Ovarian Cancer
Conditions
Keywords
Ovarian Cancer
Brief summary
A 2-part, Phase 2 controlled, open-label, randomized study in participants with platinum-resistant recurrent ovarian cancer. In Part 1, participants received SGI-110 and carboplatin. The optimum dose of SGI-110 (guadecitabine) was identified in Part 1 based on safety and efficacy. In Part 2, participants were randomized to receive the dose identified in Part 1 plus carboplatin or one of four treatment of choice at the discretion of the investigator. The treatment of choice consisted of topotecan, pegylated liposomal doxorubicin, paclitaxel or gemcitabine.
Interventions
DRUGSGI-110
DRUGTreatment of Choice (topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine)
Investigator chose to treat with either topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine
DRUGCarboplatin
Sponsors
Astex Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants who are women 18 years of age or older. 2. Participants who have histologically or cytologically confirmed recurrent high-grade serous epithelial ovarian cancer (Grade 2 or 3), primary peritoneal carcinomatosis or fallopian tube cancer. 3. Participants who have platinum-resistant disease (defined as having relapsed within 6 months of her last platinum-containing regimen). There is no limit on the number of prior treatment regimens in Part 1. In Part 2, participants may have had no more than 3 prior cytotoxic treatment regimens, excluding adjuvant or maintenance therapy. 4. Participants must have had prior paclitaxel treatment. 5. Participants who have measurable disease according to RECIST v1.1 or detectable disease. 6. Participants with ECOG performance status of 0 or 1. 7. Participants with acceptable organ function. 8. Participants must be at least 3 weeks from last chemotherapy.
Exclusion criteria
1. Participants who have hypersensitivity to SGI-110 and/or carboplatin or other components of these drug products. 2. Participants who have received prior therapy with any hypomethylating agents. 3. Participants who are refractory to platinum treatment i.e., progressed while on platinum treatment. 4. Participants with abnormal left ventricular ejection fraction. 5. Participants with Grade 2 or greater neuropathy. 6. Participants with known brain metastases. 7. Participants with known history of HIV, HCV or HBV.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Dose Limiting Toxicities | Up to 12 months | Number of participants with dose limiting toxicities (DLTs) in Stage 1 |
| Stage 2: Progression Free Survival | Up to 24 months | Progression free survival (PFS) time was defined as the time interval from the date of the first dose of study medication until the earlier of disease progression or death. Participants were treated with their assigned treatment \[guadecitabine+carboplatin (G+C) or treatment choice (TC)\] until disease progression or unacceptable treatment-related toxicity occurred. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate | Up to 24 months | Clinical benefit rate (CBR) was defined as the proportion of subjects who experienced a best overall response of complete response/full response or partial response (confirmed by a subsequent assessment at least 28 days later), or documented stable disease for at least 3 months after the first dose. Response categories were determined based on RECIST v1.1 criteria, then based on modified Rustin (CA-125) criteria if assessment could not be made using RECIST criteria. |
| CA-125 Levels | Up to 24 months | Percentage of participants with CA-125 reduction by ≥ 50% from baseline |
| Duration of Response | Up to 24 months | Duration of response is defined as the time between the date of the first documentation of complete response/full response or partial response, and the date of disease progression or date of death due to any cause, or the last adequate tumor assessment prior to the start of subsequent anti-cancer therapy including crossing over to G+C from TC arm, whichever occurred earlier. Only participants who responded were included in the duration of response calculation. |
| Progression Free Survival at 6 Months | 6 months | Progression free survival rate at 6 months is the proportion of participants who were alive and did not have disease progression at 6 months after start of treatment. |
| Stage 1: Pharmacokinetic Parameter Cmax | Pre-dose and up to 8 hours post-dose on Cycle 1 Day 1 for guadecitabine and decitabine and Day 8 for carboplatin (28 day cycles) | Time to maximum plasma concentration for guadecitabine, decitabine and carboplatin |
| Stage 1: Pharmacokinetic Parameter Tmax | Pre-dose and up to 8 hours post-dose on Cycle 1 Day 1 for guadecitabine and decitabine and Day 8 for carboplatin (28 day cycles) | Time to last measurable concentration for guadecitabine, decitabine and carboplatin |
| Stage 1: Pharmacokinetic Parameter AUC0-8 | Pre-dose and up to 8 hours post-dose on Cycle 1 Day 1 for guadecitabine and decitabine and Day 8 for carboplatin (28 day cycles) | Area under the concentration-time curve from 0 to 8 hours (AUC0-8) for guadecitabine, decitabine and carboplatin |
| Overall Survival | Up to 24 months | Overall survival was defined as the number of days from the day the participant was administered the first dose of study treatment to the date of death (regardless of cause). Survival time was censored on the last date the participant was known to be alive or lost to follow-up before reaching the event of death; in the TC group, time was censored at the date of crossover. |
| Objective Response Rate | Up to 24 months | The objective response rate (ORR) was defined as the proportion of participants who experienced an objective response (best overall response of complete response/full response or partial response, which was confirmed by a subsequent assessment at least 28 days later). Response categories were determined based on RECIST v1.1 criteria, or on modified Rustin (CA-125) criteria if response assessment could not be made using RECIST criteria. |
Countries
Canada, United Kingdom, United States
Participant flow
Recruitment details
A total of 124 participants were enrolled in the study and 120 were treated at 20 study centers, with 12 in the United States, 5 in the United Kingdom, and 3 in Canada. The enrollment period was 10 December 2012 (first participant dosed) to 12 May 2014 (last participant first dose).
