboembolic event within 6 months prior to enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least One Adverse Event (AE) | Day 1 up to 30 days after last dose of study treatment (until data cutoff 07 December 2014, up to 4 years) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.0 | Day 1, at end of Cycles 3 and 6, then every 6 cycles while receiving bevacizumab, and then at bevacizumab cessation, every 26 weeks (Q26W) after cessation of bevacizumab until disease progression or death until data cutoff 07 December 2014, up to 4 years | Best overall response (BOR) according to RECIST Version 1.0 was categorized as: CR, PR, progressive disease (PD), stable disease (SD). CR: disappearance of all target lesions and non-target lesions. PR: \>=30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non-target lesions. PD: Natural progression or deterioration of the malignancy under study (including new sites of metastasis). SD: neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started. Participants with a BOR of CR and PR were defined as responders, while participants with a BOR of SD, PD, or unable to assess were defined as non-responders. |
| Percentage of Participants Achieving an Overall Response by 50% Carcinoma Antigen 125 (CA-125) Response Criteria | 3 days prior to Day 1 of every cycle, then every 6 weeks (Q6W) during the first year, every 3 months (Q3M) in the second and third year, every 6 months (Q6M) in the fourth year of the study (until data cutoff 07 December 2014, up to 4 years) | CA-125 responders: Participants with the value of CA-125 reduced by at least 50% and confirmed with a consecutive CA-125 assessment performed at an interval of at least 28 days. Overall response according to CA-125 was only evaluated for participants with a pre-treatment CA-125 within 3 days prior to start of any study treatment of at least twice the upper limit of normal (ULN). |
| Percentage of Participants Achieving an Overall Response by RECIST Version 1.0 and/or 50% CA-125 Response Criteria | RECIST: Day 1, at end of Cycles 3 and 6, then every 6 cycles, at bevacizumab cessation, Q26W after cessation; CA-125: 3 days before Day 1 of every cycle, then Q6W(1st year), Q3M(2nd-3rd year), Q6M(4th year); until data cutoff 07Dec2014, up to 4 years | Overall response was only evaluated for participants who were evaluable according to RECIST v1.0 with a measurable disease at baseline and/or according to CA-125 with a pre-treatment CA-125 within 3 days prior to start of any study treatment of at least twice the ULN. RECIST responders: Participants achieving an overall response of CR (disappearance of all target lesions and non-target lesions) or PR (\>=30% decrease in sum of the LD of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions). CA-125 responders: Participants with the value of CA-125 reduced by at least 50% and confirmed with a consecutive CA-125 assessment performed at an interval of at least 28 days. |
| Progression-Free Survival (PFS) | Day 1, at end of Cycles 3 and 6, then every 6 cycles while receiving bevacizumab, and then at bevacizumab cessation, every 26 weeks after cessation of bevacizumab until disease progression or death until data cutoff 07 December 2014, up to 4 years | PFS was defined as the time between the date of first administration of any study treatment and the date of first documented protocol-defined disease progression (that is \[i.e.\], radiologically by Response Evaluation Criteria In Solid Tumors \[RECIST\], clinical, or symptomatic) or death, whichever occurred first. Participants who had neither progressed nor died at the time of data cut-off (07 December 2014), or participants who were withdrawn from study, or lost to follow-up without documented progression, were censored. Kaplan-Meier estimation was used for median time to PFS. |
| Overall Survival (OS) | First administration of any study treatment until death or data cutoff 07 December 2014, up to 4 years | OS was defined as the time from the date of the first administration of any study treatment to the date of death, regardless of the cause of death. Participants without the event of death were censored at the last date in the study, defined as the latest date of the following: the date of first administration of study treatment, date of last study treatment, date of last visit, or date last known to be alive. Kaplan-Meier estimation was used for OS. |
| Biological Progression-free Interval | 3 days prior to Day 1 of every cycle, then every 6 weeks during the first year, every 3 months in the second and third year, every 6 months in the fourth year of the study (until data cutoff 07 December 2014, up to 4 years) | Biological progression-free interval is defined as the interval from the date of the first administration of any study treatment to the date of the first documented serial elevation of the ovarian cancer mucin CA-125. More precisely, this is defined as the first documented increase in CA-125 levels as follows: (1) CA-125 greater than or equal to 2 times the upper level of normal (ULN) on 2 occasions at least 1 week apart (for participants with CA-125 within normal range pre-treatment) or (2) CA-125 greater than or equal to 2 times the ULN on 2 occasions at least 1 week apart (for participants with elevated CA-125 pre-treatment and initial normalization of CA-125 on-treatment) or (3) CA-125 greater than or equal to 2 times the nadir value, which is the lowest observed CA-125 value per participant on 2 occasions at least 1 week apart (for participants with elevated CA-125 pre-treatment which never normalized). |
| Duration of Objective Response (DOR) | Day 1, at end of Cycles 3 and 6, then every 6 cycles while receiving bevacizumab, and then at bevacizumab cessation, every 26 weeks after cessation of bevacizumab until disease progression or death until data cutoff 07 December 2014, up to 4 years | DOR was defined as the time from the first documented response (CR or PR per RECIST v1.0), to the first documented protocol-defined disease progression (i.e., radiologically by RECIST, clinical, or symptomatic) or death, whichever occurred first. Participants who had neither progressed nor died at the time of data cut-off (07 December 2014), or participants who were withdrawn from study, or lost to follow-up without documented progression, were censored. RECIST responders: Participants achieving an overall response of CR (disappearance of all target lesions and non-target lesions) or PR (\>=30% decrease in sum of the LD of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non-target lesions). Disease progression: Natural progression or deterioration of the malignancy under study (including new sites of metastasis). |
Countries
Argentina, Austria, Brazil, Bulgaria, Canada, Denmark, Egypt, Estonia, France, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Kuwait, Latvia, Lithuania, Mexico, Netherlands, North Macedonia, Poland, Portugal, Romania, Russia, Saudi Arabia, Serbia, Slovakia, Slovenia, South Africa, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), Uruguay
Participant flow
Pre-assignment details
This study has been completed. However, the efficacy and safety results up to the clinical database cutoff date of 07 December 2014 are provided.
