Ovarian Cancer
Conditions
Brief summary
Feasibility study to assess a novel combination of cytotoxic agents, docetaxel and oxaliplatin, as first-line therapy in the treatment of ovarian cancer and the impact of angiogenesis inhibition for the progression and prognosis of ovarian cancer by concurrent addition of bevacizumab (Avastin®).
Detailed description
Participants were * administered study medication approximately 28 days after initial surgery for ovarian cancer * received the study treatment regimen of up to one year unless there was disease progression, unacceptable toxicity, death, participant refusal, or treatment delay beyond the time frame permitted for each treatment Participants were followed for survival for a minimum 3 years from the date of enrollment
Interventions
15 mg/kg bevacizumab administered intravenously (IV) over 30 to 90 minutes on Day 1 of every 3 week cycle for 12 months or until disease progression or unacceptable toxicity
75 mg/m\^2 docetaxel was administered IV over 1 hour on Day 1 of every 3 week cycle for 6 cycles or until disease progression or unacceptable toxicity
DRUGOxaliplatin (Eloxatin®)
85 mg/m\^2 Oxaliplatin was administered IV over 2 hours on Day 1 of every 3 week cycle for 6 cycles or until disease progression or unacceptable toxicity
Sponsors
Sanofi
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Females 18 years of age or older 2. Participants with a histologic diagnosis of ovarian, primary peritoneal, or fallopian tube carcinoma, Stage Ib- IV, with either optimal (≤ 1 cm residual disease) or suboptimal residual disease ( \> 1 cm maximal diameter any remaining lesion) following initial surgery. 3. Participants with the following histologic epithelial cell types are eligible: Serious adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma,undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's Tumor, or adenocarcinoma N.O.S. 4. Participant must have adequate bone marrow function 5. Participant must have adequate renal function 6. Participant must have adequate urine protein/creatinine reaction (UPC) of \<1.0; 7. Participant must have adequate neurologic function 8. Hepatic function: Total Bilirubin ≤ ULN; AST and ALT and Alkaline Phosphatase must be within the range allowing for eligibility. In determining eligibility the more abnormal of the two values (AST or ALT) should be used. 9. Blood Coagulation parameters: PT such that international normalized ratio (INR) is \< 1.5 (or an in-range INR, usually between 2 and 3, if a participant is on stable dose of therapeutic Warfarin or low molecular weight heparin) and a PTT \< 1.2 times the upper limit normal. 10. Participants must be enrolled in the study prior to 50 days (every effort will be made for prior to 28 days) after initial surgery performed for the combined purpose of diagnosis, staging and cytoreduction. 11. Participants with measurable and non-measurable disease are eligible. Participants with suboptimal disease are eligible. Participants may or may not have cancer-related symptoms. 12. Participants who have met the pre-entry requirements specified including serologic measurement of CA-125 as a baseline for subsequent determination of response using Rustin criteria. 13. Participants with a GOG Performance Status of 0, 1, or 2.
