Advanced Cancer
Conditions
Brief summary
The objective of this study is to determine a safe dose of LY2228820 that may be given to participants with advanced cancer. Part A of this study will consist of dose escalation, and Part B will consist of dose confirmation.
Interventions
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have histological or cytological evidence of a diagnosis of cancer (including lymphoma) that is advanced or metastatic disease for which no therapy of higher priority (approved therapies or therapies with published substantial evidence of effectiveness) is available, or for whom no standard therapy exists * Have the presence of measurable or nonmeasurable disease as defined by Modified Response Evaluation Criteria in Solid Tumors (mRECIST) * Have adequate hematologic, renal, and hepatic organ function * Have a performance status of less than or equal to 2 on the Eastern Cooperative Oncology Group (ECOG) scale * Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, or other investigational therapy for at least 14 days (42 days for mitomycin-C or nitrosoureas) prior to study enrollment and recovered from the acute effects of therapy * Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 3 months following the last dose of study drug * Females with child bearing potential must have had a negative serum pregnancy test less than or equal to 7 days prior to the first dose of study drug * Have an estimated life expectancy of ≥ 12 weeks * Are able to swallow capsules and/or tablets
Exclusion criteria
* Have received treatment within 14 days of the initial dose of study drug with a drug that has not received regulatory approval for any indication * Have a history of major surgical resection involving the stomach or small bowel, or have serious preexisting medical conditions (based on judgment of the investigator) * Have symptomatic central nervous system malignancy or metastasis (screening is not required) * Have a diagnosis of inflammatory bowel disease (Crohn's disease or ulcerative colitis) * Have an active hematologic malignancy other than lymphoma * Have known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb). Screening at baseline will not be required for enrollment * Concurrent administration of any immunosuppressive therapy * Females who are pregnant or lactating * Have received, within 7 days of the initial dose of study drug, either grapefruit juice or treatment with a drug that is a known inhibitor or inducer of Cytochrome P450 Enzyme 3A4 (CYP3A4). In addition, participants should not receive grapefruit juice or treatment with a CYP3A4 inhibitor or inducer during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | Baseline to study completion (Up to 41 months) | Data presented are the number of participants who experienced at least one treatment emergent adverse event (TEAE). A TEAE is defined as an event that first occurred or worsened after the administration of at least 1 dose of study drug, regardless of causality. A summary of serious AEs (SAEs) and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Dose for Phase 2 Studies | Baseline to study completion (Up to 41 months) | Recommended Phase 2 dose was determined by maximum tolerated dose (MTD), which was determined by Dose-limiting toxicity (DLT). For the purpose of this study, the MTD was defined as the highest dose level at which no more than 33% of participants experience a DLT during Cycle 1. |
| Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | Baseline to study completion (Up to 41 months) | Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria. CR was defined as the disappearance of all target and non-target lesions and normalization of tumor marker level in non-target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter (LD) of target lesions. PD was defined as having at least a 20% increase in the sum of the LD of target lesion and appearance of ≥1 new lesion and/or unequivocal progression of existing nontarget lesions. SD was defined as small changes that did not meet the above criteria taking as reference the smallest sum LD since treatment started. |
| PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1, Days 1 and 14: predose, 0.5, 1, 2, 3, 4, 6 and 8 h postdose | — |
| PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1, Days 1 and 14: predose, 0.5, 1, 2, 3, 4, 6 and 8 h postdose | — |
| Pharmacodynamics (PD): Number of Participants With Greater Than 50% Inhibition of p38 Mitogen-Activated Protein Kinase (MAPK) Activity on Day 1 | Cycle 1 Day 1: predose, 1, 2, 4, and 6 h postdose | The effect of LY2228820 on PD biomarker was measured as MAPK-activated protein kinase -2 (MAPKAP-K2) level which is regulated by p38 MAPK activity. Inhibition of p38 MAPK activity will result in lower levels of MAPKAPK-2. |
Countries
United States
Participant flow
Pre-assignment details
The study had 4 parts, dose-escalation (Part A), 2 dose-confirmation (Parts B and C), and a tumor-specific expansion for metastatic breast cancer (Part D). Completers for Parts A and D were defined as any participant who completed Cycle 2 or had a dose-limiting toxicology (DLT) in Cycle 1 and did not enter Cycle 2.