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab + Paclitaxel + Carboplatin Participants received bevacizumab 15 mg/kg IV on Day 1 every 3 weeks from Cycle 1 (1 cycle = 3 weeks) to Cycle 36 (initially concurrent with chemotherapy, then continued as a single agent following the completion of chemotherapy), or until protocol-defined disease progression or until unacceptable toxicity (whichever occurred first). The 15 mg/kg dose every 3 weeks was the recommended dose; however a dose of IV bevacizumab 7.5 mg/kg every 3 weeks was permissible, but was to be selected prior to the first dosing of bevacizumab. Participants received paclitaxel 175 mg/m\^2 IV on Day 1 every 3 weeks or 80 mg/m\^2 IV every week and carboplatin (AUC 5-6) IV on Day 1 every 3 weeks for a minimum of 4 and maximum of 8 cycles (including up to 4 pre-surgical cycles), or until protocol-defined disease progression, or unacceptable toxicity (whichever occurred first). | 1,021 |
| Total | 1,021 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | Death | 226 |
| Overall Study | Investigator's decision | 4 |
| Overall Study | Other | 19 |
| Overall Study | Participant non compliance | 5 |
| Overall Study | Protocol Violation | 3 |
| Overall Study | Study termination by sponsor | 2 |
| Overall Study | Termination of study per protocol | 667 |
| Overall Study | Treatment failure | 2 |
| Overall Study | Withdrawal by Subject | 87 |
Baseline characteristics
| Characteristic | Bevacizumab + Paclitaxel + Carboplatin |
|---|---|
| Age, Continuous | 56.3 years STANDARD_DEVIATION 10.98 |
| Sex: Female, Male Female | 1021 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 | 980 / 1,021 |
| serious Total, serious adverse events | 285 / 1,021 |
Outcome results
Primary
Percentage of Participants With at Least One Adverse Event (AE)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Time frame: Day 1 up to 30 days after last dose of study treatment (until data cutoff 07 December 2014, up to 4 years)
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Paclitaxel + Carboplatin | Percentage of Participants With at Least One Adverse Event (AE) | 97.8 percentage of participants |
Secondary
Biological Progression-free Interval
Biological progression-free interval is defined as the interval from the date of the first administration of any study treatment to the date of the first documented serial elevation of the ovarian cancer mucin CA-125. More precisely, this is defined as the first documented increase in CA-125 levels as follows: (1) CA-125 greater than or equal to 2 times the upper level of normal (ULN) on 2 occasions at least 1 week apart (for participants with CA-125 within normal range pre-treatment) or (2) CA-125 greater than or equal to 2 times the ULN on 2 occasions at least 1 week apart (for participants with elevated CA-125 pre-treatment and initial normalization of CA-125 on-treatment) or (3) CA-125 greater than or equal to 2 times the nadir value, which is the lowest observed CA-125 value per participant on 2 occasions at least 1 week apart (for participants with elevated CA-125 pre-treatment which never normalized).
Time frame: 3 days prior to Day 1 of every cycle, then every 6 weeks during the first year, every 3 months in the second and third year, every 6 months in the fourth year of the study (until data cutoff 07 December 2014, up to 4 years)
Population: Previous studies linking CA-125 levels with bevacizumab exposure as a potential secondary outcome measure for PFS did not produce any reliable information. Therefore, it was decided that data for this outcome measure should not be analyzed, as agreed with the study steering committee.
Secondary
Duration of Objective Response (DOR)
DOR was defined as the time from the first documented response (CR or PR per RECIST v1.0), to the first documented protocol-defined disease progression (i.e., radiologically by RECIST, clinical, or symptomatic) or death, whichever occurred first. Participants who had neither progressed nor died at the time of data cut-off (07 December 2014), or participants who were withdrawn from study, or lost to follow-up without documented progression, were censored. RECIST responders: Participants achieving an overall response of CR (disappearance of all target lesions and non-target lesions) or PR (\>=30% decrease in sum of the LD of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non-target lesions). Disease progression: Natural progression or deterioration of the malignancy under study (including new sites of metastasis).