Exclusion criteria
1. Participants with a current diagnosis of epithelial ovarian tumor of low malignant potential (Borderline carcinomas) are not eligible. Participants with a prior diagnosis of a low malignant potential tumor that was surgically resected and who subsequently develop invasive adenocarcinoma are eligible, provided that they have not received prior chemotherapy for any ovarian tumor. 2. Germ cell tumors, sex cord-stromal tumors, carcinosarcomas, mixed mullerian tumors or carcinosarcomas, metastatic carcinomas from other sites to the ovary and low malignant potential tumors including so called micropapillary serous carcinomas are not eligible. 3. Participants who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded. Prior radiation for localized cancer of the skin is permitted, provided that it was completed more than 5 years prior to enrollment, and the participant remains free of recurrent or metastatic disease. 4. Participants who have received any prior anticancer chemotherapy or biologic therapy for any malignancy are excluded. 5. Participants with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, are excluded, unless all of the following conditions are met: Stage not greater than I-B; Less than 3 mm invasion without vascular or lymphatic invasion; No poorly differentiated subtypes, including papillary serous, clear cell, or other FIGO Grade 3 lesions. 6. Participants with any history of cancer, with the exception of inclusion criteria #2 and #3, and non-melanoma skin cancer, who are cancer free for the last 5 years, are excluded. 7. Participant with acute hepatitis or active infection that requires parenteral antibiotics. 8. Participants with serious, non-healing wound, ulcer, or bone fracture. This includes history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days. Participants with granulating incisions healing by secondary intention with no evidence of fascial dehiscence or infection are eligible but require weekly wound examinations. 9. Participants with active bleeding or pathologic conditions that carry high risk of bleeding,such as known bleeding disorder, coagulopathy, or tumor involving major vessels. 10. Participants with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study. 11. Participants with clinically significant cardiovascular disease. 12. Participants with clinically significant proteinuria. Urine protein should be screened by urinalysis. Participants discovered to have a urine protein: serum creatinine ratio greater than or equal to 1 should undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate \< 1000 mg protein/24 hr to allow participation in the study. 13. Participants with or with anticipation of invasive procedures. 14. Participants with GOG Performance Grade of 3 or 4. 15. Participants who are pregnant or nursing. 16. Participants with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies and hypersensitivity to polysorbate 80 or hypersensitivity to any of the study drugs and its ingredients. 17. Participants who participated in a study with any investigational product/device within the last 30 days. 18. Any medical condition that in the judgment of the investigator would jeopardize any participant safety or the study drug evaluation for efficacy and safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Twelve-month Progression-free Survival (PFS) Rate in Participants | up to 12 months following treatment initiation | Tumor assessments were performed by Computed tomography (CT) and Magnetic Resonance Imaging (MRI) to evaluate disease progression based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST). Disease progression was recorded as any one of the following: * appearance of a new lesion * symptomatic deterioration * progression of target or nontarget lesions * death Participants who did not die or show show disease progression achieved PFS. PFS rate is the percent of participants who achieved PFS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Progression-free Survival (PFS) | up to approximately 1300 days following treatment initiation | Time to PFS was the interval from the date of registration to the earliest date of disease progression or death, whichever occurred first. Time of PFS was censored * on the last available tumor assessment date for participants leaving the study prior to disease progression or death; and also for participants requiring off-study medication or additional debulking surgery (where assessment date used was the one prior to off-study medication or surgery), * at Day 1, for living participants with no post-baseline tumor assessments. Median PFS was estimated from a Kaplan-Meier curve. |
| Tumor Response Rate Based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST) | up to 12 months following treatment initiation | Tumors were assessed by CT and MRI. Tumor response was evaluated by GOG RECIST in which: * Complete response (CR) was the disappearance of all target and non-target lesions, with no evidence of new lesions * Partial response (PR) was at least a 30% decrease in the sum of longest dimensions (LD) of all measurable target lesions Participants with a response (CR or PR) were to have the initial response confirmed by tumor imaging in 4-6 weeks. |
| Twelve-month Recurrence-free Survival (RFS) Rate in Participants With Non Measurable Disease at Baseline | up to 12 months following treatment initiation | Participants with Recurrence-free survival (RFS) were participants with a non-measurable disease at baseline, who had not achieved disease progression nor had died. Disease progression included the following: * the appearance of a new lesion * symptomatic deterioration * progression of non-target lesions * a predefined serum CA 125 increase. RFS rate was the percent of participants in the non-measurable disease subgroup who achieved RFS. |
| Twenty Four-month Progression-free Survival (PFS) Rate in Participants | up to 24 months following treatment initiation | Tumor assessments were performed by Computed tomography (CT) and Magnetic Resonance Imaging (MRI) to evaluate disease progression based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST). Disease progression was recorded as any one of the following: * appearance of a new lesion * symptomatic deterioration * progression of target or nontarget lesions * death Participants who did not die or show show disease progression achieved PFS. PFS rate is the percent of participants who achieved PFS. |
| CA-125 Response Rate | up to 12 months after treatment initiation | A CA-125 response was considered at least a 50% reduction in the level of the biomarker, CA-125, from a pretreatment level, which was confirmed and maintained for at least 28 days. The overall CA-125 biomarker response rate was defined as the number of participants in the measurable disease subgroup who met the above criteria at least once within the study treatment period +21 days, divided by the number of evaluable participants in the disease subgroup. |
| Overall Survival Rate | up to up to approximately 1700 days after treatment initiation | Survival was the observed length of life from entry into the study to death or the date of last contact. The overall survival rate (percentage of participants showing survival) at 12 and 24-months is reported here. |
| Median Overall Survival Time | up to approximately 1700 days after treatment initiation | Survival was the observed length of life from entry into the study to death or the date of last contact. The median overall survival time was estimated using Kaplan-Meier Curve. |
| Median Time to Recurrence-free Survival (RFS) in Participants With Non-measurable Disease at Baseline | up to approximately 1500 days following treatment initiation | The time to RFS was programmatically defined as the interval from the date of registration to the earliest date of disease progression or death, whichever occurred first. Participants were * censored on the last available CA 125 biomarker blood draw date if * left the study prior to disease progression or death * they received off-study anti-tumor medication * underwent debulking surgery * censored at Day 1 if they were alive had no post baseline CA 125 biomarker blood draw. |
Countries
United States
Participant flow
Recruitment details
152 participants were screened for the study. 20 were screen failures. 132 participants met eligibity criteria and were treated with study medication.
