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

Phase 1 Dose Escalation Study of LY2334737 Using 2 Dosing Regimens in Patients With Advanced and/or Metastatic Solid Tumors

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.

Study Overview

• Status: Completed
• Conditions: Solid Tumor; Malignant Solid Tumor; Metastatic Tumor
• Intervention / Treatment: Drug: LY2334737

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 73
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Clichy, France, 92118
    • 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.
• Germany
  • Berlin, Germany, 13353
    • 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.
  • Nürnberg, Germany, 90419
    • 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.
• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • 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:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LY2334737 - Arm A; 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.	Drug: LY2334737; Administered orally
Experimental: LY2334737 - Arm B; 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.	Drug: LY2334737; Administered orally

What is the study measuring?

Primary 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). 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.	Baseline up to 28 days postdose in Cycle 1 (28-day cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for LY2334737	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.	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
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for 2'2'-Difluorodeoxycytidine (dFdC)	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-∞).	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
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for Difluorodeoxyuridine (dFdU)	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).	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
Pharmacokinetics: Maximum Plasma Concentration (Cmax)	Cmax for LY2334737 and its metabolites 2'2'-difluorodeoxycytidine (dFdC) and 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
Number of Participants With Best Overall Response (BOR)	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).	Baseline to measured disease progression up to 33 weeks
Progression-Free Survival (PFS)	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.	Baseline to measured disease progression or death up to 33 weeks
Percentage of Participants With Changes in QT Interval (>30 Milliseconds) From Baseline	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	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)
Percentage of Participants With Changes in R-R Interval From Baseline	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.	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
Pharmacokinetics: Minimum Plasma Concentration (Cmin)	Cmin for LY2334737 and its metabolite 2'2'-difluorodeoxycytidine (dFdC).	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-Limiting Toxicity (DLT)	DLT was defined as an adverse event (AE) during Cycle 1 that was likely related to the 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 the last dose of LY2334737 to values allowing Cycle 2 to start; other significant drug-related toxicity deemed by the investigator to be dose limiting or that caused the participant to withdraw from the study.	Cycle 1 (28-day cycle)

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: July 20, 2012
• First Submitted That Met QC Criteria: July 20, 2012
• First Posted (Estimate): July 24, 2012

Study Record Updates

• Last Update Posted (Actual): June 17, 2019
• Last Update Submitted That Met QC Criteria: March 11, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplastic Processes; Neoplasms; Neoplasm Metastasis
• Other Study ID Numbers: 11967; 2008-000807-28 (EudraCT Number); I1C-MC-JLBE (Other Identifier: Eli Lilly & Company)