A Study of LY2228820 in Participants With Advanced Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Cancer
• Intervention / Treatment: Drug: Tamoxifen; Drug: Midazolam; Drug: LY2228820

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Texas
    • San Antonio, Texas, United States
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: LY2228820; 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: Tamoxifen; Drug: Midazolam; Drug: LY2228820; Administered orally; Other Names: p38 MAP kinase

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2008
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): December 14, 2013

Study Registration Dates

• First Submitted: July 12, 2011
• First Submitted That Met QC Criteria: July 12, 2011
• First Posted (Estimate): July 14, 2011

Study Record Updates

• Last Update Posted (Actual): March 24, 2020
• Last Update Submitted That Met QC Criteria: March 8, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Midazolam; Tamoxifen
• Other Study ID Numbers: 12284; I1D-MC-JIAD (Other Identifier: Eli Lilly and Company)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO