Study of LY2181308 in Combination With Docetaxel Versus Docetaxel in Patients With Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the anti-tumor activity of LY2181308 in combination with docetaxel compared to docetaxel alone in participants with non-small cell lung cancer who were previously treated with first line chemotherapy.

Official Title
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A Randomized Phase 2 Study of LY2181308 in Combination With Docetaxel Versus Docetaxel in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Were Previously Treated With First Line Chemotherapy

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: LY2181308


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with non-small cell lung cancer with locally or advanced metastatic disease(Stage IIIB or IV at entry) not amenable to curative therapy and who have progressed after 1 line of chemotherapy Measureable disease as defined by response evaluation criteria in solid tumors (RECIST) version 1.1 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Must make available any existing tumor tissue from the primary biopsy Participants with prior radiation may be eligible if they meet certain criteria Adequate bone marrow reserve and organ functioning Women must have a negative pregnancy test and must comply with a highly reliable contraceptive method during and for 6 months after the treatment period and must not be breastfeeding Men must comply with a contraceptive regimen during and for 6 months after the treatment period Exclusion Criteria: Currently enrolled in or discontinued a clinical trial involving an investigational drug/device within the last 30 days. Participants may be permitted to enter treatment before the 30 day waiting period in special circumstances Pregnant or breastfeeding Serious concomitant systemic disorders that would compromise the safety of the participant or the participant's ability to complete the study Second primary malignancy that could affect compliance with the protocol or interpretation of the study results Known allergy or hypersensitivity to docetaxel, taxanes, LY2181308, oligonucleotides, or any component of the formulations Participants with documented central nervous system or brain metastasis at the time of study entry Pre-existing neuropathy equivalent to a common terminology criteria for adverse events(CTCAE)code greater than or equal to 2

