Advanced Cancer
Conditions
Brief summary
The purpose of this study is to determine a recommended Phase 2 dose and dosing regimen of LY2090314 in combination with pemetrexed and carboplatin in patients with advanced/metastatic cancer. Part A of this study will consist of dose escalation of the study regimen, and Part B will consist of an expanded cohort to confirm the dose provided from Part A.
Interventions
DRUGLY2090314
Administered intravenously
DRUGpemetrexed
Administered intravenously
DRUGCarboplatin
Administered intravenously
OTHERranitidine
Per I2H-MC-JWYA Protocol Amendment (d) approved 11 March 2010, 50 mg ranitidine given as pretreatment to LY2090314 for stomach pain.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a performance status of less than or equal to 2 on the Eastern Cooperative Oncology Group (ECOG) scale * Have a life expectancy of greater than or equal to 12 weeks * Males and females with reproductive potential agree to use medically approved contraceptive precautions during the trial and for 3 months following the last dose of study drug * Have histological or cytological evidence of a diagnosis of cancer that is advanced and/or metastatic disease for which no proven effective therapy exists * Have the presence of measurable or nonmeasurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) * Have adequate hematologic, hepatic, and renal function * Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, cancer-related hormonal therapy, or other investigational therapy for at least 30 days (6 weeks for mitomycin-C or nitrosoureas) prior to study enrollment and recovered from the acute effects of therapy.
Exclusion criteria
* Have received treatment within 30 days of the initial dose of study drug with a drug that has not received regulatory approval for any indication * Have serious preexisting medical conditions (left to discretion of investigator) * Have one of the following conduction abnormalities: Corrected time between start of Q wave and end of T wave (QTc) prolongation \>450 millisecond (msec) on screening electrocardiogram (ECG), previous history of QTc prolongation with another medication that required discontinuation, congenital long-QT-syndrome, or left bundle branch block (LBBB) * Are taking any concomitant medication that may cause QTc prolongation, or induce Torsades de Pointes * Have systolic blood pressure greater than or equal to 140 millimeters of Mercury (mm Hg), and diastolic blood pressure greater than or equal to 90 mm Hg that is not controlled by medical therapy * Have serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease, as defined by the New York Heart Association Class II or higher; have history of arrhythmia that is symptomatic or requires treatment * Have chronic atrial fibrillation and/or bradycardia * Have uncorrected electrolyte disorders including potassium \<3.4 molar equivalent per liter (mEq/L) (\<3.4 millimole per liter \[mmol/l\]), calcium \<8.4 milligram per deciliter (mg/dL) (2.1 mmol/L), or magnesium \<1.2 mg/dL (\<0.62 mmol/L) * Have symptomatic central nervous system (CNS) malignancy or metastasis (screening not required) * Have a hematologic malignancy * Females who are pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended LY2090314 Dose for Phase 2 Studies (Maximum Tolerated Dose [MTD]) | Baseline up to Day 28 (Cycle 1) | Recommended Phase 2 MTD was determined, when a dose limiting toxicity (DLT) occurred in 1 of 3 participants, the cohort was to be expanded to 6 participants. If a DLT occurred in 2 or more participants, accrual to the cohort was stopped, as the MTD was exceeded. A DLT was defined as an adverse event (AE) occurring in Cycle 1 (28 days) that was possibly related to study drug and met 1 of the following criteria: According to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0, ≥Grade 3 nonhematologic toxicity (except for nausea/vomiting without maximal symptomatic/prophylactic treatment) possibly or likely related to the study medication;CTCAE Grade 4 hematological toxicity of \>5 days duration; Febrile neutropenia; CTCAE Grade 4 thrombocytopenia; CTCAE ≥Grade 2 thrombocytopenia plus bleeding; CTCAE ≥Grade 3 prolonged QTc interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK Parameter: AUC0-∞ of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | Cycle 1 Day 8 of a 28-day cycle or Cycle 2 Day 1 of a 21-day cycle | AUC0-∞ was calculated from the area under the concentration versus time curves of LY2090314 from time zero to infinity when coadministered with Pem and Carb. |
| PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 | Cycle 1 Day 1 of a 28-day cycle | — |
| PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | Cycle 1 Day 8 of a 28-day cycle or Cycle 2 Day 1 of a 21-day cycle | — |
