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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 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.

LY2334737

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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.

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

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

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.

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.

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.

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-∞).

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).

Cmax for LY2334737 and its metabolites 2'2'-difluorodeoxycytidine (dFdC) and difluorodeoxyuridine (dFdU).

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).

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.

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

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.

Cmin for LY2334737 and its metabolite 2'2'-difluorodeoxycytidine (dFdC).

Eli Lilly and Company

Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.

40 milligrams (mg) LY2334737 administered orally every other day for 21 days followed by 7 days without study drug (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

40 mg LY - Arm A Dose Escalation

50 mg LY2334737 administered orally every other day for 21 days followed by 7 days without study drug (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

50 mg LY - Arm A Dose Escalation

60 mg LY2334737 administered orally every other day for 21 days followed by 7 days without study drug (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

60 mg LY - Arm A Dose Escalation

70 mg LY2334737 administered orally every other day for 21 days followed by 7 days without study drug (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

70 mg LY - Arm A Dose Escalation

80 mg LY2334737 administered orally every other day for 21 days followed by 7 days without study drug (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

80 mg LY - Arm A Dose Escalation

90 mg LY2334737 administered orally every other day for 21 days followed by 7 days without study drug (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

90 mg LY - Arm A Dose Escalation

100 mg LY2334737 administered orally every other day for 21 days followed by 7 days without study drug (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

100 mg LY - Arm A Dose Escalation

40 mg LY2334737 administered orally every day for 7 days followed by 7 days without study drug then repeated (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

40 mg LY - Arm B Dose Escalation

50 mg LY2334737 administered orally every day for 7 days followed by 7 days without study drug then repeated (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

50 mg LY - Arm B Dose Escalation

60 mg LY2334737 administered orally every day for 7 days followed by 7 days without study drug then repeated (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

60 mg LY - Arm B Dose Escalation

70 mg LY2334737 administered orally every day for 7 days followed by 7 days without study drug then repeated (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

70 mg LY - Arm B Dose Escalation

80 mg LY2334737 administered orally every day for 7 days followed by 7 days without study drug then repeated (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

80 mg LY - Arm B Dose Escalation

90 mg LY2334737 administered orally every day for 7 days followed by 7 days without study drug then repeated (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

90 mg LY - Arm B Dose Escalation

90 mg LY - Arm A Dose Confirmation

40 milligrams (mg) LY2334737 (LY) administered orally every other day for 21 days followed by 7 days without study drug (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

70 mg LY2334737 administered orally every other day for 21 days followed by 7 days without study drug (28 -ay treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

90 mg LY2334737 - Arm A Dose Confirmation

Total

Age, Continuous

Sex: Female, Male

Race

ECOG Performance Status: 0=asymptomatic, fully active, can carry on all predisease performance without restrictions; 1=symptomatic, fully ambulatory, but restricted in physically strenuous activity, able to perform light/sedentary tasks; 2=symptomatic, ambulatory, capable of all self-care but unable to carry out work activities, up and about more than 50% of waking hours and in bed less than 50% of day.

Eastern Cooperative Oncology Group (ECOG)

Stage III -the cancer has spread to nearby tissue or spread to far away lymph nodes. Stage IV -the cancer has spread to other organs of the body such as the other lung, brain or liver.

Disease Stage

Country of Enrollment

Chief Medical Officer

LY2334737 was administered as 2 Arms A and B. Participants in treatment Arm A were administered LY2334737 orally in escalating doses of 40 to 100 milligrams (mg) of LY2334737 every other day for 21 days followed by 7 days without study drug. Participants in treatment Arm B were administered LY2334737 orally in escalating doses of 40 to 90 mg every day for 7 days followed by 7 days without study drug and then repeated. Both treatment cycles were 28 days.

All participants who received at least 1 dose of study drug during dose escalation and dose confirmation treatment arms.

Recommended Dose for Phase 2 Studies

C1 D1 AUC0-Ƭ

C1 D1 AUC0-∞

C1 D21, AUC0-Ƭ

90 mg LY - Arm A Dose Escalation and Dose Confirmation

All participants who received at least 1 dose of study drug and had AUC0-Ƭ and AUC0-∞ values.

Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for LY2334737

C1 D1 AUC 0-Ƭ

C1 D1 AUC 0-∞

C1 D21 AUC 0-Ƭ

All participants who received at least 1 dose of study drug and had AUC 0-Ƭ and AUC 0-∞ values.

Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for 2'2'-Difluorodeoxycytidine (dFdC)

C1 D1

C1 D 21

40 milligram (mg) LY2334737 (LY) administered orally every other day for 21 days followed by 7 days without study drug (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

All participants who received at least 1 dose of study drug and had AUC0-24 dFdU results.

Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for Difluorodeoxyuridine (dFdU)

C1 D1-LY2334737

C1 D21-LY2334737

C1 D1-dFdC

C1 D21-dFdC

C1 D1-dFdU

C1 D21-dFdU

All participants who received at least 1 dose of study drug and had Cmax values.

Pharmacokinetics: Maximum Plasma Concentration (Cmax)

All participants who received at least 1 dose of study drug.

Number of Participants With Best Overall Response (BOR)

Zero participants analyzed. No data collected for PFS.

Progression-Free Survival (PFS)

Percentage of Participants With Changes in QT Interval (>30 Milliseconds) From Baseline

Number of Participants With Dose-Limiting Toxicity (DLT)

90 mg LY2334737 administered orally every day for 7 days followed by 7 days without study drug (28-day treatment cycle). Participants could have received additional treatment cycles until discontinuation criterion was met.

All participants who received at least 1 dose of study drug with R-R interval data at all time points.

Spots Global Cancer Trial Database for A Study of LY2334737 in Participants With Cancer That is Advanced and/or Has Spread

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