Fallopian Tube Neoplasms, Genital Neoplasms, Female, Ovarian Neoplasms, Pelvic Neoplasms, Peritoneal Neoplasms
Conditions
Brief summary
This is a phase III randomized study comparing induction treatments of Gemcitabine and Carboplatin versus Paclitaxel and Carboplatin, with or without consolidation therapy for patients that do not have any evidence of disease after completion of six cycles of induction therapy. Patients with disease after induction therapy will crossover to receive single agent therapy.
Detailed description
This study (Study B9E-US-S302) is a multicenter, comparative, open-label randomized, superiority, trial evaluating Gemcitabine and Carboplatin to the standard of care. Both treatment arms will be given the option to receive elective consolidation therapy of Paclitaxel 135 mg/m\^2 given every 28 days for one year. Patients not achieving a complete response will crossover to the opposite single agent.
Interventions
DRUGGemcitabine
1000 mg/m\^2, Intravenously (IV), day 1 and day 8 every (q) 21 days x 6 cycles If anything other than complete response in Paclitaxel arm patients, 1000 mg/m\^2, IV, day 1 and day 8 q 21 days until complete response, disease progression or unacceptable toxicity
DRUGPaclitaxel
175 mg/m\^2, IV, Day 1, q 21 days x 6 cycles If complete response both Paclitaxel and Gemcitabine arms may elect to receive consolidation therapy, 135 mg/m\^2, IV, 3 hours q 28 days x 12 cycles (1 year) If no complete response, then Gemcitabine arm patients may receive 175 mg/m\^2, IV, Day 1, q 21 days until complete response, disease progression or unacceptable toxicity
DRUGCarboplatin
Gemcitabine/Carboplatin AUC 5, IV, Day 1, q 21 days x 6 cycles Paclitaxel/Carboplatin AUC 6, IV, Day 1, q 21 days x 6 cycles
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Patients with a histologic diagnosis of primary peritoneal carcinoma, epithelial ovarian carcinoma or fallopian tube carcinoma Stage IC, II, III or IV. * All patients must have had surgery for fallopian, ovarian or peritoneal carcinoma to establish the diagnosis and have tissue available for histologic evaluation and confirmation of organ of origin. * Patients must be enrolled no more than twelve weeks postoperatively. * Patients must be willing to receive their chemotherapy drugs intravenously, as intraperitoneal therapy is not part of this trial. Key
Exclusion criteria
* Patients with a current diagnosis of epithelial ovarian tumor of low malignant potential (Borderline carcinomas) are not eligible. * Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded * Patients who have received prior chemotherapy for any abdominal or pelvic tumor are excluded * With the exception of non-melanoma skin cancer and other specific malignancies patients who had (or have) any evidence of the other cancer present within the last 5 years or whose previous cancer treatment contraindicates this protocol therapy are excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Baseline to measured progressive disease or death up to 82 months | Progression free survival was defined as the duration from the date of randomization to the first date of documented disease progression or death from any cause. Tumor assessments were performed every three 21-day cycles during induction and crossover. Progression free survival was censored at the date of the last follow-up visit for participants who were still alive and who had not progressed. Results are presented as a comparison between the two study treatment sequences (induction therapy followed by elective consolidation or crossover therapy) rather than the two induction therapies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Response (Response Rate) | Baseline to measured progressive disease up to 82 months | Response rate (RR) = proportion of participants with best overall Complete Response (CR: disappearance of all target lesions \[TL\]) or Partial Response (PR: 30% decrease in sum of longest diameter of TL). Induction therapy RR = number of participants with CR or PR during induction divided by number of participants with measurable disease at baseline (TL measurement during screening). Crossover therapy RR = number of participants with CR or PR during crossover divided by number of participants with measurable disease at baseline (latest TL measurement by first dose date of crossover therapy). |
| Time to Treatment Failure | Baseline to stopping treatment up to 82 months | Time to treatment failure was defined as the duration from date of randomization to the date of the first of the following events: early discontinuation of study therapy; progression of disease, or death due to any cause. Time to treatment failure will be censored at the date of the last follow-up visit for participants who did not discontinue early, who are still alive, and who have not progressed. Results are presented as a comparison between the two study treatment sequences (induction therapy followed by elective consolidation or crossover therapy) rather than the two induction therapies. |
| Overall Survival | Baseline to death from any cause up to 82 months | Overall survival is defined as the duration from baseline to death. For participants who are still alive at the data cut-off date, survival will be censored at the last contact date. Results are presented as a comparison between the two study treatment sequences (induction therapy followed by elective consolidation or crossover therapy) rather than the two induction therapies. |
Countries
Puerto Rico, United States
Participant flow
Pre-assignment details
919 patients were randomized, only 831 randomized patients were included in any analyses. 85 randomized patients were excluded due to significant noncompliant issues and 3 patients were excluded due to unavailable data.
Participants by arm
| Arm | Count |
|---|---|
| Gemcitabine/Carboplatin Induction: Gemcitabine 1000 mg/m\^2 Days 1 and 8 followed by Carboplatin Area Under the Curve (AUC) 5 Day 1; every 21-days.
Consolidation (gemcitabine to paclitaxel): Paclitaxel 135 mg/m\^2 Intravenous Piggy-Back (IVPB), 3 hours every 28 days for 12 cycles (one year).
Paclitaxel (crossover): Single agent Paclitaxel 175 mg/m\^2 day 1 to be repeated every 21 days. | 417 |
| Paclitaxel/Carboplatin Induction: Paclitaxel 175 mg/m\^2 and Carboplatin AUC 6 Day 1, every 21 days. Consolidation (paclitaxel to paclitaxel): Paclitaxel 135 mg/m\^2 IVPB, 3 hours every 28 days for 12 cycles (one year).
Gemcitabine (crossover): Single agent Gemcitabine 1000 mg/m\^2 days 1, 8 to be repeated every 21 days. | 414 |
| Total | 831 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 6 | 8 |
| Overall Study | Disease Progression | 5 | 6 |
| Overall Study | Missing Data | 18 | 11 |
| Overall Study | Other | 33 | 34 |
| Overall Study | Physician Decision | 20 | 11 |
| Overall Study | Protocol Violation | 5 | 7 |
| Overall Study | Toxicity | 26 | 37 |
| Overall Study | Withdrawal by Subject | 58 | 39 |
Baseline characteristics
| Characteristic | Gemcitabine/Carboplatin | Paclitaxel/Carboplatin | Total |
|---|---|---|---|
| Age Continuous | 59.7 years STANDARD_DEVIATION 11.4 | 60.3 years STANDARD_DEVIATION 10.8 | 60.0 years STANDARD_DEVIATION 11.1 |
| CA-125 Units per milliliter at Baseline for All Patients | 492.772 units per milliliter STANDARD_DEVIATION 1138.556 | 479.854 units per milliliter STANDARD_DEVIATION 1117.04 | 486.329 units per milliliter STANDARD_DEVIATION 1127.213 |
| Extent of Residual Disease Measurable | 139 participants | 114 participants | 253 participants |
| Extent of Residual Disease Missing Data | 2 participants | 0 participants | 2 participants |
| Extent of Residual Disease Non-measurable | 276 participants | 300 participants | 576 participants |
| Histology Adenocarcinoma Not Otherwise Specified (NOS) | 22 participants | 23 participants | 45 participants |
| Histology Clear Cell | 21 participants | 23 participants | 44 participants |
| Histology Endometroid | 44 participants | 40 participants | 84 participants |
| Histology Malignant Brenner's Tumor | 0 participants | 0 participants | 0 participants |
| Histology Missing Data | 1 participants | 0 participants | 1 participants |
| Histology Mixed Epithelial | 9 participants | 13 participants | 22 participants |
| Histology Mucinous | 10 participants | 10 participants | 20 participants |
| Histology Other | 17 participants | 21 participants | 38 participants |
| Histology Serous | 283 participants | 276 participants | 559 participants |
| Histology Transitional Cell | 3 participants | 1 participants | 4 participants |
| Histology Undifferentiated | 7 participants | 7 participants | 14 participants |
| International Federation of Gynecology and Obstetrics (FIGO) Stage at Initial Surgery Missing Data | 0 participants | 1 participants | 1 participants |
| International Federation of Gynecology and Obstetrics (FIGO) Stage at Initial Surgery Stage Ic | 21 participants | 22 participants | 43 participants |
| International Federation of Gynecology and Obstetrics (FIGO) Stage at Initial Surgery Stage II | 44 participants | 39 participants | 83 participants |
| International Federation of Gynecology and Obstetrics (FIGO) Stage at Initial Surgery Stage III | 284 participants | 289 participants | 573 participants |
| International Federation of Gynecology and Obstetrics (FIGO) Stage at Initial Surgery Stage IV | 68 participants | 63 participants | 131 participants |
| Organ of Origin Missing Data | 6 participants | 2 participants | 8 participants |
| Organ of Origin Ovary | 355 participants | 362 participants | 717 participants |
| Organ of Origin Peritoneum | 56 participants | 50 participants | 106 participants |
| Race/Ethnicity, Customized Asian | 5 participants | 5 participants | 10 participants |
| Race/Ethnicity, Customized Black or African American | 12 participants | 13 participants | 25 participants |
| Race/Ethnicity, Customized Caucasian | 379 participants | 379 participants | 758 participants |
| Race/Ethnicity, Customized Native American | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Other | 19 participants | 16 participants | 35 participants |
| Sex: Female, Male Female | 417 Participants | 414 Participants | 831 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Volume of Residual Tumor Following Debulking Surgery < 2 centimeters | 309 participants | 314 participants | 623 participants |
| Volume of Residual Tumor Following Debulking Surgery >= 2 centimeters | 102 participants | 96 participants | 198 participants |
| Volume of Residual Tumor Following Debulking Surgery Missing Data | 6 participants | 4 participants | 10 participants |
| Zubrod Performance Status 0 | 239 participants | 232 participants | 471 participants |
| Zubrod Performance Status 1 | 139 participants | 157 participants | 296 participants |
| Zubrod Performance Status 2 | 27 participants | 16 participants | 43 participants |
| Zubrod Performance Status >= 3 | 0 participants | 0 participants | 0 participants |
| Zubrod Performance Status Missing Data | 12 participants | 9 participants | 21 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 404 / 412 | 394 / 408 | 157 / 169 | 170 / 183 | 76 / 78 | 73 / 77 |
| serious Total, serious adverse events | 96 / 412 | 72 / 408 | 14 / 169 | 12 / 183 | 8 / 78 | 8 / 77 |
Outcome results
Primary
Progression Free Survival (PFS)
Progression free survival was defined as the duration from the date of randomization to the first date of documented disease progression or death from any cause. Tumor assessments were performed every three 21-day cycles during induction and crossover. Progression free survival was censored at the date of the last follow-up visit for participants who were still alive and who had not progressed. Results are presented as a comparison between the two study treatment sequences (induction therapy followed by elective consolidation or crossover therapy) rather than the two induction therapies.
Time frame: Baseline to measured progressive disease or death up to 82 months
Population: Intent to treat (ITT) population, which includes all randomized participants. 3 participants in the Gemcitabine/Carboplatin treatment sequence were excluded due to missing data, and 1 participant in the Paclitaxel/Carboplatin treatment sequence was excluded for missing data. G/C Arm: 292 events, 122 censored. P/C Arm: 279 events, 134 censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gemcitabine/Carboplatin | Progression Free Survival (PFS) | 20.0 Months |
| Paclitaxel/Carboplatin | Progression Free Survival (PFS) | 22.2 Months |
Comparison: Using a two-sided log-rank test with a Type I error of 0.05, 636 events for PFS out of the 919 patients would give an 80% statistical power under the alternative hypothesis that the hazard ratio of the G/C arm versus the P/C arm was 0.08.p-value: 0.199Log Rank
Secondary
Overall Survival
Overall survival is defined as the duration from baseline to death. For participants who are still alive at the data cut-off date, survival will be censored at the last contact date. Results are presented as a comparison between the two study treatment sequences (induction therapy followed by elective consolidation or crossover therapy) rather than the two induction therapies.
Time frame: Baseline to death from any cause up to 82 months
Population: Intent to treat (ITT) population, which includes all randomized participants. 3 participants in the Gemcitabine/Carboplatin treatment sequence were excluded due to missing data, and 1 participant in the Paclitaxel/Carboplatin treatment sequence was excluded for missing data. G/C Arm: 194 events, 220 censored. P/C Arm: 159 events, 254 censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gemcitabine/Carboplatin | Overall Survival | 43.8 months |
| Paclitaxel/Carboplatin | Overall Survival | 57.3 months |
p-value: 0.013Log Rank
Secondary
Proportion of Participants With Response (Response Rate)
Response rate (RR) = proportion of participants with best overall Complete Response (CR: disappearance of all target lesions \[TL\]) or Partial Response (PR: 30% decrease in sum of longest diameter of TL). Induction therapy RR = number of participants with CR or PR during induction divided by number of participants with measurable disease at baseline (TL measurement during screening). Crossover therapy RR = number of participants with CR or PR during crossover divided by number of participants with measurable disease at baseline (latest TL measurement by first dose date of crossover therapy).
Time frame: Baseline to measured progressive disease up to 82 months
Population: All ITT participants with measurable disease at baseline (screening) for induction period; all ITT participants who crossed over to single agent therapy and had measurable disease before or at crossover for crossover period. Participants in consolidation therapy achieved CR during induction therapy and were not included in analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Gemcitabine/Carboplatin | Proportion of Participants With Response (Response Rate) | 0.676 proportion of responders |
| Paclitaxel/Carboplatin | Proportion of Participants With Response (Response Rate) | 0.711 proportion of responders |
| Gemcitabine (Crossover) | Proportion of Participants With Response (Response Rate) | 0.357 proportion of responders |
| Paclitaxel (Crossover) | Proportion of Participants With Response (Response Rate) | 0.303 proportion of responders |
p-value: 0.771Fisher Exact
p-value: 0.784Fisher Exact
Secondary
Time to Treatment Failure
Time to treatment failure was defined as the duration from date of randomization to the date of the first of the following events: early discontinuation of study therapy; progression of disease, or death due to any cause. Time to treatment failure will be censored at the date of the last follow-up visit for participants who did not discontinue early, who are still alive, and who have not progressed. Results are presented as a comparison between the two study treatment sequences (induction therapy followed by elective consolidation or crossover therapy) rather than the two induction therapies.
Time frame: Baseline to stopping treatment up to 82 months
Population: Intent to treat (ITT) population, which includes all randomized participants. 3 participants in the Gemcitabine/Carboplatin treatment sequence were excluded due to missing data, and 1 participant in the Paclitaxel/Carboplatin treatment sequence was excluded for missing data. G/C Arm: 336 events, 78 censored. P/C Arm: 330 events, 83 censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gemcitabine/Carboplatin | Time to Treatment Failure | 13.0 months |
| Paclitaxel/Carboplatin | Time to Treatment Failure | 13.1 months |
p-value: 0.621Log Rank