Participants by arm
| Arm | Count |
|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 Guadecitabine 30 mg/m2 on Days 1-5 and carboplatin AUC 4 on Day 8 of 28-day treatment cycles. | 14 |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 Guadecitabine 45 mg/m2 on Days 1-5 and carboplatin AUC 4 on Day 8 of 28-day treatment cycles. Due to dose limiting toxicities, the guadecitabine dose for this group was reduced from 45 mg/m2 to 30 mg/m2 after Cycle 1 for 4 of 6 participants and the carboplatin dose was reduced for 2 of 6 participants. | 6 |
| Stage 2: Guadecitabine+Carboplatin 30 mg/m2 Guadecitabine 30 mg/m2 on Days 1-5 and carboplatin AUC 4 on Day 8 of 28-day treatment cycles. | 51 |
| Stage 2: Treatment Choice Treatment was selected at the investigator's discretion and administered based on recommended dosing for topotecan (3.5-4.0 mg/m2/wk administered on Days 1, 8, and 15 via IV infusion); PLD (40-50 mg/m2 administered on Day 1 via IV infusion), paclitaxel (60-80 mg/m2/wk administered on Days 1, 8, 15, and 22 via IV infusion), or gemcitabine (800-1000 mg/m2 administered on Days 1, 8, and 15 via IV infusion. Participants initially randomized to TC were able to cross over to receive 30 mg/m2 G+C due to disease progression. | 49 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Database lock | 0 | 1 | 7 | 2 |
| Overall Study | Death | 14 | 4 | 43 | 18 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 2: Guadecitabine+Carboplatin 30 mg/m2 | Stage 2: Treatment Choice | Total |
|---|---|---|---|---|---|
| Age, Continuous | 57.99 Years STANDARD_DEVIATION 9.47 | 56.79 Years STANDARD_DEVIATION 13.2 | 61.96 Years STANDARD_DEVIATION 9.17 | 62.09 Years STANDARD_DEVIATION 9.62 | 61.29 Years STANDARD_DEVIATION 9.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 6 Participants | 49 Participants | 46 Participants | 114 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 5 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 12 Participants | 5 Participants | 43 Participants | 40 Participants | 100 Participants |
| Sex: Female, Male Female | 14 Participants | 6 Participants | 51 Participants | 49 Participants | 120 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 14 / 14 | 4 / 6 | 43 / 51 | 18 / 49 | 22 / 27 |
| other Total, other adverse events | 14 / 14 | 6 / 6 | 50 / 51 | 49 / 49 | 27 / 27 |
| serious Total, serious adverse events | 8 / 14 | 4 / 6 | 26 / 51 | 24 / 49 | 12 / 27 |
Outcome results
Primary
Stage 1: Dose Limiting Toxicities
Number of participants with dose limiting toxicities (DLTs) in Stage 1
Time frame: Up to 12 months
Population: Safety data set includes data from all participants who received any amount of study drug, including any component of a multi-dose study treatment regimen.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Dose Limiting Toxicities | 0 Participants |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 1: Dose Limiting Toxicities | 4 Participants |
Primary
Stage 2: Progression Free Survival
Progression free survival (PFS) time was defined as the time interval from the date of the first dose of study medication until the earlier of disease progression or death. Participants were treated with their assigned treatment \[guadecitabine+carboplatin (G+C) or treatment choice (TC)\] until disease progression or unacceptable treatment-related toxicity occurred.