Participants by arm
| Arm | Count |
|---|---|
| Part A: 10 mg LY2228820 Capsules 10 milligrams (mg) LY2228820 was administered orally in capsule form every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 4 |
| Part A: 20 mg LY2228820 Capsules 20 mg LY2228820 was administered orally in capsule form every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 3 |
| Part A: 40 mg LY2228820 Capsules 40 mg LY2228820 was administered orally in capsule form every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 3 |
| Part A: 65 mg LY2228820 Capsules 65 mg LY2228820 was administered orally in capsule form every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 3 |
| Part A: 90 mg LY2228820 Capsules 90 mg LY2228820 was administered orally in capsule form every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 5 |
| Part A: 120 mg LY2228820 Capsules 120 mg LY2228820 was administered orally in capsule form every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 3 |
| Part A: 160 mg LY2228820 Capsules 160 mg LY2228820 was administered orally in capsule form every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 3 |
| Part A: 200 mg LY2228820 Capsules 200 mg LY2228820 was administered orally in capsule form every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 7 |
| Part A: 160 mg Bridge LY2228820 In Cycle 1, participants received a single dose of 160 mg LY2228820 comprising tablets (Day -14) or capsules (Day -7). In Cycle 2 and beyond, participants received capsules or tablets of 160 mg LY2228820 twice a day on Days 1 through 14 of a 28 day cycle. | 6 |
| Part A: 160 mg LY2228820 Tablets 160 mg LY2228820 was administered orally as tablets every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 3 |
| Part A: 200 mg LY2228820 Tablets 200 mg LY2228820 was administered orally as tablets every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 3 |
| Part A: 300 mg LY2228820 Tablets 300 mg LY2228820 was administered orally as tablets every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 3 |
| Part A: 420 mg LY2228820 Tablets 420 mg LY2228820 was administered orally as tablets every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 3 |
| Part A: 560 mg LY2228820 Tablets 560 mg LY2228820 was administered orally as tablets every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants could continue treatment if there was benefit and they did not meet the discontinuation criteria. | 5 |
| Part B: 420 mg LY2228820 Tablets 420 mg LY2228820 was administered orally as tablets every 12 hours on Days 1 through 14 of a 28-day cycle cycle for at least 2 cycles if no discontinuation criteria were met. Participants received 20 mg oral midazolam 2 days before the first dose of LY2228820 and again after the morning dose of study drug on Day 8 of Cycle 1. | 18 |
| Part C: 300 mg LY2228820 Tablets 300 mg LY2228820 was administered orally as tablets every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. | 8 |
| Part D: 200 mg LY2228820 Tablets 200 mg LY2228820 was administered orally as tablets every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants received 20 mg tamoxifen once a day. | 3 |
| Part D: 300 mg LY2228820 Tablets 300 mg LY2228820 was administered orally as tablets every 12 hours on Days 1 through 14 of a 28-day cycle for at least 2 cycles if no discontinuation criteria were met. Participants received 20 mg tamoxifen once a day. | 6 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | 3 | 1 | 0 | 0 | 0 | 1 | 6 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: 10 mg LY2228820 Capsules | Part A: 20 mg LY2228820 Capsules | Part A: 40 mg LY2228820 Capsules | Part A: 65 mg LY2228820 Capsules | Part A: 90 mg LY2228820 Capsules | Part A: 120 mg LY2228820 Capsules | Part A: 160 mg LY2228820 Capsules | Part A: 200 mg LY2228820 Capsules | Part A: 160 mg Bridge LY2228820 | Part A: 160 mg LY2228820 Tablets | Part A: 200 mg LY2228820 Tablets | Part A: 300 mg LY2228820 Tablets | Part A: 420 mg LY2228820 Tablets | Part A: 560 mg LY2228820 Tablets | Part B: 420 mg LY2228820 Tablets | Part C: 300 mg LY2228820 Tablets | Part D: 200 mg LY2228820 Tablets | Part D: 300 mg LY2228820 Tablets | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.5 years STANDARD_DEVIATION 11.82 | 60.9 years STANDARD_DEVIATION 2.09 | 63.8 years STANDARD_DEVIATION 2.63 | 61.3 years STANDARD_DEVIATION 9.66 | 64.5 years STANDARD_DEVIATION 11.13 | 66.0 years STANDARD_DEVIATION 13.58 | 61.5 years STANDARD_DEVIATION 1.98 | 64.9 years STANDARD_DEVIATION 11.9 | 61.5 years STANDARD_DEVIATION 10.8 | 64.4 years STANDARD_DEVIATION 4.54 | 49.6 years STANDARD_DEVIATION 16.79 | 51.1 years STANDARD_DEVIATION 15.5 | 56.2 years STANDARD_DEVIATION 17.6 | 70.6 years STANDARD_DEVIATION 8.33 | 61.1 years STANDARD_DEVIATION 10.42 | 58.3 years STANDARD_DEVIATION 8.49 | 56.4 years STANDARD_DEVIATION 1.15 | 62.5 years STANDARD_DEVIATION 4.64 | 61.3 years STANDARD_DEVIATION 10.13 |
