Fallopian Tube Neoplasms, Ovarian Cancer, Peritoneal Neoplasm
Conditions
Brief summary
Participants with ovarian cancer usually get the drugs carboplatin and paclitaxel as initial treatment. In many participants the tumor will shrink, or even disappear, after treatment with these drugs. But, unfortunately, the tumor will grow again in many participants. This trial will try to address the question: Can we delay the time till the tumor grows again by adding a 3rd drug to the standard therapy? To answer this question, participants will, by chance, either get the experimental drug enzastaurin or a dummy pill (placebo) during the chemotherapy and for up to 3 years after chemotherapy. Participants and physicians will not know if a participant gets enzastaurin or placebo (double-blinded trial). After a predefined time, the treatment will be uncovered, and the number of participants with tumor growth at a specific time point will be compared between the two treatments.
Interventions
DRUGenzastaurin
DRUGcarboplatin
DRUGpaclitaxel
DRUGplacebo
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have specific stages of disease, known as Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stages IIB, IIC, III or IV * Organ functions (blood, renal, liver, cardiac) must meet specific requirements. * Participants who could become pregnant must take care not to become pregnant during the study participation and for 6 months after study discontinuation * Participants must give written consent for study participation.
Exclusion criteria
* Participants received any experimental drug within the last 30 days. * Participants received any prior chemotherapy or other drug therapy for the current disease. * Participants receive any other treatment for the cancer during study participation. * Participants are unable to discontinue concurrent administration of carbamazepine, phenobarbital, or phenytoin. * Participants are pregnant, breast feeding, or not using adequate contraceptive methods to prevent pregnancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Progression-Free Survival (PFS) | Randomization up to date of PD or death (up to 28.6 months) | PFS was defined as time from date of randomization to first date of determined progressive disease (PD) or death from any cause. PD defined using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) and Gynecological Cancer Intergroup (GCIG) criteria. RECIST: ≥20% increase in sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since treatment started or appearance of ≥ 1new lesions and/or unequivocal progression of existing non-target lesions. GCIG: Cancer Antigen-125 (CA-125) serum ≥2 times upper limit of normal (ULN) for those in normal range or nadir for participants who never achieved normal range. Participants not known to have died and did not have PD were censored at last progression-free assessment. Those who received subsequent systemic anticancer therapy (after study drug discontinued) prior to determined PD or death, were censored at date of last progression-free disease assessment prior to post-discontinuation chemotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] | Randomization to PD or death from any cause (up to 28.6 months) | ORR was the percentage of participants with a CR or PR using RECIST v1.0 and CA-125 GCIG criteria. RECIST v1.0: CR was defined as the disappearance of all tumors. PR was defined ≥30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD or complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesions and appearance of no new lesions. GCIG: CA-125 serum ≥2 times above ULN for those in normal range or nadir for participants who never achieved normal range. ORR calculated as: (CR + PR) / (total number of participants qualified for tumor response analysis per arm) \* 100. |
| Part 2: Percentage of Participants With CR or PR or Stable Disease (SD) (Rate of Response) | Randomization to PD or death from any cause (up to 28.6 months) | Rate of response was defined using RECIST v1.0 and CA-125 GCIG criteria. RECIST v1.0: CR was defined as the disappearance of all target lesions. PR was defined ≥30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD or complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesions and appearance of no new lesions. SD was defined as small changes that did not meet the above criteria. PD was defined as having a ≥20% increase in the sum of the LD of target lesions. GCIG: CA-125 serum ≥2 times above ULN for those in normal range or nadir for participants who never achieved normal range. Rate of response calculated as: (CR + PR + SD)/(total number of participants qualified for tumor response analysis per arm) \*100. |
| Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | Randomization up to date of PD or death (up to 28.6 months) | PE measured using Immunohistochemistry (IHC) assay, scored 0 (negative, no staining) to 3+ (brightest staining). IHC H-scores for protein biomarkers (PKCβ2, PTEN, pCREB, pGSK3b, pS6) calculated as: \[1\*(percentage of cells stained \[PCS\] as 1+)\]+\[2\*(PCS as 2+)\]+\[3\*(PCS as 3+)\]. High PE: ≥marker threshold value and Low PE: \<marker threshold value. PFS: date of randomization to PD or death. PD defined using RECIST v1.0 and GCIG criteria. RECIST: ≥20% increase in sum of LD of target lesions taking as references smallest sum LD recorded since treatment started or appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. GCIG: CA-125 serum ≥2 times ULN for those in normal range or nadir for those who never achieved normal range. Per protocol, Part 1 was not included as it is an open-label safety lead-in portion with PK characterization. |
| Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | Randomization up to 28.6 months | Clinically significant events were defined as SAEs and other non-serious AEs regardless of causality. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module. The number of participants SAEs, other non-serious AEs, and those who died due to PD are included. |
| Pharmacokinetics (PK): Maximum Concentration (Cmax) for Carboplatin With and Without Enzastaurin for Part 1 of Study | Cycle 1 Day 1 (carb) and Cycle 2 Day 1 (carb + enz); carb 0.25 hours (h) (prior to infusion), 0.5, 1, 2, 3, 5, and 21h after start of infusion | — |
| Part 2: Percentage of Participants With PFS at 2 Years | Randomization to measured PD evaluated at 2 years | PFS was defined as time from date of randomization to first date of determined PD or death from any cause. PD defined using RECIST v1.0 and GCIG criteria. RECIST v1.0: as ≥20% increase in sum of LD of target lesions taking as reference the smallest sum LD recorded since treatment started or appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. GCIG: CA-125 serum ≥2 times ULN for those in normal range or nadir (the lowest value of blood counts after chemotherapy) for participants who never achieved normal range. Participants not known to have died and did not have PD were censored at last progression-free assessment. Those who received subsequent systemic anticancer therapy (after study drug discontinued) prior to determined PD or death, were censored at date of last progression-free disease assessment prior to post-discontinuation chemotherapy. |
| PK: AUC From Time 0 to Infinity (AUC0-∞) for Carboplatin With and Without Enzastaurin for Part 1 of Study | Cycle 1 Day 1 (carb) and Cycle 2 Day 1 (carb + enz); carb at 0.25h (prior to infusion), 0.5, 1, 2, 3, 5, and 21h after start of infusion | — |
| PK: AUC0-∞ for Paclitaxel With and Without Enzastaurin for Part 1 of Study | Cycle 1 Day 1 (pac) and Cycle 2 Day 1 (pac + enz); pac at 1, 2, 3h (immediately after stopping infusion), 3.25, 3.5, 4, 5, 6, 8, 24, and 30h after start of infusion | — |
| PK: Cmax at Steady State (Cmax,ss) for Part 1 of Study | Cycle 1 Day 21 (enz) and Cycle 2 Day 1 (carb + pac + enz) at pre-dose, 2, 4, 6, 8 and 24h after the enz dose | Cmax,ss for enzastaurin, its metabolite LSN326020 (LY326020) and total analytes are reported. |
| PK: AUC During the Dosing Interval at Steady State (AUCτ,ss) for Part 2 of Study | Cycle 2 Day 1 (carb + pac + enz) at pre-dose, 2, 4, 6, 8 and 24h after the enz dose | AUCτ,ss for enzastaurin, its metabolite LSN326020 (LY326020), and total analytes are reported. |
| PK: Cmax for Paclitaxel With and Without Enzastaurin for Part 1 of Study | Cycle 1 Day 1 (pac) and Cycle 2 Day 1 (pac + enz); pac 1, 2, 3h (immediately after stopping infusion), 3.25, 3.5, 4, 5, 6, 8, 24, and 30h after start of infusion | — |
Countries
Belgium, Germany, Poland, Russia, Spain
Participant flow
Pre-assignment details
Part 1: Unblinded, single cohort safety lead-in of enzastaurin (enz) with paclitaxel (pac)/carboplatin (carb). Part 2: Randomized, double-blind, placebo-controlled trial consisting of: Baseline, Chemotherapy (start of study drug to discontinuation of pac and carb), Maintenance (day chemotherapy ends to study completion), Follow-up (up to 3 years).