Participants by arm
| Arm | Count |
|---|---|
| Oxaliplatin/Docetaxel/Bevacizumab (Measurable Disease) Participants with International Federation of Gynecology and Obstetrics (FIGO) stage IB through IV ovarian, primary peritoneal, or fallopian tube carcinoma treated with Oxaliplatin, Docetaxel, and Bevacizumab - 28 days after initial surgery, with a measurable disease at baseline.
Measurable disease was defined as having at least one lesion that could be accurately measured in at least one dimension. | 80 |
| Oxaliplatin/Docetaxel/Bevacizumab (Non-Measurable Disease) Participants with International Federation of Gynecology and Obstetrics (FIGO) stage IB through IV ovarian, primary peritoneal, or fallopian tube carcinoma treated with Oxaliplatin, Docetaxel, and Bevacizumab - 28 days after initial surgery, who did not have a measurable disease at baseline.
Measurable disease was defined as having at least one lesion that could be accurately measured in at least one dimension. | 52 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 18 |
| Overall Study | Disease Progression | 37 |
| Overall Study | ineligibility due to radiation treatment | 1 |
| Overall Study | Investigator/Participant request | 5 |
| Overall Study | Missing for end of treatment | 4 |
| Overall Study | Neuropathy/patient preference | 1 |
| Overall Study | Non-compliance | 1 |
| Overall Study | Noncompliance/decision to discontinue | 1 |
| Overall Study | Poor performance status | 1 |
| Overall Study | Progression based on CA-125 (biomarker) | 2 |
| Overall Study | Proteinuria | 1 |
| Overall Study | Relocation to Florida | 1 |
| Overall Study | Urine protein/creatinine ratio delay | 1 |
Baseline characteristics
| Characteristic | Oxaliplatin/Docetaxel/Bevacizumab (Measurable Disease) | Oxaliplatin/Docetaxel/Bevacizumab (Non-Measurable Disease) | Total |
|---|---|---|---|
| Age Continuous | 57.5 years STANDARD_DEVIATION 10.43 | 60.9 years STANDARD_DEVIATION 9.54 | 58.8 years STANDARD_DEVIATION 10.19 |
| FIGO stage at diagnosis Stage IB | 0 participants | 0 participants | 0 participants |
| FIGO stage at diagnosis Stage IC | 0 participants | 3 participants | 3 participants |
| FIGO stage at diagnosis Stage IIA | 0 participants | 0 participants | 0 participants |
| FIGO stage at diagnosis Stage IIB | 0 participants | 0 participants | 0 participants |
| FIGO stage at diagnosis Stage IIC | 3 participants | 5 participants | 8 participants |
| FIGO stage at diagnosis Stage IIIA | 3 participants | 2 participants | 5 participants |
| FIGO stage at diagnosis Stage IIIB | 2 participants | 5 participants | 7 participants |
| FIGO stage at diagnosis Stage IIIC | 57 participants | 32 participants | 89 participants |
| FIGO stage at diagnosis Stage IV | 15 participants | 5 participants | 20 participants |
| Primary Tumor Site Fallopian tube | 6 participants | 5 participants | 11 participants |
| Primary Tumor Site Ovary | 65 participants | 45 participants | 110 participants |
| Primary Tumor Site Peritoneum | 9 participants | 2 participants | 11 participants |
| Sex: Female, Male Female | 80 Participants | 52 Participants | 132 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 130 / 132 |
| serious Total, serious adverse events | 33 / 132 |
Outcome results
Primary
Twelve-month Progression-free Survival (PFS) Rate in Participants
Tumor assessments were performed by Computed tomography (CT) and Magnetic Resonance Imaging (MRI) to evaluate disease progression based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST). Disease progression was recorded as any one of the following: * appearance of a new lesion * symptomatic deterioration * progression of target or nontarget lesions * death Participants who did not die or show show disease progression achieved PFS. PFS rate is the percent of participants who achieved PFS.