| Race/Ethnicity, Customized African | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 6 Participants | 6 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 4 Participants | 18 Participants | 8 Participants | 3 Participants | 5 Participants | 82 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 7 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 5 Participants | 18 Participants | 8 Participants | 3 Participants | 6 Participants | 89 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants | 4 Participants | 1 Participants | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 12 Participants | 4 Participants | 3 Participants | 6 Participants | 52 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 3 Participants | 1 Participants | 4 Participants | 6 Participants | 4 Participants | 0 Participants | 0 Participants | 37 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 | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 3 | 0 / 3 | 1 / 5 | 0 / 3 | 0 / 3 | 0 / 7 | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 1 / 5 | 1 / 18 | 0 / 8 | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 3 / 4 | 3 / 3 | 3 / 3 | 3 / 3 | 2 / 5 | 3 / 3 | 2 / 3 | 6 / 7 | 6 / 6 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 5 / 5 | 18 / 18 | 7 / 8 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 2 / 4 | 0 / 3 | 0 / 3 | 1 / 3 | 3 / 5 | 0 / 3 | 2 / 3 | 2 / 7 | 2 / 6 | 3 / 3 | 1 / 3 | 0 / 3 | 0 / 3 | 3 / 5 | 7 / 18 | 4 / 8 | 0 / 3 | 0 / 6 |
Outcome results
Primary
Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests)
Data presented are the number of participants who experienced at least one treatment emergent adverse event (TEAE). A TEAE is defined as an event that first occurred or worsened after the administration of at least 1 dose of study drug, regardless of causality. A summary of serious AEs (SAEs) and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time frame: Baseline to study completion (Up to 41 months)
Population: Any participant who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: 10 mg LY2228820 Capsules | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 1 Participants |
| Part A: 20 mg LY2228820 Capsules | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 3 Participants |
| Part A: 40 mg LY2228820 Capsules | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 2 Participants |
| Part A: 65 mg LY2228820 Capsules | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 3 Participants |
| Part A: 90 mg LY2228820 Capsules | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 1 Participants |
| Part A: 120 mg LY2228820 Capsules | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 1 Participants |
| Part A: 160 mg LY2228820 Capsules | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 1 Participants |
| Part A: 200 mg LY2228820 Capsules | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 5 Participants |
| Part A: 160 mg LY2228820 Bridge | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 4 Participants |
| Part A: 160 mg LY2228820 Tablets | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 1 Participants |
| Part A: 200 mg LY2228820 Tablets | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 3 Participants |
| Part A: 300 mg LY2228820 Tablets | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 3 Participants |
| Part A: 420 mg LY2228820 Tablets | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 3 Participants |
| Part A: 560 mg LY2228820 Tablets | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 4 Participants |
| Part B: 420 mg LY2228820 Tablets | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 18 Participants |
| Part C: 300 mg LY2228820 Tablets | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 7 Participants |
| Part D: 200 mg LY2228820 Tablets | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 3 Participants |
| Part D: 300 mg LY2228820 Tablets | Number of Participants With Clinically Significant Effects (Physical Assessments and Safety Lab Tests) | 6 Participants |
Secondary
Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)]
Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria. CR was defined as the disappearance of all target and non-target lesions and normalization of tumor marker level in non-target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter (LD) of target lesions. PD was defined as having at least a 20% increase in the sum of the LD of target lesion and appearance of ≥1 new lesion and/or unequivocal progression of existing nontarget lesions. SD was defined as small changes that did not meet the above criteria taking as reference the smallest sum LD since treatment started.