Time frame: Up to 24 months
Population: Efficacy data set included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 2: Progression Free Survival | 114 Days |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 2: Progression Free Survival | 64 Days |
p-value: 0.0654Log Rank
Secondary
CA-125 Levels
Percentage of participants with CA-125 reduction by ≥ 50% from baseline
Time frame: Up to 24 months
Population: Efficacy data set included all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | CA-125 Levels | 27 Percent of participants |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | CA-125 Levels | 50 Percent of participants |
| Stage 2: Guadecitabine+Carboplatin 30 mg/m2 | CA-125 Levels | 36 Percent of participants |
| Stage 2: Treatment Choice | CA-125 Levels | 32 Percent of participants |
| Stage 2: Crossover Treatment Choice to Guadecitabine+Carboplatin 30 mg/m2 | CA-125 Levels | 29 Percent of participants |
Secondary
Clinical Benefit Rate
Clinical benefit rate (CBR) was defined as the proportion of subjects who experienced a best overall response of complete response/full response or partial response (confirmed by a subsequent assessment at least 28 days later), or documented stable disease for at least 3 months after the first dose. Response categories were determined based on RECIST v1.1 criteria, then based on modified Rustin (CA-125) criteria if assessment could not be made using RECIST criteria.
Time frame: Up to 24 months
Population: Efficacy data set included all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Clinical Benefit Rate | 43 Percent of participants |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Clinical Benefit Rate | 50 Percent of participants |
| Stage 2: Guadecitabine+Carboplatin 30 mg/m2 | Clinical Benefit Rate | 41 Percent of participants |
| Stage 2: Treatment Choice | Clinical Benefit Rate | 29 Percent of participants |
| Stage 2: Crossover Treatment Choice to Guadecitabine+Carboplatin 30 mg/m2 | Clinical Benefit Rate | 19 Percent of participants |
Secondary
Duration of Response
Duration of response is defined as the time between the date of the first documentation of complete response/full response or partial response, and the date of disease progression or date of death due to any cause, or the last adequate tumor assessment prior to the start of subsequent anti-cancer therapy including crossing over to G+C from TC arm, whichever occurred earlier. Only participants who responded were included in the duration of response calculation.
Time frame: Up to 24 months
Population: Efficacy data set included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Duration of Response | 225 Days |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Duration of Response | 195 Days |
| Stage 2: Guadecitabine+Carboplatin 30 mg/m2 | Duration of Response | 186 Days |
| Stage 2: Treatment Choice | Duration of Response | 173 Days |
| Stage 2: Crossover Treatment Choice to Guadecitabine+Carboplatin 30 mg/m2 | Duration of Response | 182 Days |
Secondary
Objective Response Rate
The objective response rate (ORR) was defined as the proportion of participants who experienced an objective response (best overall response of complete response/full response or partial response, which was confirmed by a subsequent assessment at least 28 days later). Response categories were determined based on RECIST v1.1 criteria, or on modified Rustin (CA-125) criteria if response assessment could not be made using RECIST criteria.
Time frame: Up to 24 months
Population: Efficacy data set included all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Objective Response Rate | 21 Percent |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Objective Response Rate | 0 Percent |
| Stage 2: Guadecitabine+Carboplatin 30 mg/m2 | Objective Response Rate | 16 Percent |
| Stage 2: Treatment Choice | Objective Response Rate | 8 Percent |
| Stage 2: Crossover Treatment Choice to Guadecitabine+Carboplatin 30 mg/m2 | Objective Response Rate | 4 Percent |
Secondary
Overall Survival
Overall survival was defined as the number of days from the day the participant was administered the first dose of study treatment to the date of death (regardless of cause). Survival time was censored on the last date the participant was known to be alive or lost to follow-up before reaching the event of death; in the TC group, time was censored at the date of crossover.
Time frame: Up to 24 months
Population: Efficacy data set included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Overall Survival | 341 Days |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Overall Survival | 195 Days |
| Stage 2: Guadecitabine+Carboplatin 30 mg/m2 | Overall Survival | 331 Days |
| Stage 2: Treatment Choice | Overall Survival | 221 Days |
| Stage 2: Crossover Treatment Choice to Guadecitabine+Carboplatin 30 mg/m2 | Overall Survival | 279 Days |
Secondary
Progression Free Survival at 6 Months
Progression free survival rate at 6 months is the proportion of participants who were alive and did not have disease progression at 6 months after start of treatment.