Time frame: up to 12 months following treatment initiation
Population: Intent-to-treat population with measurable disease at baseline - All participants with measurable disease at baseline who received study drugs, except for participants from one site which was closed prematurely, and for whom efficacy data was not available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin/Docetaxel/Bevacizumab | Twelve-month Progression-free Survival (PFS) Rate in Participants | 65.7 percentage of participants |
Secondary
CA-125 Response Rate
A CA-125 response was considered at least a 50% reduction in the level of the biomarker, CA-125, from a pretreatment level, which was confirmed and maintained for at least 28 days. The overall CA-125 biomarker response rate was defined as the number of participants in the measurable disease subgroup who met the above criteria at least once within the study treatment period +21 days, divided by the number of evaluable participants in the disease subgroup.
Time frame: up to 12 months after treatment initiation
Population: All participants with non-measurable and measurable disease at baseline, and a pretreatment sample that was at least twice the ULN value for CA-125 within 2 weeks of first study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oxaliplatin/Docetaxel/Bevacizumab | CA-125 Response Rate | With non-measurable disease at baseline (N=27) | 81.5 percentage of participants |
| Oxaliplatin/Docetaxel/Bevacizumab | CA-125 Response Rate | With measurable disease at baseline (N=53) | 83.0 percentage of participants |
Secondary
Median Overall Survival Time
Survival was the observed length of life from entry into the study to death or the date of last contact. The median overall survival time was estimated using Kaplan-Meier Curve.
Time frame: up to approximately 1700 days after treatment initiation
Population: Intent-to-treat population - All participants who received study drugs, except for participants from one site which was closed prematurely, and for whom efficacy data was not available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin/Docetaxel/Bevacizumab | Median Overall Survival Time | 1437.0 days |
Secondary
Median Time to Progression-free Survival (PFS)
Time to PFS was the interval from the date of registration to the earliest date of disease progression or death, whichever occurred first. Time of PFS was censored * on the last available tumor assessment date for participants leaving the study prior to disease progression or death; and also for participants requiring off-study medication or additional debulking surgery (where assessment date used was the one prior to off-study medication or surgery), * at Day 1, for living participants with no post-baseline tumor assessments. Median PFS was estimated from a Kaplan-Meier curve.
Time frame: up to approximately 1300 days following treatment initiation
Population: Intent-to-treat population with measurable disease at baseline - All participants with measurable disease at baseline who received study drugs, except for participants from one site which was closed prematurely, and for whom efficacy data was not available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin/Docetaxel/Bevacizumab | Median Time to Progression-free Survival (PFS) | 495 days |
Secondary
Median Time to Recurrence-free Survival (RFS) in Participants With Non-measurable Disease at Baseline
The time to RFS was programmatically defined as the interval from the date of registration to the earliest date of disease progression or death, whichever occurred first. Participants were * censored on the last available CA 125 biomarker blood draw date if * left the study prior to disease progression or death * they received off-study anti-tumor medication * underwent debulking surgery * censored at Day 1 if they were alive had no post baseline CA 125 biomarker blood draw.
Time frame: up to approximately 1500 days following treatment initiation
Population: All participants with non-measurable disease at baseline, except for those at one site that closed prematurely, as their data was not available for efficacy measures.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oxaliplatin/Docetaxel/Bevacizumab | Median Time to Recurrence-free Survival (RFS) in Participants With Non-measurable Disease at Baseline | 631 days |
Secondary
Overall Survival Rate
Survival was the observed length of life from entry into the study to death or the date of last contact. The overall survival rate (percentage of participants showing survival) at 12 and 24-months is reported here.
