Epithelial Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer
Conditions
Brief summary
A study for women with ovarian cancer that has returned at least 6 months after platinum-based chemotherapy.
Detailed description
Phase 1b is unblinded and will have a small number of participants that will take LY2228820 plus gemcitabine and carboplatin to test the safety of the combination and determine a recommended dose for the Phase 2 portion. Phase 2 will be blinded and all study participants will receive carboplatin and gemcitabine. Participants of one group will receive LY2228820, and the other group will receive placebo. If the participant achieves at least stable disease, there is a maintenance phase following the first 6 cycles. The participant will take either LY2228820 or placebo. The participant will continue therapy until disease progression or other discontinuation criteria are fulfilled.
Interventions
DRUGLY2228820
Administered Orally
DRUGCarboplatin
Administered IV
DRUGPlacebo
Administered Orally
DRUGGemcitabine
Administered IV
Sponsors
Eli Lilly and Company
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
* Have been diagnosed with ovarian, fallopian tube, or primary peritoneal cancer * Have been treated one time with a platinum-based chemotherapy and your disease has come back at least six months after you completed treatment * Are able to swallow tablets * Have given written informed consent prior to any study procedures * Have adequate blood counts, hepatic and renal function * Have performance status equal to or less than 2 on Eastern Cooperative Oncology Group (ECOG) scale * Have negative pregnancy test, and if participant is of child bearing potential must use birth control while on study and for three months after stopping study drug
Exclusion criteria
* Have been previously treated with Gemcitabine for ovarian, fallopian tube or primary peritoneal cancer * Are currently enrolled or discontinued less than 14 days from another clinical trial * Have a history of inflammatory bowel disease (Crohn's disease or ulcerative colitis) * Have taken certain medications or had grapefruit juice within 7 days of initial dose of study drug, as levels of the study drug may be affected. * Must not be pregnant or breastfeeding. * Have malignancy or metastasis of the central nervous system * Have borderline malignancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Recommended Phase 2 Dose of LY2228820 in Combination With Gemcitabine and Carboplatin (Maximum Tolerated Dose [MTD]) | Cycle 1 (21 Days) | Recommended Phase 2 dose of LY2228820 that could be safely administered in combination with gemcitabine and carboplatin based on defined dose limiting toxicities (DLT) assessment and MTD definition. The MTD is defined as the highest dose level at which no more than 33% of patients experience a DLT during Cycle 1 that does not exceed the single-agent MTD for LY2228820 (300 mg Q12H). |
| Phase 2: Progression-free Survival (PFS) in Participants Treated With LY2228820 Plus Gemcitabine and Carboplatin Versus Placebo Plus Gemcitabine and Carboplatin | Randomization to Date of Disease Progression or Death from any cause (up to 3 years) | PFS was defined as time from date of randomization to the date of investigator-determined objective progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurred first. Progressive disease (PD) is defined as at least a 20% increase in the sum of the largest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Percentage of Participants Who Achieve Complete Response or Partial Response (Overall Response Rate) | Baseline to Disease Progression (up to 3 years) | Overall Response Rate was estimated as the percentage of participants with best response of Complete Response (CR) or Partial Response (PR), based on RECIST version 1.1 divided by the total number of randomized participants. CR is defined as disappearance of all target lesions. PR is defined as at least 30% disease in the sum of the largest diameter (LD) of target lesions, taking as reference the baseline sum LD. |
