A Study of LY2334737 in Participants With Cancer That is Advanced and/or Has Spread

Phase 1

Completed

Conditions: Metastatic Tumor
Malignant Solid Tumor
Solid Tumor

Interventions: Drug: LY2334737

Registration Number: NCT01648764

Lead Sponsor: Eli Lilly and Company

Brief Summary: The purpose of this study is to evaluate two different dosing regimens of LY2334737 in participants with cancer that is advanced and/or has spread to other parts of the body. Information about side effects will be collected.

Detailed Description: This study will consist of a Dose Escalation Phase (Arms A and B) followed by a Dose Confirmation Phase.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 73

Inclusion Criteria

Diagnosis of advanced and/or metastatic cancer (including lymphoma) for which no treatment of higher priority exists
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Estimated life expectancy of more than 12 weeks
Have discontinued all previous therapies for cancer for at least 30 days (6 weeks for mitomycin-C or nitrosoureas) and recovered from acute effects of therapy
Have discontinued radiotherapy more than one week before enrolling in the study and have recovered from the acute effects of therapy
Have adequate organ function
Follow your doctor's directions and live close enough to the study site so you can continue to go to the clinic for follow-up
Are willing and able to swallow capsules and follow study procedures
Have given written informed consent prior to any study-specific procedures
Males and females with reproductive potential should use medically approved contraceptive precautions during the study and for 6 months following the last dose of study drug
Females with child-bearing potential must have had a negative urine or serum pregnancy test 7 days prior to the first dose of study drug

Exclusion Criteria

Have gastrointestinal diseases or prior surgery that may interfere with the absorption of medication taken by mouth
Females who are pregnant or lactating
Symptomatic central nervous system malignancy or metastasis
Known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb)
Liver cirrhosis or chronic hepatitis
Acute or chronic leukemia
Are currently receiving treatment with valproic acid (VPA) and its derivatives, or if you have a history of intolerance to VPA
Known hypersensitivity to gemcitabine

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
LY2334737 - Arm A	LY2334737	LY2334737 administered orally at escalating doses \[40 milligrams (mg) - 200 mg\] every other day for 21 days followed by 7 days without study drug (28 day treatment cycle). Participants may receive additional treatment cycles until discontinuation criterion is met.
LY2334737 - Arm B	LY2334737	LY2334737 administered orally at escalating doses (40 mg - 200 mg) every day for 7 days followed by 7 days without study drug then repeated (28 day treatment cycle). Participants may receive additional treatment cycles until discontinuation criterion is met.