| Number of Participants With Best Overall Tumor Response | Baseline up to Cycle 9 (Cycle 1 was 28 days, Cycles 2 to 9 were 21 days) | Best overall observed tumor response at any point during the study until disease progression/recurrence defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Complete Response (CR) was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter (mm) and normalization of tumor marker level of non-target lesions; Partial Response (PR) was defined as at least 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD) was defined as at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase over nadir; Stable Disease (SD) was defined as small changes that did not meet above criteria. |
| Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of LY2090314 | Cycle 1 Day 1 of a 28 day cycle | AUC0-∞ was calculated from the area under the concentration versus time curve from time 0 to infinity of LY2090314 when administered alone. |
| PK Parameter: Maximum Plasma Concentration (Cmax) of Pemetrexed (Pem) | Cycle 1 Day 8 of 28-day cycle and Cycle 2 up to Cycle 10 Day 1 of 21-day cycle | Cmax of Pem given as a single dose with Carb (doublet therapy) and when coadministered with Carb and LY2090314 (triplet therapy). |
| PK Parameter: AUC0-∞ of Free Carboplatin (Carb) | Cycle 1 Day 8 of 28-day cycle and Cycle 2 up to Cycle 9: Day 1 of 21-day cycle | AUC0-∞ of free Carb was calculated from the area under the concentration versus time curves of Carb given as a single dose with Pem (doublet therapy) and when co-administered with Pem and LY2090314 (triplet therapy). |
| PK Parameter: Cmax of Free Carboplatin | Cycle 1, Day 8 of 28-day cycle and Cycle 2 up to Cycle 9: Day 1 of 21-day cycle | Cmax of free Carb given as a single dose with Pem (doublet therapy) and when co-administered with Pem and LY2090314 (triplet therapy). |
| Pharmacodynamic (PD) Changes in Beta-Catenin (β-catenin) | Baseline, Cycle 1 , Day 1 of a 28-day cycle and Cycle 2 up to Cycle 9: Day 1 of 21-day cycles | PD change from baseline to endpoint (up to Cycle 9) in β-catenin levels in peripheral blood mononuclear cells (PBMCs) following the administration of LY2090314 given alone and in combination with Pem and Carb. This outcome measure was not analyzed due to insufficient data. |
| Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of Pemetrexed (Pem) | Cycle 1 Day 8 of 28-day cycle and Cycle 2 up to Cycle 10 Day 1 of 21-day cycle | AUC0-∞ was calculated from the area under the concentration versus time curves of Pem given as a single dose with Carb (doublet therapy) and when co-administered with Carb and LY2090314 (triplet therapy). |
Countries
United States
Participant flow
Pre-assignment details
The reasons for discontinuation listed in the participant flow are the reasons the participant discontinued treatment and a participant was considered to have completed the trial if they discontinued treatment due to progressive disease or an adverse event.
Participants by arm
| Arm | Count |
|---|---|
| LY 10/Carb 5/Pem 500 (Cohort 1) * Cycle 1 Day 1 of 28-day cycle: 10 mg LY2090314 by intravenous infusion.
* Cycle 1 Day 8 of 28-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 5 mg/mL \* min Carb by intravenous infusion.
* Cycle 2 up to Cycle 9: Day 1 of 21-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 5 mg/mL \* min Carb by intravenous infusion followed by 10 mg LY2090314 by intravenous infusion. | 3 |
| LY 10/Carb 6/Pem 500 (Cohort 2) * Cycle 1 Day 1 of 28-day cycle: 10 mg LY2090314 by intravenous infusion.
* Cycle 1 Day 8 of 28-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion.
* Cycle 2 up to Cycle 9: Day 1 of 21-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 10 mg LY2090314 by intravenous infusion. | 7 |
| LY 20/Carb 6/Pem 500 (Cohort 3) * Cycle 1 Day 1 of 28-day cycle: 20 mg LY2090314 by intravenous infusion.
* Cycle 1 Day 8 of 28-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion.
* Cycle 2 up to Cycle 9: Day 1 of 21-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 20 mg LY2090314 by intravenous infusion. | 5 |
| LY 40/Carb 6/Pem 500 (Cohort 4) * Cycle 1 Day 1 of 28-day cycle: 40 mg LY2090314 by intravenous infusion.
* Cycle 1 Day 8 of 28-day cycle 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 40 mg LY2090314 by intravenous infusion.
* Cycle 2 Day 1 of 21-day cycle: AUC 6 mg/mL \* min Carb by intravenous infusion followed by 500 mg/m\^2 Pem by intravenous infusion.
* Cycle 3 up to Cycle 9: Day 1 of 21-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 40 mg LY2090314 by intravenous infusion. | 7 |
| LY 80/Carb 6/Pem 500 (Cohort 5) * Cycle 1 Day 1 of 28-day cycle: 80 mg LY2090314 by intravenous infusion.
* Cycle 1 Day 8 of 28-day cycle 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 80 mg LY2090314 by intravenous infusion.