| Phase 2: Overall Survival | Baseline to Date of Death from any cause (up to 5 years) | Data presented are the median overall survival in months for participants in the Phase 2 treatment arms. |
| Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820 | Phase1b:Cycle(C)1 Day(D)1:Predose(PRD),0.5,1,2,4,6,8 hours(hr)postdose(PD); C1D10:PRD,0.5,1,2,8hrPD; C2D10:PRD,0.5,1,2,4,6,8,12hrPD; C7D3:PRD,0.5,1,2,4,6hrPD; Phase 2: C1D3:PRD,0.5,1,2,4,6,8hrPD; C1D10:PRD,0.5,1,2,4,6,8hrPD; C7D3:PRD,0.5,1,2,4,6,8hrPD | PK parameters after administration of LY2228820 for both Phase 1b and Phase 2. |
| Phase 2: Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) Total Score | Baseline, Study Completion (up to 3 years) | The Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) instrument measures health related quality of life (HRQoL) in participants with ovarian cancer. The instrument is organized into sections of physical, social/family, emotional, functional well-being and ovarian subscales with a 5-point rating scale in which 0 = not at all and 4 = very much. Data presented here are change from baseline at follow-up in the FACT-O Total Score. The total score is the sum of Physical Well Being (PWB) + Social Well-being (SWB) + Emotional Well Being (EWB) + Family Well-being (FWB) + Ovarian Cancer Subscale (OCS). The FACT-O Total score range 0 - 152 with higher scores indicating better quality of life. |
Countries
Australia, Belgium, Germany, United States
Participant flow
Pre-assignment details
Participants in Phase 1b are considered to have completed the study if they experience a dose-limiting toxicity or completed the Pharmacokinetic (PK) sampling set. Participants in Phase 2 are considered to have completed if they die due to any cause or who are alive and on study at conclusion, but are off treatment.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Cohort 1: LY2228820 +Gemcitabine+Carboplatin Cohort 1:LY2228820 200 milligrams (mg) administered orally every 12 hours (hr) on Days 1-10 of a 21-day cycle (Cycles 1-6).
Gemcitabine 1000 mg per square meter (m2) administered intravenously (IV) over 30 minutes (min) on Days 3 and 10.
Carboplatin area under the concentration curve administered intravenously (IV) over 30 minutes (AUC) 4 (maximum dose 600mg) IV over 30 min. on Day 3.
Cohort 1: LY2228820 300 mg orally every 12 hr. on Days 1-10 of a 21-day cycle (Cycles 1-6). | 6 |
| Phase 1b: Cohort 2: LY2228820 +Gemcitabine+Carboplatin Cohort 2: LY2228820 300 mg administered orally every 12 hr. on Days 1-10 of a 21-day cycle (Cycles 1-6).
Gemcitabine 1000 mg/m2 administered IV over 30 min on Days 3 and 10.
Carboplatin AUC 4 (maximum dose 600mg) IV over 30 min. on Day 3.
Cohort 2:LY2228820 300 mg orally every 12 hr. on Days 1-14 of a 28-day cycle (Cycles 7+). | 2 |
| Arm A: LY2228820 + Gemcitabine + Carboplatin Arm A:LY2228820 200 mg orally every 12 hr. on Days 1-10 of a 21-day cycle (Cycles 1-6).
Gemcitabine 1000 mg/m2 IV over 30 min. on Days 3 and 10.
Carboplatin AUC 4 (maximum dose 600mg) IV over 30 min. on Day 3.
Arm A:LY2228820 300 mg orally every 12 hr. on Days 1-14 of a 28 day cycle (Cycles 7+). | 58 |
| Arm B Placebo + Gemcitabine +Carboplatin Arm B: Placebo orally every 12 hrs. on Days 1-10 of a 21-day cycle (Cycles 1-6).
Gemcitabine 1000 mg/m2 IV over 30 min. on Days 3 and 10.
Carboplatin AUC 4 (maximum dose 600mg) IV over 30 min. on Day 3.
Arm B: Placebo orally every 12 hr. on Days 1-14 of a 28 day cycle (Cycles 7+). | 52 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 3 | 1 |
| Overall Study | Withdrew Consent to Study Participation | 0 | 1 | 7 | 3 |
Baseline characteristics
| Characteristic | Phase 1b: Cohort 1: LY2228820 +Gemcitabine+Carboplatin | Phase 1b: Cohort 2: LY2228820 +Gemcitabine+Carboplatin | Arm A: LY2228820 + Gemcitabine + Carboplatin | Arm B Placebo + Gemcitabine +Carboplatin | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 6.8 | 65.0 years STANDARD_DEVIATION 5.7 | 60.9 years STANDARD_DEVIATION 10.4 | 62.2 years STANDARD_DEVIATION 9.2 | 61.6 years STANDARD_DEVIATION 9.6 |
| Maintenance Therapy as a Part of or After a First Line Platinum Regimen Data Missing or Not Collected | — | — | 36 Participants | 30 Participants | 66 Participants |
| Maintenance Therapy as a Part of or After a First Line Platinum Regimen Did Not Receive Maintenance Therapy | — | — | 15 Participants | 15 Participants | 30 Participants |
| Maintenance Therapy as a Part of or After a First Line Platinum Regimen Received Maintenance Therapy | — | — | 7 Participants | 7 Participants | 14 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 | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 1 Participants | 57 Participants | 49 Participants | 113 Participants |
| Region of Enrollment Australia | 0 Participants | 0 Participants | 4 Participants | 6 Participants | 10 Participants |
| Region of Enrollment Belgium | 0 Participants | 0 Participants | 11 Participants | 9 Participants | 20 Participants |
| Region of Enrollment Germany | 1 Participants | 0 Participants | 13 Participants | 12 Participants | 26 Participants |
| Region of Enrollment United States | 5 Participants | 2 Participants | 30 Participants | 25 Participants | 62 Participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 58 Participants | 52 Participants | 118 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 |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 6 | 1 / 2 | 30 / 58 | 31 / 52 |
| other Total, other adverse events | 6 / 6 | 2 / 2 | 58 / 58 | 52 / 52 |
| serious Total, serious adverse events | 3 / 6 | 1 / 2 | 26 / 58 | 12 / 52 |
Outcome results
Primary
Phase 1b: Recommended Phase 2 Dose of LY2228820 in Combination With Gemcitabine and Carboplatin (Maximum Tolerated Dose [MTD])
Recommended Phase 2 dose of LY2228820 that could be safely administered in combination with gemcitabine and carboplatin based on defined dose limiting toxicities (DLT) assessment and MTD definition. The MTD is defined as the highest dose level at which no more than 33% of patients experience a DLT during Cycle 1 that does not exceed the single-agent MTD for LY2228820 (300 mg Q12H).
Time frame: Cycle 1 (21 Days)
Population: All participants who received at least one dose of study drug in Phase 1b.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2228820 + Gemcitabine + Carboplatin | Phase 1b: Recommended Phase 2 Dose of LY2228820 in Combination With Gemcitabine and Carboplatin (Maximum Tolerated Dose [MTD]) | 200 milligrams (mg) |
Primary
Phase 2: Progression-free Survival (PFS) in Participants Treated With LY2228820 Plus Gemcitabine and Carboplatin Versus Placebo Plus Gemcitabine and Carboplatin
PFS was defined as time from date of randomization to the date of investigator-determined objective progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurred first. Progressive disease (PD) is defined as at least a 20% increase in the sum of the largest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Time frame: Randomization to Date of Disease Progression or Death from any cause (up to 3 years)
Population: All participants in Phase 2 who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LY2228820 + Gemcitabine + Carboplatin | Phase 2: Progression-free Survival (PFS) in Participants Treated With LY2228820 Plus Gemcitabine and Carboplatin Versus Placebo Plus Gemcitabine and Carboplatin | 10.25 months |
| Placebo + Gemcitabine + Carboplatin | Phase 2: Progression-free Survival (PFS) in Participants Treated With LY2228820 Plus Gemcitabine and Carboplatin Versus Placebo Plus Gemcitabine and Carboplatin | 8.44 months |
p-value: 0.4Log Rank
Secondary
Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820
PK parameters after administration of LY2228820 for both Phase 1b and Phase 2.