Participants by arm
| Arm | Count |
|---|---|
| Part 1 - Modified Regimen A Enzastaurin: 1125 mg loading dose on Cycle 1 Day 4 then 500 mg oral tablet, QD, for six 21-day cycles on subsequent days of chemotherapy
Carboplatin: AUC5, IV, q21 days, for six 21-day cycles of chemotherapy
Paclitaxel: 175 mg/m², IV, q21 days, for six 21-day cycles of chemotherapy | 11 |
| Part 2 - Regimen A Enzastaurin: 1125 mg loading dose then 500 mg oral tablet, QD, for up to six 21-day cycles on subsequent days of chemotherapy and maintenance therapy up to 2 years
Carboplatin: AUC5, IV, q21 days, for up to six 21-day cycles of chemotherapy
Paclitaxel: 175 mg/m², IV, q21 days, for up to six 21-day cycles of chemotherapy | 69 |
| Part 2 - Regimen B Carboplatin: AUC5 IV, q21 days, for up to six 21-day cycles of chemotherapy
Paclitaxel: 175 mg/m², IV, q21 days, for up to six 21-day cycles of chemotherapy
Placebo: oral tablet, QD, of chemotherapy and maintenance therapy up to 2 years | 73 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 10 | 7 |
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 | 3 |
| Overall Study | Physician Decision | 0 | 3 | 0 |
| Overall Study | Progressive Disease | 7 | 26 | 43 |
| Overall Study | Protocol Entry Criteria Not Met | 0 | 3 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Sponsor Decision | 0 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 9 | 1 |
Baseline characteristics
| Characteristic | Part 1 - Modified Regimen A | Part 2 - Regimen A | Part 2 - Regimen B | Total |
|---|---|---|---|---|
| Age, Continuous | 52.4 years | 55.3 years | 53.4 years | 54.90 years |
| Race/Ethnicity, Customized Caucasian | 11 Participants | 68 Participants | 72 Participants | 151 Participants |
| Race/Ethnicity, Customized East Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized West Asian (Indian sub-continent) | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Belgium | 5 Participants | 14 Participants | 13 Participants | 32 Participants |
| Region of Enrollment Germany | 6 Participants | 28 Participants | 25 Participants | 59 Participants |
| Region of Enrollment Poland | 0 Participants | 7 Participants | 7 Participants | 14 Participants |
| Region of Enrollment Russia | 0 Participants | 17 Participants | 20 Participants | 37 Participants |
| Region of Enrollment Spain | 0 Participants | 3 Participants | 8 Participants | 11 Participants |
| Sex: Female, Male Female | 11 Participants | 69 Participants | 73 Participants | 153 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 11 | 60 / 67 | 56 / 72 |
| serious Total, serious adverse events | 7 / 11 | 26 / 67 | 20 / 72 |
Outcome results
Primary
Part 2: Progression-Free Survival (PFS)
PFS was defined as time from date of randomization to first date of determined progressive disease (PD) or death from any cause. PD defined using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) and Gynecological Cancer Intergroup (GCIG) criteria. RECIST: ≥20% increase in sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since treatment started or appearance of ≥ 1new lesions and/or unequivocal progression of existing non-target lesions. GCIG: Cancer Antigen-125 (CA-125) serum ≥2 times upper limit of normal (ULN) for those in normal range or nadir for participants who never achieved normal range. Participants not known to have died and did not have PD were censored at last progression-free assessment. Those who received subsequent systemic anticancer therapy (after study drug discontinued) prior to determined PD or death, were censored at date of last progression-free disease assessment prior to post-discontinuation chemotherapy.