* Cycle 2 Day 1 of 21-day cycle: AUC 6 mg/mL \* min Carb by intravenous infusion followed by 500 mg/m\^2 Pem by intravenous infusion.
* Cycle 3 up to Cycle 9: Day 1 of 21-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 80 mg LY2090314 by intravenous infusion. | 3 |
| LY 120/Carb 6/Pem 500 (Cohort 6) * Cycle 1 Day 1 of 28-day cycle: 120 mg LY2090314 by intravenous infusion.
* Cycle 1 Day 8 of 28-day cycle 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 120 mg LY2090314 by intravenous infusion.
* Cycle 2 Day 1 of 21-day cycle: AUC 6 mg/mL \* min Carb by intravenous infusion followed by 500 mg/m\^2 Pem by intravenous infusion.
* Cycle 3 up to Cycle 9: Day 1 of 21-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 120 mg LY2090314 by intravenous infusion. | 4 |
| LY 80/Carb 6/Pem 500 + R50 (Cohort 7) * Cycle 1 Day 1 of 28-day cycle: pretreated with 50 mg ranitidine intravenous, 80 mg LY2090314 by intravenous infusion.
* Cycle 1 Day 8 of 28-day cycle 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6mg/mL \* min Carb intravenous infusion followed by 50 mg ranitidine intravenous pretreatment and 80 mg LY2090314 by intravenous infusion.
* Cycle 2 Day 1 of 21-day cycle: AUC 6 mg/mL \* min Carb by intravenous infusion followed by 500 mg/m\^2 Pem intravenous infusion.
* Cycle 3 up to Cycle 10: Day 1 of 21-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 50 mg ranitidine intravenous pretreatment and 80 mg LY2090314 intravenous infusion.
Based on I2H-MC-JWYA Protocol Amendment (d) approved 11 March 2010, 50 mg ranitidine was given as a pretreatment to LY2090314 as prophylaxis for stomach pain. | 2 |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) * Cycle 1 Day 1 of 28-day cycle: pretreated with 50 mg ranitidine intravenous, 60 mg LY2090314 by intravenous infusion.
* Cycle 1 Day 8 of 28-day cycle 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6mg/mL \* min Carb intravenous infusion followed by 50 mg ranitidine intravenous pretreatment and 60 mg LY2090314 by intravenous infusion.
* Cycle 2 Day 1 of 21-day cycle: AUC 6 mg/mL \* min Carb by intravenous infusion followed by 500 mg/m\^2 Pem intravenous infusion.
* Cycle 3 up to Cycle 9: Day 1 of 21-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 50 mg ranitidine intravenous pretreatment and 60 mg LY2090314 intravenous infusion.
Based on I2H-MC-JWYA Protocol Amendment (d) approved 11 March 2010, 50 mg ranitidine was given as a pretreatment to LY2090314 as prophylaxis for stomach pain. | 5 |
| LY 40/Carb 6/Pem 500 + R50 (Cohort 9) * Cycle 1 Day 1 of 28-day cycle: pretreated with 50 mg ranitidine intravenous, 40 mg LY2090314 by intravenous infusion.
* Cycle 1 Day 8 of 28-day cycle 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6mg/mL \* min Carb intravenous infusion followed by 50 mg ranitidine intravenous pretreatment and 40 mg LY2090314 by intravenous infusion.
* Cycle 2 Day 1 of 21-day cycle: AUC 6 mg/mL \* min Carb by intravenous infusion followed by 500 mg/m\^2 Pem intravenous infusion.
* Cycle 3 up to Cycle 9: Day 1 of 21-day cycle: 500 mg/m\^2 Pem by intravenous infusion followed by AUC 6 mg/mL \* min Carb by intravenous infusion followed by 50 mg ranitidine intravenous pretreatment and 40 mg LY2090314 intravenous infusion.