Time frame: Phase1b:Cycle(C)1 Day(D)1:Predose(PRD),0.5,1,2,4,6,8 hours(hr)postdose(PD); C1D10:PRD,0.5,1,2,8hrPD; C2D10:PRD,0.5,1,2,4,6,8,12hrPD; C7D3:PRD,0.5,1,2,4,6hrPD; Phase 2: C1D3:PRD,0.5,1,2,4,6,8hrPD; C1D10:PRD,0.5,1,2,4,6,8hrPD; C7D3:PRD,0.5,1,2,4,6,8hrPD
Population: All participants in Phase 1b and Phase 2 who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2228820 + Gemcitabine + Carboplatin | Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820 | Cycle 1 Day 3 | 3170 nanograms * hr per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 22 |
| LY2228820 + Gemcitabine + Carboplatin | Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820 | Cycle 2 Day 10 | 3270 nanograms * hr per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 38 |
| LY2228820 + Gemcitabine + Carboplatin | Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820 | Cycle 1 Day 10 | 4270 nanograms * hr per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 62 |
| LY2228820 + Gemcitabine + Carboplatin | Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820 | Cycle 1 Day 1 | 3470 nanograms * hr per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 91 |
| Placebo + Gemcitabine + Carboplatin | Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820 | Cycle 7 Day 3 | 7230 nanograms * hr per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 72 |
| Placebo + Gemcitabine + Carboplatin | Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820 | Cycle 1 Day 1 | 3560 nanograms * hr per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 1 |
| Placebo + Gemcitabine + Carboplatin | Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820 | Cycle 1 Day 10 | 9350 nanograms * hr per milliliter (ng*hr/mL) | — |
| Placebo + Gemcitabine + Carboplatin | Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820 | Cycle 2 Day 10 | 3490 nanograms * hr per milliliter (ng*hr/mL) | — |
Secondary
Phase 2: Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) Total Score
The Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) instrument measures health related quality of life (HRQoL) in participants with ovarian cancer. The instrument is organized into sections of physical, social/family, emotional, functional well-being and ovarian subscales with a 5-point rating scale in which 0 = not at all and 4 = very much. Data presented here are change from baseline at follow-up in the FACT-O Total Score. The total score is the sum of Physical Well Being (PWB) + Social Well-being (SWB) + Emotional Well Being (EWB) + Family Well-being (FWB) + Ovarian Cancer Subscale (OCS). The FACT-O Total score range 0 - 152 with higher scores indicating better quality of life.
Time frame: Baseline, Study Completion (up to 3 years)
Population: All participants in Phase 2 who received at least one dose of study drug and had at least one post baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY2228820 + Gemcitabine + Carboplatin | Phase 2: Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) Total Score | -0.6 units on a scale | Standard Deviation 21.14 |
| Placebo + Gemcitabine + Carboplatin | Phase 2: Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) Total Score | -8.9 units on a scale | Standard Deviation 19.92 |
Secondary
Phase 2: Overall Survival
Data presented are the median overall survival in months for participants in the Phase 2 treatment arms.
Time frame: Baseline to Date of Death from any cause (up to 5 years)
Population: All participants in Phase 2 who received at least one dose of drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LY2228820 + Gemcitabine + Carboplatin | Phase 2: Overall Survival | 29.17 months |
| Placebo + Gemcitabine + Carboplatin | Phase 2: Overall Survival | 25.10 months |
p-value: 0.4686Log Rank
Secondary
Phase 2: Percentage of Participants Who Achieve Complete Response or Partial Response (Overall Response Rate)
Overall Response Rate was estimated as the percentage of participants with best response of Complete Response (CR) or Partial Response (PR), based on RECIST version 1.1 divided by the total number of randomized participants. CR is defined as disappearance of all target lesions. PR is defined as at least 30% disease in the sum of the largest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Time frame: Baseline to Disease Progression (up to 3 years)
Population: All participants who received at least one dose of study drug in Phase 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2228820 + Gemcitabine + Carboplatin | Phase 2: Percentage of Participants Who Achieve Complete Response or Partial Response (Overall Response Rate) | 46.6 percentage of participants |
| Placebo + Gemcitabine + Carboplatin | Phase 2: Percentage of Participants Who Achieve Complete Response or Partial Response (Overall Response Rate) | 46.2 percentage of participants |