Time frame: Randomization up to date of PD or death (up to 28.6 months)
Population: All randomized participants from Part 2 group. Participants censored for Part 2: Regimen A=38, Regimen B=35. Per protocol, Part 1 was not included as it is an open-label safety lead-in portion with PK characterization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2 - Regimen A | Part 2: Progression-Free Survival (PFS) | 18.9 months |
| Part 2 - Regimen B | Part 2: Progression-Free Survival (PFS) | 15.2 months |
Secondary
Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments)
Clinically significant events were defined as SAEs and other non-serious AEs regardless of causality. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module. The number of participants SAEs, other non-serious AEs, and those who died due to PD are included.
Time frame: Randomization up to 28.6 months
Population: All enrolled (Part 1) and all randomized (Part 2) participants who received at least 1 dose of study drug according to the treatment to which the participants were assigned.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 2 - Regimen A | Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | Died | 0 Participants |
| Part 2 - Regimen A | Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | SAEs | 7 Participants |
| Part 2 - Regimen A | Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | Non-Serious AEs | 11 Participants |
| Part 2 - Regimen B | Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | Non-Serious AEs | 60 Participants |
| Part 2 - Regimen B | Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | SAEs | 26 Participants |
| Part 2 - Regimen B | Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | Died | 3 Participants |
| Part 2 - Regimen B | Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | SAEs | 20 Participants |
| Part 2 - Regimen B | Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | Died | 0 Participants |
| Part 2 - Regimen B | Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | Non-Serious AEs | 56 Participants |
Secondary
Part 2: Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)]
ORR was the percentage of participants with a CR or PR using RECIST v1.0 and CA-125 GCIG criteria. RECIST v1.0: CR was defined as the disappearance of all tumors. PR was defined ≥30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD or complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesions and appearance of no new lesions. GCIG: CA-125 serum ≥2 times above ULN for those in normal range or nadir for participants who never achieved normal range. ORR calculated as: (CR + PR) / (total number of participants qualified for tumor response analysis per arm) \* 100.
Time frame: Randomization to PD or death from any cause (up to 28.6 months)
Population: All randomized participants from Part 2 group, who were evaluated for tumor response. Per protocol, Part 1 was not included as it is an open-label safety lead-in portion with PK characterization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 - Regimen A | Part 2: Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] | 42.9 percentage of participants |
| Part 2 - Regimen B | Part 2: Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] | 38.9 percentage of participants |
Secondary
Part 2: Percentage of Participants With CR or PR or Stable Disease (SD) (Rate of Response)
Rate of response was defined using RECIST v1.0 and CA-125 GCIG criteria. RECIST v1.0: CR was defined as the disappearance of all target lesions. PR was defined ≥30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD or complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesions and appearance of no new lesions. SD was defined as small changes that did not meet the above criteria. PD was defined as having a ≥20% increase in the sum of the LD of target lesions. GCIG: CA-125 serum ≥2 times above ULN for those in normal range or nadir for participants who never achieved normal range. Rate of response calculated as: (CR + PR + SD)/(total number of participants qualified for tumor response analysis per arm) \*100.