Based on I2H-MC-JWYA Protocol Amendment (d) approved 11 March 2010, 50 mg ranitidine was given as a pretreatment to LY2090314 as prophylaxis for stomach pain. | 5 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 2 | 1 | 1 | 2 | 0 | 2 | 0 |
| Overall Study | Physician Decision | 1 | 1 | 2 | 0 | 1 | 1 | 0 | 1 | 0 |
| Overall Study | Progressive disease | 0 | 4 | 1 | 6 | 1 | 0 | 2 | 2 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | LY 40/Carb 6/Pem 500 + R50 (Cohort 9) | LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | LY 80/Carb 6/Pem 500 + R50 (Cohort 7) | LY 120/Carb 6/Pem 500 (Cohort 6) | Total | LY 80/Carb 6/Pem 500 (Cohort 5) | LY 40/Carb 6/Pem 500 (Cohort 4) | LY 20/Carb 6/Pem 500 (Cohort 3) | LY 10/Carb 6/Pem 500 (Cohort 2) | LY 10/Carb 5/Pem 500 (Cohort 1) |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 61.35 years STANDARD_DEVIATION 4.41 | 58.78 years STANDARD_DEVIATION 9.06 | 55.39 years STANDARD_DEVIATION 9.86 | 56.73 years STANDARD_DEVIATION 7.52 | 57.79 years STANDARD_DEVIATION 7.65 | 57.35 years STANDARD_DEVIATION 7.59 | 58.32 years STANDARD_DEVIATION 8.95 | 59.31 years STANDARD_DEVIATION 5.62 | 55.27 years STANDARD_DEVIATION 9.19 | 55.81 years STANDARD_DEVIATION 11.88 |
| Basis of Diagnosis Cytological | 0 participants | 1 participants | 1 participants | 0 participants | 8 participants | 2 participants | 1 participants | 1 participants | 1 participants | 1 participants |
| Basis of Diagnosis Histopathological | 5 participants | 4 participants | 1 participants | 4 participants | 33 participants | 1 participants | 6 participants | 4 participants | 6 participants | 2 participants |
| Body Surface Area | 2.04 meters squared (m^2) STANDARD_DEVIATION 0.15 | 1.90 meters squared (m^2) STANDARD_DEVIATION 0.3 | 2.07 meters squared (m^2) STANDARD_DEVIATION 0.14 | 2.11 meters squared (m^2) STANDARD_DEVIATION 0.33 | 1.94 meters squared (m^2) STANDARD_DEVIATION 0.27 | 1.77 meters squared (m^2) STANDARD_DEVIATION 0.46 | 1.94 meters squared (m^2) STANDARD_DEVIATION 0.29 | 1.66 meters squared (m^2) STANDARD_DEVIATION 0.14 | 2.10 meters squared (m^2) STANDARD_DEVIATION 0.13 | 1.76 meters squared (m^2) STANDARD_DEVIATION 0.11 |
| Eastern Cooperative Oncology Group (ECOG) performance 0 | 5 participants | 3 participants | 2 participants | 4 participants | 36 participants | 2 participants | 7 participants | 5 participants | 5 participants | 3 participants |
| Eastern Cooperative Oncology Group (ECOG) performance 1 | 0 participants | 2 participants | 0 participants | 0 participants | 5 participants | 1 participants | 0 participants | 0 participants | 2 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Adenocarcinoma not otherwise specified (NOS) | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Adenoid | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Bile duct | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Breast | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Cancer NOS | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Colon | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Esophagus | 0 participants | 1 participants | 0 participants | 0 participants | 3 participants | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Gall bladder | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Gastric | 1 participants | 0 participants | 0 participants | 0 participants | 2 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Head and neck | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Initial Pathological Tumor Diagnosis Leimyosarcoma | 0 participants | 0 participants | 0 participants | 1 participants | 3 participants | 0 participants | 0 participants | 0 participants | 2 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Lung adenocarcinoma | 1 participants | 1 participants | 1 participants | 0 participants | 3 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Mesothelioma | 1 participants | 1 participants | 0 participants | 1 participants | 9 participants | 0 participants | 0 participants | 1 participants | 3 participants | 2 participants |
| Initial Pathological Tumor Diagnosis Non-small cell lung carcinoma (NSCLC) | 1 participants | 1 participants | 0 participants | 0 participants | 7 participants | 1 participants | 1 participants | 3 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Pancreas | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Rectum | 0 participants | 0 participants | 0 participants | 1 participants | 2 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Small cell lung carcinoma (SCLC) | 1 participants | 0 participants | 0 participants | 0 participants | 2 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Initial Pathological Tumor Diagnosis Thymoma | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized African | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Caucasian | 5 participants | 5 participants | 2 participants | 4 participants | 38 participants | 2 participants | 7 participants | 4 participants | 6 participants | 3 participants |
| Race/Ethnicity, Customized Hispanic | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants |
| Region of Enrollment United States | 5 participants | 5 participants | 2 participants | 4 participants | 41 participants | 3 participants | 7 participants | 5 participants | 7 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 18 Participants | 2 Participants | 3 Participants | 5 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 2 Participants | 4 Participants | 23 Participants | 1 Participants | 4 Participants | 0 Participants | 4 Participants | 1 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 5 / 5 | 7 / 7 | 3 / 3 | 3 / 4 | 2 / 2 | 5 / 5 | 5 / 5 |
| serious Total, serious adverse events | 1 / 3 | 3 / 7 | 3 / 5 | 2 / 7 | 1 / 3 | 1 / 4 | 1 / 2 | 0 / 5 | 1 / 5 |
Outcome results
Primary
Recommended LY2090314 Dose for Phase 2 Studies (Maximum Tolerated Dose [MTD])
Recommended Phase 2 MTD was determined, when a dose limiting toxicity (DLT) occurred in 1 of 3 participants, the cohort was to be expanded to 6 participants. If a DLT occurred in 2 or more participants, accrual to the cohort was stopped, as the MTD was exceeded. A DLT was defined as an adverse event (AE) occurring in Cycle 1 (28 days) that was possibly related to study drug and met 1 of the following criteria: According to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0, ≥Grade 3 nonhematologic toxicity (except for nausea/vomiting without maximal symptomatic/prophylactic treatment) possibly or likely related to the study medication;CTCAE Grade 4 hematological toxicity of \>5 days duration; Febrile neutropenia; CTCAE Grade 4 thrombocytopenia; CTCAE ≥Grade 2 thrombocytopenia plus bleeding; CTCAE ≥Grade 3 prolonged QTc interval.
Time frame: Baseline up to Day 28 (Cycle 1)
Population: Safety population: all participants who have received at least 1 dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2090314/Pemetrexed/Carboplatin | Recommended LY2090314 Dose for Phase 2 Studies (Maximum Tolerated Dose [MTD]) | 40 milligrams (mg) |
Secondary
Number of Participants With Best Overall Tumor Response
Best overall observed tumor response at any point during the study until disease progression/recurrence defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Complete Response (CR) was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter (mm) and normalization of tumor marker level of non-target lesions; Partial Response (PR) was defined as at least 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD) was defined as at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase over nadir; Stable Disease (SD) was defined as small changes that did not meet above criteria.
Time frame: Baseline up to Cycle 9 (Cycle 1 was 28 days, Cycles 2 to 9 were 21 days)
Population: Analysis population: all participants who received at least 1 dose of study drug and had tumor response assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2090314/Pemetrexed/Carboplatin | Number of Participants With Best Overall Tumor Response | CR | 0 participants |
| LY2090314/Pemetrexed/Carboplatin | Number of Participants With Best Overall Tumor Response | SD | 2 participants |
| LY2090314/Pemetrexed/Carboplatin | Number of Participants With Best Overall Tumor Response | PD | 0 participants |
| LY2090314/Pemetrexed/Carboplatin | Number of Participants With Best Overall Tumor Response | PR | 0 participants |
| LY2090314/Pemetrexed/Carboplatin | Number of Participants With Best Overall Tumor Response | Unknown (discontinued before response assessment) | 1 participants |
| LY 20/Carb 6/Pem 500 (Cohort 3) | Number of Participants With Best Overall Tumor Response | SD | 4 participants |
| LY 20/Carb 6/Pem 500 (Cohort 3) | Number of Participants With Best Overall Tumor Response | PR | 0 participants |
| LY 20/Carb 6/Pem 500 (Cohort 3) | Number of Participants With Best Overall Tumor Response | CR | 0 participants |
| LY 20/Carb 6/Pem 500 (Cohort 3) | Number of Participants With Best Overall Tumor Response | Unknown (discontinued before response assessment) | 1 participants |
| LY 20/Carb 6/Pem 500 (Cohort 3) | Number of Participants With Best Overall Tumor Response | PD | 2 participants |
| LY 40/Carb 6/Pem 500 (Cohorts 4 and 9) | Number of Participants With Best Overall Tumor Response | SD | 2 participants |
| LY 40/Carb 6/Pem 500 (Cohorts 4 and 9) | Number of Participants With Best Overall Tumor Response | CR | 0 participants |
| LY 40/Carb 6/Pem 500 (Cohorts 4 and 9) | Number of Participants With Best Overall Tumor Response | Unknown (discontinued before response assessment) | 1 participants |
| LY 40/Carb 6/Pem 500 (Cohorts 4 and 9) | Number of Participants With Best Overall Tumor Response | PR | 1 participants |
| LY 40/Carb 6/Pem 500 (Cohorts 4 and 9) | Number of Participants With Best Overall Tumor Response | PD | 1 participants |
| LY 80/Carb 6/Pem 500 (Cohorts 5 and 7) | Number of Participants With Best Overall Tumor Response | Unknown (discontinued before response assessment) | 0 participants |
| LY 80/Carb 6/Pem 500 (Cohorts 5 and 7) | Number of Participants With Best Overall Tumor Response | PD | 3 participants |
| LY 80/Carb 6/Pem 500 (Cohorts 5 and 7) | Number of Participants With Best Overall Tumor Response | CR | 0 participants |
| LY 80/Carb 6/Pem 500 (Cohorts 5 and 7) | Number of Participants With Best Overall Tumor Response | SD | 2 participants |
| LY 80/Carb 6/Pem 500 (Cohorts 5 and 7) | Number of Participants With Best Overall Tumor Response | PR | 1 participants |
| LY 120/Carb 6/Pem 500 (Cohort 6) | Number of Participants With Best Overall Tumor Response | SD | 0 participants |
| LY 120/Carb 6/Pem 500 (Cohort 6) | Number of Participants With Best Overall Tumor Response | PR | 0 participants |
| LY 120/Carb 6/Pem 500 (Cohort 6) | Number of Participants With Best Overall Tumor Response | Unknown (discontinued before response assessment) | 2 participants |
| LY 120/Carb 6/Pem 500 (Cohort 6) | Number of Participants With Best Overall Tumor Response | CR | 0 participants |
| LY 120/Carb 6/Pem 500 (Cohort 6) | Number of Participants With Best Overall Tumor Response | PD | 1 participants |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Number of Participants With Best Overall Tumor Response | SD | 0 participants |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Number of Participants With Best Overall Tumor Response | CR | 0 participants |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Number of Participants With Best Overall Tumor Response | PR | 0 participants |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Number of Participants With Best Overall Tumor Response | PD | 0 participants |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Number of Participants With Best Overall Tumor Response | Unknown (discontinued before response assessment) | 0 participants |
| LY 80/Carb 6/Pem 500 + R50 (Cohort 7) | Number of Participants With Best Overall Tumor Response | SD | 1 participants |
| LY 80/Carb 6/Pem 500 + R50 (Cohort 7) | Number of Participants With Best Overall Tumor Response | PD | 0 participants |
| LY 80/Carb 6/Pem 500 + R50 (Cohort 7) | Number of Participants With Best Overall Tumor Response | PR | 1 participants |
| LY 80/Carb 6/Pem 500 + R50 (Cohort 7) | Number of Participants With Best Overall Tumor Response | Unknown (discontinued before response assessment) | 0 participants |
| LY 80/Carb 6/Pem 500 + R50 (Cohort 7) | Number of Participants With Best Overall Tumor Response | CR | 0 participants |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Number of Participants With Best Overall Tumor Response | SD | 1 participants |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Number of Participants With Best Overall Tumor Response | PR | 1 participants |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Number of Participants With Best Overall Tumor Response | PD | 2 participants |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Number of Participants With Best Overall Tumor Response | Unknown (discontinued before response assessment) | 0 participants |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Number of Participants With Best Overall Tumor Response | CR | 0 participants |
| LY 40/Carb 6/Pem 500 + R50 (Cohort 9) | Number of Participants With Best Overall Tumor Response | CR | 0 participants |
| LY 40/Carb 6/Pem 500 + R50 (Cohort 9) | Number of Participants With Best Overall Tumor Response | Unknown (discontinued before response assessment) | 1 participants |
| LY 40/Carb 6/Pem 500 + R50 (Cohort 9) | Number of Participants With Best Overall Tumor Response | PD | 2 participants |
| LY 40/Carb 6/Pem 500 + R50 (Cohort 9) | Number of Participants With Best Overall Tumor Response | PR | 0 participants |
| LY 40/Carb 6/Pem 500 + R50 (Cohort 9) | Number of Participants With Best Overall Tumor Response | SD | 2 participants |
Secondary
Pharmacodynamic (PD) Changes in Beta-Catenin (β-catenin)
PD change from baseline to endpoint (up to Cycle 9) in β-catenin levels in peripheral blood mononuclear cells (PBMCs) following the administration of LY2090314 given alone and in combination with Pem and Carb. This outcome measure was not analyzed due to insufficient data.
Time frame: Baseline, Cycle 1 , Day 1 of a 28-day cycle and Cycle 2 up to Cycle 9: Day 1 of 21-day cycles
Population: There was insufficient data from participants who received at least 1 dose of LY2090314 to perform β-catenin modeling, thus zero participants were analyzed.
Secondary
Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of LY2090314
AUC0-∞ was calculated from the area under the concentration versus time curve from time 0 to infinity of LY2090314 when administered alone.