Primary Outcome Measures

Name	Time	Method
Recommended Dose for Phase 2 Studies	Baseline up to 28 days postdose in Cycle 1 (28-day cycle)	Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). The MTD was the highest dose level at which \<2 out of 6 participants experienced a dose-limiting toxicity (DLT) in Cycle 1. DLT was an adverse event (AE) during Cycle 1 that was likely related to LY2334737 and fulfilled any of the following criteria: Common Terminology Criteria for Adverse Events (CTCAE) ≥Grade 3 nonhematological (except nausea/vomiting controlled with treatment); Grade 3 neutropenia with fever or any Grade 4 neutropenia with or without fever; Grade 3 thrombocytopenia with ≥Grade 2 bleeding or Grade 4 thrombocytopenia with or without bleeding; A recovery period longer than 14 days from last dose of LY2334737 to values allowing Cycle 2 to start; Other significant drug-related toxicity deemed by investigator to be dose limiting or that caused the participant to withdraw from the study. Pharmacokinetics and pharmacodynamics (PK/PD) were also taken into consideration for Phase 2 recommended dose.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Changes in QT Interval (>30 Milliseconds) From Baseline	Day -1: 24.5 hours, 22 hours and 17 hours predose; Cycle 1 Days 1 and 21, 0.5 hours predose, 2 hours, 7 hours and 24 hours postdose (28-day cycles)	Fridericia-corrected QT (QTcF) interval corrected for heart rate was assessed using triplicate 12-lead electrocardiograms (ECGs). Change in QT interval from baseline was calculated using a time matched approach, that is change from baseline was calculated by subtracting the respective reading taken at the same nominal time on Day-1 from the reading taken on Days 1 and 21; change from baseline was calculated by subtracting the last non-missing ECG assessment on or prior to Day 1, 0.5 hours prior to dose from assessment on Day 2 and Day 22. The outlying QTcF intervals were defined using the criteria: change from baseline in mean QTcF interval \>30 milliseconds
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for LY2334737	Cycle 1 Day 1 (C1 D1): 0.5, 1.5, 2, 3.5, 7 24 hours postdose; Cycle 1 Day 21 (C1 D21): predose, 0.5, 2, 3 to 4, 7, 24 hours postdose of 28-day cycle	AUC over the dosing interval (AUC0-Ƭ) of LY2334737 for Arm A (single dose) is 0 to 48 hours postdose. AUC0-Ƭ of LY2334737 for Arm B (multiple doses) is 0 to 24 hours postdose and AUC time 0 to infinity (AUC0-∞) for LY2334737.
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for 2'2'-Difluorodeoxycytidine (dFdC)	Cycle 1 Day 1 (C1 D1): 0.5, 1.5, 2, 3.5, 7 24 hours post dose; Cycle 1 Day 21 (C1 D21): predose, 0.5, 2, 3 to 4, 7, 24 hours post dose of 28-day cycle	AUC over the dosing interval (AUC0-Ƭ) of dFdC (a metabolite of LY2334737) for Arm A (following a single dose of LY2334737) AUC0-Ƭ is 0-48 hours postdose, Arm B (following multiple doses of LY2334737) AUC 0-Ƭ is 0-24 hours postdose and AUC from time 0 to infinity (AUC0-∞).
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for Difluorodeoxyuridine (dFdU)	Cycle 1 Day 1 (C1 D1): 0.5, 1.5, 2, 3.5, 7 24 hours postdose; Cycle 1 Day 21 (C1 D21): predose, 0.5, 2, 3 to 4, 7, 24 hours postdose of 28-day cycle	Daily AUC from time 0 to 24 hours (AUC 0-24) of dFdU (a metabolite of LY2334737) for Arm A (single dose of LY2334737) and Arm B (multiple doses of LY2334737).
Pharmacokinetics: Minimum Plasma Concentration (Cmin)	Cycle 1 Day 1 (C1 D1): 0.5, 1.5, 2, 3.5, 7, 24 hours postdose; Cycle 1 Day 21 (C1 D21): predose, 0.5, 2, 3 to 4, 7, 24 hours postdose of 28-day cycle	Cmin for LY2334737 and its metabolite 2'2'-difluorodeoxycytidine (dFdC).
Pharmacokinetics: Maximum Plasma Concentration (Cmax)	Cycle 1 Day 1 (C1 D1): 0.5, 1.5, 2, 3.5, 7 24 hours postdose; Cycle 1 Day 21 (C1 D21): predose, 0.5, 2, 3 to 4, 7, 24 hours postdose of 28-day cycle	Cmax for LY2334737 and its metabolites 2'2'-difluorodeoxycytidine (dFdC) and difluorodeoxyuridine (dFdU).
Number of Participants With Best Overall Response (BOR)	Baseline to measured disease progression up to 33 weeks	Response defined using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria. Complete Response defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Partial Response defined as ≥30% decrease in sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD) defined as ≥20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions, or appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Stable Disease was defined as small changes that did not meet above criteria and unknown defined as response status was not known. The BOR was the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).
Progression-Free Survival (PFS)	Baseline to measured disease progression or death up to 33 weeks	PFS was defined as the time from date of first dose to the first observation of disease progression or death due to any cause. Due to the different tumor types, schedules and doses, the PFS was not analyzed.
Percentage of Participants With Changes in R-R Interval From Baseline	Day -1: 24.5 hours, 22 hours and 17 hours predose; Cycle 1 Days 1 and 21: 0.5 hours predose, 2 hours, 7 hours and 24 hours postdose	Changes in R-R interval from baseline was calculated using a time matched approach, that is change from baseline was calculated by subtracting the respective reading taken at the same nominal time on Day -1 from the reading taken on Days 1 and 21; change from baseline was calculated by subtracting the last non-missing electrocardiogram (ECG) assessment on or prior to Day 1 and 0.5 hours prior to dose for Day 2 and Day 22. Percentage of participants with changes in R-R interval from baseline was calculated as the number of participants with a change not equal to 0 across all time points divided by the number of treated participants multiplied by 100.

Trial Locations

Locations (1): 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.
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Nürnberg, Germany