Time frame: 6 months
Population: Efficacy data set included all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Progression Free Survival at 6 Months | 0.36 Percent of participants |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Progression Free Survival at 6 Months | 0.33 Percent of participants |
| Stage 2: Guadecitabine+Carboplatin 30 mg/m2 | Progression Free Survival at 6 Months | 0.37 Percent of participants |
| Stage 2: Treatment Choice | Progression Free Survival at 6 Months | 0.11 Percent of participants |
| Stage 2: Crossover Treatment Choice to Guadecitabine+Carboplatin 30 mg/m2 | Progression Free Survival at 6 Months | 0.19 Percent of participants |
Secondary
Stage 1: Pharmacokinetic Parameter AUC0-8
Area under the concentration-time curve from 0 to 8 hours (AUC0-8) for guadecitabine, decitabine and carboplatin
Time frame: Pre-dose and up to 8 hours post-dose on Cycle 1 Day 1 for guadecitabine and decitabine and Day 8 for carboplatin (28 day cycles)
Population: The pharmacokinetic (PK) population included participants for which sufficient data were available to calculate PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Pharmacokinetic Parameter AUC0-8 | Guadecitabine | 239 Hours*ng/mL | Standard Deviation 136 |
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Pharmacokinetic Parameter AUC0-8 | Decitabine | 71.1 Hours*ng/mL | Standard Deviation 26.6 |
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Pharmacokinetic Parameter AUC0-8 | Carboplatin | 51200 Hours*ng/mL | Standard Deviation 12100 |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 1: Pharmacokinetic Parameter AUC0-8 | Guadecitabine | 416 Hours*ng/mL | Standard Deviation 217 |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 1: Pharmacokinetic Parameter AUC0-8 | Decitabine | 129 Hours*ng/mL | Standard Deviation 17.9 |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 1: Pharmacokinetic Parameter AUC0-8 | Carboplatin | 41900 Hours*ng/mL | Standard Deviation 31700 |
Secondary
Stage 1: Pharmacokinetic Parameter Cmax
Time to maximum plasma concentration for guadecitabine, decitabine and carboplatin
Time frame: Pre-dose and up to 8 hours post-dose on Cycle 1 Day 1 for guadecitabine and decitabine and Day 8 for carboplatin (28 day cycles)
Population: The pharmacokinetic (PK) population included participants for which sufficient data were available to calculate PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Pharmacokinetic Parameter Cmax | Guadecitabine | 96.2 ng/mL | Standard Deviation 78.3 |
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Pharmacokinetic Parameter Cmax | Decitabine | 22.6 ng/mL | Standard Deviation 13.3 |
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Pharmacokinetic Parameter Cmax | Carboplatin | 19600 ng/mL | Standard Deviation 5650 |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 1: Pharmacokinetic Parameter Cmax | Guadecitabine | 109 ng/mL | Standard Deviation 70.8 |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 1: Pharmacokinetic Parameter Cmax | Decitabine | 26.3 ng/mL | Standard Deviation 14.5 |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 1: Pharmacokinetic Parameter Cmax | Carboplatin | 21900 ng/mL | Standard Deviation 13800 |
Secondary
Stage 1: Pharmacokinetic Parameter Tmax
Time to last measurable concentration for guadecitabine, decitabine and carboplatin
Time frame: Pre-dose and up to 8 hours post-dose on Cycle 1 Day 1 for guadecitabine and decitabine and Day 8 for carboplatin (28 day cycles)
Population: The pharmacokinetic (PK) population included participants for which sufficient data were available to calculate PK parameters.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Pharmacokinetic Parameter Tmax | Guadecitabine | 1.42 Hours |
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Pharmacokinetic Parameter Tmax | Decitabine | 1.98 Hours |
| Stage 1: Guadecitabine+Carboplatin 30 mg/m2 | Stage 1: Pharmacokinetic Parameter Tmax | Carboplatin | 1.03 Hours |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 1: Pharmacokinetic Parameter Tmax | Carboplatin | 1.05 Hours |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 1: Pharmacokinetic Parameter Tmax | Guadecitabine | 1.98 Hours |
| Stage 1: Guadecitabine+Carboplatin 45 mg/m2 | Stage 1: Pharmacokinetic Parameter Tmax | Decitabine | 3.95 Hours |