Time frame: Cycle 1 Day 1 of a 28 day cycle
Population: All participants who received at least 1 dose of LY2090314 and had evaluable AUC0-∞ data, excluding 2 participants (1 in dose groups LY80 and 1 in dose group LY120) who received the wrong dose of LY2090314.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2090314/Pemetrexed/Carboplatin | Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of LY2090314 | 216 nanograms*hour per milliliter | Geometric Coefficient of Variation 26.3 |
| LY 20/Carb 6/Pem 500 (Cohort 3) | Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of LY2090314 | 427 nanograms*hour per milliliter | Geometric Coefficient of Variation 21.8 |
| LY 40/Carb 6/Pem 500 (Cohorts 4 and 9) | Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of LY2090314 | 976 nanograms*hour per milliliter | Geometric Coefficient of Variation 42.6 |
| LY 80/Carb 6/Pem 500 (Cohorts 5 and 7) | Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of LY2090314 | 1870 nanograms*hour per milliliter | Geometric Coefficient of Variation 76.7 |
| LY 120/Carb 6/Pem 500 (Cohort 6) | Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of LY2090314 | 3310 nanograms*hour per milliliter | Geometric Coefficient of Variation 18.7 |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of LY2090314 | 1600 nanograms*hour per milliliter | Geometric Coefficient of Variation 47.3 |
Secondary
Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of Pemetrexed (Pem)
AUC0-∞ was calculated from the area under the concentration versus time curves of Pem given as a single dose with Carb (doublet therapy) and when co-administered with Carb and LY2090314 (triplet therapy).
Time frame: Cycle 1 Day 8 of 28-day cycle and Cycle 2 up to Cycle 10 Day 1 of 21-day cycle
Population: All participants who were treated with Pem and Carb (doublet therapy) or who were treated with Pem, Carb and LY2090314 (triplet therapy) and had evaluable AUC0-∞ Pem data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2090314/Pemetrexed/Carboplatin | Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of Pemetrexed (Pem) | 212 hours*nanograms/milliliter/ milligram | Geometric Coefficient of Variation 34.4 |
| LY 20/Carb 6/Pem 500 (Cohort 3) | Pharmacokinetic (PK) Parameter: Area Under the Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of Pemetrexed (Pem) | 202 hours*nanograms/milliliter/ milligram | Geometric Coefficient of Variation 37.5 |
Secondary
PK Parameter: AUC0-∞ of Free Carboplatin (Carb)
AUC0-∞ of free Carb was calculated from the area under the concentration versus time curves of Carb given as a single dose with Pem (doublet therapy) and when co-administered with Pem and LY2090314 (triplet therapy).
Time frame: Cycle 1 Day 8 of 28-day cycle and Cycle 2 up to Cycle 9: Day 1 of 21-day cycle
Population: All participants who were treated with Pem and Carb (doublet therapy) or Pem, Carb and LY2090314 (triplet therapy) and who had evaluable Carb AUC0-∞ data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2090314/Pemetrexed/Carboplatin | PK Parameter: AUC0-∞ of Free Carboplatin (Carb) | 81.6 hours*nanograms per milliliter per mg | Geometric Coefficient of Variation 41.8 |
| LY 20/Carb 6/Pem 500 (Cohort 3) | PK Parameter: AUC0-∞ of Free Carboplatin (Carb) | 88.1 hours*nanograms per milliliter per mg | Geometric Coefficient of Variation 49.2 |
Secondary
PK Parameter: AUC0-∞ of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb)
AUC0-∞ was calculated from the area under the concentration versus time curves of LY2090314 from time zero to infinity when coadministered with Pem and Carb.
Time frame: Cycle 1 Day 8 of a 28-day cycle or Cycle 2 Day 1 of a 21-day cycle
Population: All participants who received at least 1 dose LY2090314 coadministered with Pem and Carb and had enough samples to allow estimation of AUC0-∞ parameters excluding 2 participants (1 in dose groups LY80 and 1 in dose group LY120) who received the incorrect dose of LY2090314.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2090314/Pemetrexed/Carboplatin | PK Parameter: AUC0-∞ of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 192 nanograms*hour per milliliter | Geometric Coefficient of Variation 48.2 |
| LY 20/Carb 6/Pem 500 (Cohort 3) | PK Parameter: AUC0-∞ of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 404 nanograms*hour per milliliter | Geometric Coefficient of Variation 33.2 |
| LY 40/Carb 6/Pem 500 (Cohorts 4 and 9) | PK Parameter: AUC0-∞ of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 938 nanograms*hour per milliliter | Geometric Coefficient of Variation 33.5 |
| LY 80/Carb 6/Pem 500 (Cohorts 5 and 7) | PK Parameter: AUC0-∞ of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 1830 nanograms*hour per milliliter | Geometric Coefficient of Variation 7.84 |
| LY 120/Carb 6/Pem 500 (Cohort 6) | PK Parameter: AUC0-∞ of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 2190 nanograms*hour per milliliter | — |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | PK Parameter: AUC0-∞ of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 1570 nanograms*hour per milliliter | Geometric Coefficient of Variation 36.5 |
Secondary
PK Parameter: Cmax of Free Carboplatin
Cmax of free Carb given as a single dose with Pem (doublet therapy) and when co-administered with Pem and LY2090314 (triplet therapy).