Time frame: Randomization to PD or death from any cause (up to 28.6 months)
Population: All randomized participants from Part 2 group, who qualified for tumor response analysis. Per protocol, Part 1 was not included as it is an open-label safety lead-in portion with PK characterization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 2 - Regimen A | Part 2: Percentage of Participants With CR or PR or Stable Disease (SD) (Rate of Response) | CR | 7.1 percentage of participants |
| Part 2 - Regimen A | Part 2: Percentage of Participants With CR or PR or Stable Disease (SD) (Rate of Response) | PR | 35.7 percentage of participants |
| Part 2 - Regimen A | Part 2: Percentage of Participants With CR or PR or Stable Disease (SD) (Rate of Response) | SD | 42.9 percentage of participants |
| Part 2 - Regimen B | Part 2: Percentage of Participants With CR or PR or Stable Disease (SD) (Rate of Response) | CR | 22.2 percentage of participants |
| Part 2 - Regimen B | Part 2: Percentage of Participants With CR or PR or Stable Disease (SD) (Rate of Response) | PR | 16.7 percentage of participants |
| Part 2 - Regimen B | Part 2: Percentage of Participants With CR or PR or Stable Disease (SD) (Rate of Response) | SD | 50.0 percentage of participants |
Secondary
Part 2: Percentage of Participants With PFS at 2 Years
PFS was defined as time from date of randomization to first date of determined PD or death from any cause. PD defined using RECIST v1.0 and GCIG criteria. RECIST v1.0: as ≥20% increase in sum of LD of target lesions taking as reference the smallest sum LD recorded since treatment started or appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. GCIG: CA-125 serum ≥2 times ULN for those in normal range or nadir (the lowest value of blood counts after chemotherapy) for participants who never achieved normal range. Participants not known to have died and did not have PD were censored at last progression-free assessment. Those who received subsequent systemic anticancer therapy (after study drug discontinued) prior to determined PD or death, were censored at date of last progression-free disease assessment prior to post-discontinuation chemotherapy.
Time frame: Randomization to measured PD evaluated at 2 years
Population: All randomized participants from Part 2 group. Participants censored for Part 2: Regimen A=38, Regimen B=35. Per protocol, Part 1 was not included as it is an open-label safety lead-in portion with PK characterization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 - Regimen A | Part 2: Percentage of Participants With PFS at 2 Years | 35.2 percentage of participants |
| Part 2 - Regimen B | Part 2: Percentage of Participants With PFS at 2 Years | 28.2 percentage of participants |
Secondary
Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment)
PE measured using Immunohistochemistry (IHC) assay, scored 0 (negative, no staining) to 3+ (brightest staining). IHC H-scores for protein biomarkers (PKCβ2, PTEN, pCREB, pGSK3b, pS6) calculated as: \[1\*(percentage of cells stained \[PCS\] as 1+)\]+\[2\*(PCS as 2+)\]+\[3\*(PCS as 3+)\]. High PE: ≥marker threshold value and Low PE: \<marker threshold value. PFS: date of randomization to PD or death. PD defined using RECIST v1.0 and GCIG criteria. RECIST: ≥20% increase in sum of LD of target lesions taking as references smallest sum LD recorded since treatment started or appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. GCIG: CA-125 serum ≥2 times ULN for those in normal range or nadir for those who never achieved normal range. Per protocol, Part 1 was not included as it is an open-label safety lead-in portion with PK characterization.
Time frame: Randomization up to date of PD or death (up to 28.6 months)
Population: All randomized participants (Pts) from Part 2 group. Pts censored: Regimens A/B (A/B)-High (H), Low (L) Expression: PKCβ2 Cytoplasm (Cyto) (H4/5,L26/22), PTEN Cyto (H24/24, L6/3), PTEN Membrane (H9/8, L21/19), PTEN Nucleus (H13/6, L17/21), pCREB Nucleus (H14/10, L16/17), pGSK3b Cyto (H7/3, L22/23), pS6 Cyto (H21/18, L9/9).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pGSK3b Cytoplasm Low Expression (H<160) | 14.0 months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PKCβ2 Cytoplasm Low Expression (H<115) | 19.1 months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pS6 Cytoplasm High Expression (H≥105) | 19.6 months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pS6 Cytoplasm Low Expression (H<105) | 11.5 months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Cytoplasm High Expression (H≥50) | 18.9 months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Cytoplasm Low Expression (H<50) | NA months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Membrane High Expression (H≥15) | 18.4 months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Membrane Low Expression (H<15) | 19.1 months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Nucleus High Expression (H≥12) | NA months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Nucleus Low Expression (H<12) | 18.4 months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pCREB Nucleus High Expression (H≥217) | 19.6 months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pCREB Nucleus Low Expression (H<217) | 14.0 months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pGSK3b Cytoplasm High Expression (H≥160) | NA months |
| Part 2 - Regimen A | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PKCβ2 Cytoplasm High Expression (H≥115) | 18.9 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Nucleus Low Expression (H<12) | 16.9 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PKCβ2 Cytoplasm High Expression (H≥115) | 10.4 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pCREB Nucleus Low Expression (H<217) | 18.2 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PKCβ2 Cytoplasm Low Expression (H<115) | 18.2 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Membrane High Expression (H≥15) | NA months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pGSK3b Cytoplasm Low Expression (H<160) | 17.4 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Membrane Low Expression (H<15) | 14.7 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pS6 Cytoplasm High Expression (H≥105) | 18.0 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pCREB Nucleus High Expression (H≥217) | 13.2 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pS6 Cytoplasm Low Expression (H<105) | 17.4 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Nucleus High Expression (H≥12) | 16.8 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Cytoplasm High Expression (H≥50) | 18.2 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | pGSK3b Cytoplasm High Expression (H≥160) | 14.5 months |
| Part 2 - Regimen B | Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PTEN Cytoplasm Low Expression (H<50) | 10.4 months |
Secondary
Pharmacokinetics (PK): Maximum Concentration (Cmax) for Carboplatin With and Without Enzastaurin for Part 1 of Study
Time frame: Cycle 1 Day 1 (carb) and Cycle 2 Day 1 (carb + enz); carb 0.25 hours (h) (prior to infusion), 0.5, 1, 2, 3, 5, and 21h after start of infusion
Population: All enrolled participants with measurable Cmax in Part 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2 - Regimen A | Pharmacokinetics (PK): Maximum Concentration (Cmax) for Carboplatin With and Without Enzastaurin for Part 1 of Study | Cycle 2 Day 1 | 10.8 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 13 |
| Part 2 - Regimen A | Pharmacokinetics (PK): Maximum Concentration (Cmax) for Carboplatin With and Without Enzastaurin for Part 1 of Study | Cycle 1 Day 1 | 11.1 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 21 |
Secondary
PK: AUC0-∞ for Paclitaxel With and Without Enzastaurin for Part 1 of Study
Time frame: Cycle 1 Day 1 (pac) and Cycle 2 Day 1 (pac + enz); pac at 1, 2, 3h (immediately after stopping infusion), 3.25, 3.5, 4, 5, 6, 8, 24, and 30h after start of infusion
Population: All enrolled participants with measurable AUC0-∞ in Part 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2 - Regimen A | PK: AUC0-∞ for Paclitaxel With and Without Enzastaurin for Part 1 of Study | Cycle 1 Day 1 | 12000 ng*h/mL | Geometric Coefficient of Variation 24 |
| Part 2 - Regimen A | PK: AUC0-∞ for Paclitaxel With and Without Enzastaurin for Part 1 of Study | Cycle 2 Day 1 | 14400 ng*h/mL | Geometric Coefficient of Variation 23 |
Secondary
PK: AUC During the Dosing Interval at Steady State (AUCτ,ss) for Part 2 of Study
AUCτ,ss for enzastaurin, its metabolite LSN326020 (LY326020), and total analytes are reported.