Time frame: Baseline to study completion (Up to 41 months)
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: 10 mg LY2228820 Capsules | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 25.0 percentage of participants |
| Part A: 20 mg LY2228820 Capsules | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 33.3 percentage of participants |
| Part A: 40 mg LY2228820 Capsules | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 33.3 percentage of participants |
| Part A: 65 mg LY2228820 Capsules | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 33.3 percentage of participants |
| Part A: 90 mg LY2228820 Capsules | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 40.0 percentage of participants |
| Part A: 120 mg LY2228820 Capsules | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 33.3 percentage of participants |
| Part A: 160 mg LY2228820 Capsules | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 66.7 percentage of participants |
| Part A: 200 mg LY2228820 Capsules | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 28.6 percentage of participants |
| Part A: 160 mg LY2228820 Bridge | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 16.7 percentage of participants |
| Part A: 160 mg LY2228820 Tablets | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 33.3 percentage of participants |
| Part A: 200 mg LY2228820 Tablets | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 33.3 percentage of participants |
| Part A: 300 mg LY2228820 Tablets | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 0.0 percentage of participants |
| Part A: 420 mg LY2228820 Tablets | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 33.3 percentage of participants |
| Part A: 560 mg LY2228820 Tablets | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 0.0 percentage of participants |
| Part B: 420 mg LY2228820 Tablets | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 16.7 percentage of participants |
| Part C: 300 mg LY2228820 Tablets | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 0.0 percentage of participants |
| Part D: 200 mg LY2228820 Tablets | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 0.0 percentage of participants |
| Part D: 300 mg LY2228820 Tablets | Percentage of Participants With Best Overall Response [Complete Response (CR)+Partial Response (PR)+Stable Disease (SD)] | 16.7 percentage of participants |
Secondary
Pharmacodynamics (PD): Number of Participants With Greater Than 50% Inhibition of p38 Mitogen-Activated Protein Kinase (MAPK) Activity on Day 1
The effect of LY2228820 on PD biomarker was measured as MAPK-activated protein kinase -2 (MAPKAP-K2) level which is regulated by p38 MAPK activity. Inhibition of p38 MAPK activity will result in lower levels of MAPKAPK-2.
Time frame: Cycle 1 Day 1: predose, 1, 2, 4, and 6 h postdose
Population: All participants who received at least 1 dose of study drug and had evaluable PD data. At the dose confirmation of 300 mg, the pMAPKAP-K2 inhibition reached above 50% on Day 1 as maximum inhibition.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: 10 mg LY2228820 Capsules | Pharmacodynamics (PD): Number of Participants With Greater Than 50% Inhibition of p38 Mitogen-Activated Protein Kinase (MAPK) Activity on Day 1 | 14 Participants |
Secondary
PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820
Time frame: Cycle 1, Days 1 and 14: predose, 0.5, 1, 2, 3, 4, 6 and 8 h postdose
Population: All participants who received at least 1 dose of study drug and had evaluable PK data. Participants in 300 mg and 420 mg are combined to measure PK outcome; as dose, formulations and population are same.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: 10 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 55.6 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 36 |
| Part A: 10 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 151 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 83 |
| Part A: 20 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 257 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 26 |
| Part A: 20 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 372 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 28 |
| Part A: 40 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 375 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 79 |
| Part A: 40 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 1070 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 130 |
| Part A: 65 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 445 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 83 |
| Part A: 65 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 1300 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 13 |
| Part A: 90 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 827 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 61 |
| Part A: 90 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 707 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 45 |
| Part A: 120 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 1960 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 50 |
| Part A: 120 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 1310 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 33 |
| Part A: 160 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 2120 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 39 |
| Part A: 160 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 6000 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 29 |
| Part A: 200 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 2550 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 55 |
| Part A: 200 mg LY2228820 Capsules | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 6220 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 42 |
| Part A: 160 mg LY2228820 Bridge | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 1750 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 20 |
| Part A: 160 mg LY2228820 Bridge | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 2810 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 22 |
| Part A: 160 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | NA nanograms*hour/milliliter (ng*hr/mL) | — |