Time frame: up to up to approximately 1700 days after treatment initiation
Population: Intent-to-treat population - All participants who received study drugs, except for participants from one site which was closed prematurely, and for whom efficacy data was not available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oxaliplatin/Docetaxel/Bevacizumab | Overall Survival Rate | Overall survival at 12 months | 85.5 percentage of participants |
| Oxaliplatin/Docetaxel/Bevacizumab | Overall Survival Rate | Overall survival at 24 months | 71.8 percentage of participants |
Secondary
Tumor Response Rate Based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST)
Tumors were assessed by CT and MRI. Tumor response was evaluated by GOG RECIST in which: * Complete response (CR) was the disappearance of all target and non-target lesions, with no evidence of new lesions * Partial response (PR) was at least a 30% decrease in the sum of longest dimensions (LD) of all measurable target lesions Participants with a response (CR or PR) were to have the initial response confirmed by tumor imaging in 4-6 weeks.
Time frame: up to 12 months following treatment initiation
Population: Intent-to-treat population with measurable disease at baseline - All participants with measurable disease at baseline who received study drugs, except for participants from one site which was closed prematurely, and for whom efficacy data was not available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oxaliplatin/Docetaxel/Bevacizumab | Tumor Response Rate Based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST) | Unconfirmed progressive disease (PD) | 5 participants |
| Oxaliplatin/Docetaxel/Bevacizumab | Tumor Response Rate Based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST) | Confirmed response (CR+PR) | 41 participants |
| Oxaliplatin/Docetaxel/Bevacizumab | Tumor Response Rate Based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST) | Confirmed complete response (CR) | 21 participants |
| Oxaliplatin/Docetaxel/Bevacizumab | Tumor Response Rate Based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST) | Unconfirmed response (CR+PR) | 51 participants |
| Oxaliplatin/Docetaxel/Bevacizumab | Tumor Response Rate Based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST) | Unconfirmed complete response (CR) | 23 participants |
| Oxaliplatin/Docetaxel/Bevacizumab | Tumor Response Rate Based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST) | Unconfirmed partial response (PR) | 28 participants |
| Oxaliplatin/Docetaxel/Bevacizumab | Tumor Response Rate Based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST) | Confirmed partial response (PR) | 20 participants |
Secondary
Twelve-month Recurrence-free Survival (RFS) Rate in Participants With Non Measurable Disease at Baseline
Participants with Recurrence-free survival (RFS) were participants with a non-measurable disease at baseline, who had not achieved disease progression nor had died. Disease progression included the following: * the appearance of a new lesion * symptomatic deterioration * progression of non-target lesions * a predefined serum CA 125 increase. RFS rate was the percent of participants in the non-measurable disease subgroup who achieved RFS.
Time frame: up to 12 months following treatment initiation
Population: All participants with non-measurable disease at baseline, except for those at one site that closed prematurely, as their data was not available for efficacy measures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin/Docetaxel/Bevacizumab | Twelve-month Recurrence-free Survival (RFS) Rate in Participants With Non Measurable Disease at Baseline | 67.5 percentage of participants |
Secondary
Twenty Four-month Progression-free Survival (PFS) Rate in Participants
Tumor assessments were performed by Computed tomography (CT) and Magnetic Resonance Imaging (MRI) to evaluate disease progression based on Gynecologic Oncology Group (GOG) Response Evaluation Criteria in Solid Tumors (RECIST). Disease progression was recorded as any one of the following: * appearance of a new lesion * symptomatic deterioration * progression of target or nontarget lesions * death Participants who did not die or show show disease progression achieved PFS. PFS rate is the percent of participants who achieved PFS.
Time frame: up to 24 months following treatment initiation
Population: Intent-to-treat population with measurable disease at baseline - All participants with measurable disease at baseline who received study drugs, except for participants from one site which was closed prematurely, and for whom efficacy data was not available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oxaliplatin/Docetaxel/Bevacizumab | Twenty Four-month Progression-free Survival (PFS) Rate in Participants | 34.3 percentage of participants |