Time frame: Day 1, at end of Cycles 3 and 6, then every 6 cycles while receiving bevacizumab, and then at bevacizumab cessation, every 26 weeks after cessation of bevacizumab until disease progression or death until data cutoff 07 December 2014, up to 4 years
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Paclitaxel + Carboplatin | Duration of Objective Response (DOR) | 18.2 months |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of the first administration of any study treatment to the date of death, regardless of the cause of death. Participants without the event of death were censored at the last date in the study, defined as the latest date of the following: the date of first administration of study treatment, date of last study treatment, date of last visit, or date last known to be alive. Kaplan-Meier estimation was used for OS.
Time frame: First administration of any study treatment until death or data cutoff 07 December 2014, up to 4 years
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Paclitaxel + Carboplatin | Overall Survival (OS) | NA months |
Secondary
Percentage of Participants Achieving an Overall Response by 50% Carcinoma Antigen 125 (CA-125) Response Criteria
CA-125 responders: Participants with the value of CA-125 reduced by at least 50% and confirmed with a consecutive CA-125 assessment performed at an interval of at least 28 days. Overall response according to CA-125 was only evaluated for participants with a pre-treatment CA-125 within 3 days prior to start of any study treatment of at least twice the upper limit of normal (ULN).
Time frame: 3 days prior to Day 1 of every cycle, then every 6 weeks (Q6W) during the first year, every 3 months (Q3M) in the second and third year, every 6 months (Q6M) in the fourth year of the study (until data cutoff 07 December 2014, up to 4 years)
Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Paclitaxel + Carboplatin | Percentage of Participants Achieving an Overall Response by 50% Carcinoma Antigen 125 (CA-125) Response Criteria | 91.8 percentage of participants |
Secondary
Percentage of Participants Achieving an Overall Response by RECIST Version 1.0 and/or 50% CA-125 Response Criteria
Overall response was only evaluated for participants who were evaluable according to RECIST v1.0 with a measurable disease at baseline and/or according to CA-125 with a pre-treatment CA-125 within 3 days prior to start of any study treatment of at least twice the ULN. RECIST responders: Participants achieving an overall response of CR (disappearance of all target lesions and non-target lesions) or PR (\>=30% decrease in sum of the LD of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions). CA-125 responders: Participants with the value of CA-125 reduced by at least 50% and confirmed with a consecutive CA-125 assessment performed at an interval of at least 28 days.
Time frame: RECIST: Day 1, at end of Cycles 3 and 6, then every 6 cycles, at bevacizumab cessation, Q26W after cessation; CA-125: 3 days before Day 1 of every cycle, then Q6W(1st year), Q3M(2nd-3rd year), Q6M(4th year); until data cutoff 07Dec2014, up to 4 years
Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Paclitaxel + Carboplatin | Percentage of Participants Achieving an Overall Response by RECIST Version 1.0 and/or 50% CA-125 Response Criteria | 82.4 percentage of participants |
Secondary
Percentage of Participants Achieving Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.0
Best overall response (BOR) according to RECIST Version 1.0 was categorized as: CR, PR, progressive disease (PD), stable disease (SD). CR: disappearance of all target lesions and non-target lesions. PR: \>=30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non-target lesions. PD: Natural progression or deterioration of the malignancy under study (including new sites of metastasis). SD: neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started. Participants with a BOR of CR and PR were defined as responders, while participants with a BOR of SD, PD, or unable to assess were defined as non-responders.
Time frame: Day 1, at end of Cycles 3 and 6, then every 6 cycles while receiving bevacizumab, and then at bevacizumab cessation, every 26 weeks (Q26W) after cessation of bevacizumab until disease progression or death until data cutoff 07 December 2014, up to 4 years
Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Paclitaxel + Carboplatin | Percentage of Participants Achieving Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.0 | 72.7 percentage of participants |
Secondary
Progression-Free Survival (PFS)
PFS was defined as the time between the date of first administration of any study treatment and the date of first documented protocol-defined disease progression (that is \[i.e.\], radiologically by Response Evaluation Criteria In Solid Tumors \[RECIST\], clinical, or symptomatic) or death, whichever occurred first. Participants who had neither progressed nor died at the time of data cut-off (07 December 2014), or participants who were withdrawn from study, or lost to follow-up without documented progression, were censored. Kaplan-Meier estimation was used for median time to PFS.
Time frame: Day 1, at end of Cycles 3 and 6, then every 6 cycles while receiving bevacizumab, and then at bevacizumab cessation, every 26 weeks after cessation of bevacizumab until disease progression or death until data cutoff 07 December 2014, up to 4 years
Population: Intent to treat population included all participants who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Paclitaxel + Carboplatin | Progression-Free Survival (PFS) | 25.5 months |