| Part A: 160 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 1720 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 70 |
| Part A: 200 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 3460 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 51 |
| Part A: 200 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 6620 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 85 |
| Part A: 300 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 10200 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 55 |
| Part A: 300 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 5780 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 57 |
| Part A: 420 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | NA nanograms*hour/milliliter (ng*hr/mL) | — |
| Part A: 420 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 8880 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 37 |
| Part A: 560 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 2360 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 35 |
| Part A: 560 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 3810 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 116 |
| Part B: 420 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 14 | 6910 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 55 |
| Part B: 420 mg LY2228820 Tablets | PK: Area Under the Concentration-Time Curve From Time Zero to 8 Hours (AUC0-8) of LY2228820 | Cycle 1 Day 1 | 4500 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 36 |
Secondary
PK: Maximum Plasma Concentration (Cmax) of LY2228820
Time frame: Cycle 1, Days 1 and 14: predose, 0.5, 1, 2, 3, 4, 6 and 8 h postdose
Population: All participants who received at least 1 dose of study treatment and had evaluable PK data. Participants in 300 mg and 420 mg are combined to measure PK outcome; as dose, formulations and population are same.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: 10 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 28.4 ng/mL | Geometric Coefficient of Variation 63 |
| Part A: 10 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 14.7 ng/mL | Geometric Coefficient of Variation 75 |
| Part A: 20 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 81.4 ng/mL | Geometric Coefficient of Variation 63 |
| Part A: 20 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 90.1 ng/mL | Geometric Coefficient of Variation 75 |
| Part A: 40 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 252 ng/mL | Geometric Coefficient of Variation 144 |
| Part A: 40 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 144 ng/mL | Geometric Coefficient of Variation 83 |
| Part A: 65 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 415 ng/mL | Geometric Coefficient of Variation 14 |
| Part A: 65 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 135 ng/mL | Geometric Coefficient of Variation 87 |
| Part A: 90 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 208 ng/mL | Geometric Coefficient of Variation 74 |
| Part A: 90 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 202 ng/mL | Geometric Coefficient of Variation 62 |
| Part A: 120 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 405 ng/mL | Geometric Coefficient of Variation 68 |
| Part A: 120 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 530 ng/mL | Geometric Coefficient of Variation 38 |
| Part A: 160 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 1930 ng/mL | Geometric Coefficient of Variation 64 |
| Part A: 160 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 606 ng/mL | Geometric Coefficient of Variation 53 |
| Part A: 200 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 1330 ng/mL | Geometric Coefficient of Variation 56 |
| Part A: 200 mg LY2228820 Capsules | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 673 ng/mL | Geometric Coefficient of Variation 55 |
| Part A: 160 mg LY2228820 Bridge | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 454 ng/mL | Geometric Coefficient of Variation 18 |
| Part A: 160 mg LY2228820 Bridge | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 574 ng/mL | Geometric Coefficient of Variation 11 |
| Part A: 160 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 963 ng/mL | Geometric Coefficient of Variation 82 |
| Part A: 160 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 636 ng/mL | Geometric Coefficient of Variation 78 |
| Part A: 200 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 1400 ng/mL | Geometric Coefficient of Variation 81 |
| Part A: 200 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 1020 ng/mL | Geometric Coefficient of Variation 58 |
| Part A: 300 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 2230 ng/mL | Geometric Coefficient of Variation 53 |
| Part A: 300 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 1700 ng/mL | Geometric Coefficient of Variation 71 |
| Part A: 420 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 2360 ng/mL | Geometric Coefficient of Variation 28 |
| Part A: 420 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | NA ng/mL | — |
| Part A: 560 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 718 ng/mL | Geometric Coefficient of Variation 27 |
| Part A: 560 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 1030 ng/mL | Geometric Coefficient of Variation 185 |
| Part B: 420 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 14 | 1700 ng/mL | Geometric Coefficient of Variation 52 |
| Part B: 420 mg LY2228820 Tablets | PK: Maximum Plasma Concentration (Cmax) of LY2228820 | Cycle 1 Day 1 | 1810 ng/mL | Geometric Coefficient of Variation 42 |
Secondary
Recommended Dose for Phase 2 Studies
Recommended Phase 2 dose was determined by maximum tolerated dose (MTD), which was determined by Dose-limiting toxicity (DLT). For the purpose of this study, the MTD was defined as the highest dose level at which no more than 33% of participants experience a DLT during Cycle 1.
Time frame: Baseline to study completion (Up to 41 months)
Population: Any participant who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: 10 mg LY2228820 Capsules | Recommended Dose for Phase 2 Studies | 300 milligrams (mg) |