Time frame: Cycle 2 Day 1 (carb + pac + enz) at pre-dose, 2, 4, 6, 8 and 24h after the enz dose
Population: All randomized participants with measurable AUCτ,ss in Part 2.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2 - Regimen A | PK: AUC During the Dosing Interval at Steady State (AUCτ,ss) for Part 2 of Study | Enzastaurin | 47100 nmol*h/L | Geometric Coefficient of Variation 95 |
| Part 2 - Regimen A | PK: AUC During the Dosing Interval at Steady State (AUCτ,ss) for Part 2 of Study | LSN326020 | 55600 nmol*h/L | Geometric Coefficient of Variation 47 |
| Part 2 - Regimen A | PK: AUC During the Dosing Interval at Steady State (AUCτ,ss) for Part 2 of Study | Total Analyte | 106000 nmol*h/L | Geometric Coefficient of Variation 63 |
Secondary
PK: AUC From Time 0 to Infinity (AUC0-∞) for Carboplatin With and Without Enzastaurin for Part 1 of Study
Time frame: Cycle 1 Day 1 (carb) and Cycle 2 Day 1 (carb + enz); carb at 0.25h (prior to infusion), 0.5, 1, 2, 3, 5, and 21h after start of infusion
Population: All enrolled participants with measurable AUC0-∞ in Part 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2 - Regimen A | PK: AUC From Time 0 to Infinity (AUC0-∞) for Carboplatin With and Without Enzastaurin for Part 1 of Study | Cycle 1 Day 1 | 3.32 milligrams*minute/milliliter (mg*min/mL | Geometric Coefficient of Variation 10 |
| Part 2 - Regimen A | PK: AUC From Time 0 to Infinity (AUC0-∞) for Carboplatin With and Without Enzastaurin for Part 1 of Study | Cycle 2 Day 1 | 3.80 milligrams*minute/milliliter (mg*min/mL | Geometric Coefficient of Variation 16 |
Secondary
PK: Cmax at Steady State (Cmax,ss) for Part 1 of Study
Cmax,ss for enzastaurin, its metabolite LSN326020 (LY326020) and total analytes are reported.
Time frame: Cycle 1 Day 21 (enz) and Cycle 2 Day 1 (carb + pac + enz) at pre-dose, 2, 4, 6, 8 and 24h after the enz dose
Population: All enrolled participants with measurable Cmax,ss in Part 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2 - Regimen A | PK: Cmax at Steady State (Cmax,ss) for Part 1 of Study | Enzastaurin Cycle 1 Day 21 | 1230 nmol/L | Geometric Coefficient of Variation 110 |
| Part 2 - Regimen A | PK: Cmax at Steady State (Cmax,ss) for Part 1 of Study | Enzastaurin Cycle 2 Day 1 | 935 nmol/L | Geometric Coefficient of Variation 80 |
| Part 2 - Regimen A | PK: Cmax at Steady State (Cmax,ss) for Part 1 of Study | LSN326020 Cycle 2 Day1 | 814 nmol/L | Geometric Coefficient of Variation 30 |
| Part 2 - Regimen A | PK: Cmax at Steady State (Cmax,ss) for Part 1 of Study | Total Analyte Cycle 1 Day 21 | 2190 nmol/L | Geometric Coefficient of Variation 81 |
| Part 2 - Regimen A | PK: Cmax at Steady State (Cmax,ss) for Part 1 of Study | Total Analyte Cycle 2 Day 1 | 1640 nmol/L | Geometric Coefficient of Variation 57 |
| Part 2 - Regimen A | PK: Cmax at Steady State (Cmax,ss) for Part 1 of Study | LSN326020 Cycle 1 Day 21 | 890 nmol/L | Geometric Coefficient of Variation 58 |
Secondary
PK: Cmax for Paclitaxel With and Without Enzastaurin for Part 1 of Study
Time frame: Cycle 1 Day 1 (pac) and Cycle 2 Day 1 (pac + enz); pac 1, 2, 3h (immediately after stopping infusion), 3.25, 3.5, 4, 5, 6, 8, 24, and 30h after start of infusion
Population: All enrolled participants with measurable Cmax for pac in Part 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2 - Regimen A | PK: Cmax for Paclitaxel With and Without Enzastaurin for Part 1 of Study | Cycle 1 Day 1 | 3580 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 43 |
| Part 2 - Regimen A | PK: Cmax for Paclitaxel With and Without Enzastaurin for Part 1 of Study | Cycle 2 Day 1 | 3670 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 33 |