A Study of LY2228820 in Participants With Advanced Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1 Study of an Oral p38 MAPK Inhibitor in Patients With Advanced Cancer

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: LY2228820
* Drug: Midazolam
* Drug: Tamoxifen


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2228820<br>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). Part A: Participants received escalating doses of 10, 20, 40, 65, 90, 120, 160, 200, 300, 420 and 560 milligrams (mg) of LY2228820 every 12 hours on Days 1 through 14 of a 28-day cycle. Part B: Participants received 420 mg of LY2228820 every 12 hours Days 1 through 14 of a 28-day cycle. Participants received midazolam orally 2 days before the first dose and again after the morning dose of study drug on Day 8 during the first cycle of treatment. Part C: Participants received 300 mg of LY2228820 every 12 hours Days 1 through 14 of a 28-day cycle. Part D: Participants received 200 mg and 300 mg of LY2228820 in combination with tamoxifen. | Drug: LY2228820<br>* Administered orally<br>* Other names: p38 MAP kinase;Drug: Midazolam<br> <br> Drug: Tamoxifen<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to study completion (Up to 41 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to study completion (Up to 41 months) | 
| 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. | Baseline to study completion (Up to 41 months) | 
| 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 | 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. | Cycle 1 Day 1: predose, 1, 2, 4, and 6 h postdose |