Time frame: Cycle 1, Day 8 of 28-day cycle and Cycle 2 up to Cycle 9: Day 1 of 21-day cycle
Population: All participants who were treated with Pem and Carb (doublet therapy) or who were treated with Pem, Carb and LY2090314 (triplet therapy) and had evaluable Carb Cmax data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2090314/Pemetrexed/Carboplatin | PK Parameter: Cmax of Free Carboplatin | 24.0 nanograms/milliliter/milligram | Geometric Coefficient of Variation 43.9 |
| LY 20/Carb 6/Pem 500 (Cohort 3) | PK Parameter: Cmax of Free Carboplatin | 25.5 nanograms/milliliter/milligram | Geometric Coefficient of Variation 46 |
Secondary
PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314
Time frame: Cycle 1 Day 1 of a 28-day cycle
Population: All participants who received at least 1 dose of LY2090314 and had evaluable AUC0-∞ data, excluding 2 participants (1 in dose groups LY80 and 1 in dose group LY120) who received the incorrect dose of LY2090314.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2090314/Pemetrexed/Carboplatin | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 | 122 nanograms per milliliter | Geometric Coefficient of Variation 21.5 |
| LY 20/Carb 6/Pem 500 (Cohort 3) | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 | 246 nanograms per milliliter | Geometric Coefficient of Variation 29 |
| LY 40/Carb 6/Pem 500 (Cohorts 4 and 9) | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 | 603 nanograms per milliliter | Geometric Coefficient of Variation 47.7 |
| LY 80/Carb 6/Pem 500 (Cohorts 5 and 7) | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 | 898 nanograms per milliliter | Geometric Coefficient of Variation 50.5 |
| LY 120/Carb 6/Pem 500 (Cohort 6) | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 | 1700 nanograms per milliliter | Geometric Coefficient of Variation 63.2 |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 | 881 nanograms per milliliter | Geometric Coefficient of Variation 53.3 |
Secondary
PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb)
Time frame: Cycle 1 Day 8 of a 28-day cycle or Cycle 2 Day 1 of a 21-day cycle
Population: All participants who received at least 1 dose of LY2090314 and had evaluable AUC0-∞ data, excluding 2 participants (1 in dose groups LY80 and 1 in dose group LY120) who received the incorrect dose of LY2090314.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2090314/Pemetrexed/Carboplatin | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 106 nanograms per milliliter | Geometric Coefficient of Variation 57.5 |
| LY 20/Carb 6/Pem 500 (Cohort 3) | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 271 nanograms per milliliter | Geometric Coefficient of Variation 62.5 |
| LY 40/Carb 6/Pem 500 (Cohorts 4 and 9) | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 657 nanograms per milliliter | Geometric Coefficient of Variation 44.1 |
| LY 80/Carb 6/Pem 500 (Cohorts 5 and 7) | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 1150 nanograms per milliliter | Geometric Coefficient of Variation 27.8 |
| LY 120/Carb 6/Pem 500 (Cohort 6) | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 768 nanograms per milliliter | — |
| LY 60/Carb 6/Pem 500 + R50 (Cohort 8) | PK Parameter: Maximum Plasma Concentration (Cmax) of LY2090314 Coadministered With Pemetrexed (Pem) and Carboplatin (Carb) | 1040 nanograms per milliliter | Geometric Coefficient of Variation 48.2 |
Secondary
PK Parameter: Maximum Plasma Concentration (Cmax) of Pemetrexed (Pem)
Cmax of Pem given as a single dose with Carb (doublet therapy) and when coadministered with Carb and LY2090314 (triplet therapy).
Time frame: Cycle 1 Day 8 of 28-day cycle and Cycle 2 up to Cycle 10 Day 1 of 21-day cycle
Population: All participants who were treated with Pem and Carb (doublet therapy) or who were treated with Pem, Carb and LY2090314 (triplet therapy) and had evaluable Cmax Pem data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2090314/Pemetrexed/Carboplatin | PK Parameter: Maximum Plasma Concentration (Cmax) of Pemetrexed (Pem) | 109 nanogram per milliliter per milligram | Geometric Coefficient of Variation 38 |
| LY 20/Carb 6/Pem 500 (Cohort 3) | PK Parameter: Maximum Plasma Concentration (Cmax) of Pemetrexed (Pem) | 108 nanogram per milliliter per milligram | Geometric Coefficient of Variation 43.1 |