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2181308 + Docetaxel<br>LY2181308: 750 milligrams (mg), intravenous (IV), on Day -2 and Day -1 of a 2 day lead-in period; on Day 1, Day 6, and Day 14 for Cycle 1 (1 cycle = 21 days); and once weekly for Days 1 through 21 for Cycles 2 through 6 (1 cycle = 21 days). After 6 cycles, it was possible to continue therapy until progression of disease, unacceptable toxicity, or another withdrawal criterion was met. Docetaxel: 75 milligrams/square meter (mg/m^2), intravenous (IV), on Day 1 of Cycle 1 (1 cycle = 21 days) and on Day 1 of Cycles 2 through 6 (1 cycle = 21 days). After 6 cycles, it was possible to continue therapy until progression of disease, unacceptable toxicity, or another withdrawal criterion was met. | Drug: Docetaxel<br>* Administered intravenously<br>Drug: LY2181308<br>* Administered intravenously<br>|
| Active Comparator: Docetaxel<br>Docetaxel: 75 milligrams/square meter (mg/m^2), intravenous (IV) on Day 1 of Cycles 1 through 6 (1 cycle = 21 days). After 6 cycles, it was possible to continue therapy until progression of disease, unacceptable toxicity, or another withdrawal criterion was met. | Drug: Docetaxel<br>* Administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Tumor Size to the End of Cycle 2 | The tumor size was defined as the sum of the longest diameters for the target lesions. The sum of lesion diameters was calculated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. The log ratio of tumor size at the end of Cycle 2 to tumor size at baseline was calculated for each participant. | Baseline, End of Cycle 2 (1 cycle = 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Characterization of Toxicities as Defined by Common Terminology Criteria for Adverse Events (CTCAE) Coding | Safety analyses included listings and/or summaries of the following: CTCAE for laboratory and non-laboratory parameters possibly related to study drug; CTCAE Grades 3 and 4 for laboratory and non-laboratory parameters possibly related to study drug (Grade 3 - severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care. Grade 4 - life-threatening consequences; urgent intervention indicated); Dose adjustments due to adverse events (AEs). | Randomization through long-term follow up (up to 21.6 months) | 
| Progression Free Survival (PFS) | Progression Free Survival (PFS) was defined as the time from date of first dose to the first observation of disease progression or death due to any cause. PFS time was censored at the date of the last assessment visit for participants who were still alive and who did not have documented progressive disease as of the data cut-off date. | Randomization to the first date of progressive disease or death from any cause (up to 12.88 months) | 
| Pharmacokinetics: Area Under the Concentration Curve From Zero to 4 Hours (AUC[0-4]) for LY2181309 and Docetaxel | Pharmacokinetics: Area Under the Concentration Curve From Zero to 4 hours (AUC[0-4]) for LY2181309 and Docetaxel | Docetaxel: Cycle(C)1 Day(D)1:0,1,1.25,1.75,3,4 hours(h);LY2181308 + Docetaxel: C1 D-1:3,4 h;D1:0,3,4 h | 
| Pharmacokinetics: Area Under the Drug Concentration-Time Curve From Zero to Infinity (AUC[0 ∞]) of LY2181309 and Docetaxel | Pharmacokinetics: Area Under the Drug Concentration-Time Curve From Zero to Infinity (AUC[0 ∞]) of LY2181309 and Docetaxel | Docetaxel: Cycle(C)1 Day(D)1:0,1,1.25,1.75,3,4,5,505,513,2521 hours(h);LY2181308 + Docetaxel: C1 D -1:3,4 h;D1:0,3,4,5,5.25,5.75,7,8,120,504,507,509,1008,1512,1515,1517,2016, 2520,2523,2525 h | 
| Overall Survival (OS) | Overall survival (OS) was the duration from enrollment to death from any cause. For participants who were alive, OS is censored at the date of last contact. | Randomization to date of death from any cause (up to 21.6 months) | 
| Time to Worsening of Symptoms as Defined by Lung Cancer Symptom Score (LCSS) Questionnaire | The worsening of symptoms was defined as a 15-millimeter (mm) increase in any 1 symptom on the LCSS. The LCSS is an assessment used to evaluate 6 major symptoms associated with lung malignancies and their effect on overall symptomatic distress, functional activities, and global quality of life. LCSS consists of 2 scales: 1 completed by the participant and 1 completed by the health care professional (which is the average symptom burden index [ASBI]). Participant-reported outcomes are assessed using 9 visual analog scales (100-mm horizontal line). Participants indicate intensity of response to the items in question (0 = lowest rating, 100 = highest rating). The LCSS total score ranges from 0 (lowest rating) to 100 (highest rating). The LCSS total score was defined as the mean over all 9 items. Time to worsening of symptoms was censored at the date of the last assessment visit for participants who did not experience any worsening of symptoms as of the data cut-off date. | Baseline to the worsening of symptoms (up to 4.6 months) | 
| Time to Objective Tumor Response of Partial Response (PR) or Complete Response (CR) | Time to objective tumor response was defined as the time from the date of randomization to the first date of documented objective tumor response. Time to objective tumor response was censored at the date of the last assessment visit for participants who had not had documented response as of the data cut-off date. Complete response (CR) was defined as the disappearance of all target lesions; partial response (PR) was defined as at least a 30% decrease in sum of the longest diameter of target lesions. | Randomization to the date of first response (up to 12.1 months) | 
| Time to Documented Disease Progression | Time to documented disease progression was defined as the time from the date of randomization to the first date of documented progression. Progressive disease (PD) was defined as at least a 20% increase in sum of longest diameter of target lesions. Time to documented disease progression was censored at the date of the last assessment visit for participants who had not had documented progressive disease as of the data cut-off date. | Randomization to the first date of progressive disease (up to 12.9 months) | 
| Percent of Participants Having a Partial Response (PR) or a Complete Response (CR) | Complete response (CR) was defined as the disappearance of all target lesions; partial response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions. | Randomization to the first date of progressive disease (up to 12.1 months) | 
| Duration of Response | Duration of response was measured from the time measurement criteria were met for complete response (CR) or partial response (PR) (whichever was first recorded) until the first date of documented progressive disease (PD) or death. Complete response (CR) was defined as the disappearance of all target lesions; PR was defined as at least a 30% decrease in sum of longest diameter of target lesions; PD was defined as at least a 20% increase in sum of longest diameter of target lesions. Duration of response was censored at the date of the last assessment or follow-up visit for responders who were still alive and had not progressed. | Time of response to progressive disease (PD) (approximately 8.7 months) | 
| Lung Cancer Symptom Scale (LCSS) Average Symptom Burden Index (ASBI) on Cycle 2 Day 1 | The worsening of symptoms was defined as a 15-millimeter (mm) increase in any 1 symptom on the Lung Cancer Symptom Scale (LCSS). The LCSS is an assessment used to evaluate 6 major symptoms associated with lung malignancies and their effect on 3 overall symptomatic items: distress, functional activities and global quality of life. LCSS consists of 2 scales: 1 completed by the participant and 1 completed by the health care professional (which is the average symptom burden index [ASBI]). Participant-reported outcomes are assessed using 9 visual analog scales (100-mm horizontal line). Participants indicate intensity of response to the items in question (0 = lowest rating, 100 = highest rating). The LCSS total score ranges from 0 (lowest rating) to 100 (highest rating) and was defined as the mean over all 9 items. ASBI was calculated as the mean of six symptom-specific questions from the LCSS, with scores range from 0 (for best outcome) to 100 (for worst outcome). | Cycle 2 Day 1 | 
| Lung Cancer Symptom Scale (LCSS) Average Total Score at Cycle 2 Day 1 | The worsening of symptoms was defined as a 15-millimeter (mm) increase in any 1 symptom on the Lung Cancer Symptom Scale (LCSS). The LCSS is an assessment used to evaluate 6 major symptoms associated with lung malignancies and their effect on 3 overall symptomatic items: distress, functional activities and global quality of life. LCSS consists of 2 scales: 1 completed by the participant and 1 completed by the health care professional (which is the average symptom burden index [ASBI]). Participant-reported outcomes are assessed using 9 visual analog scales (100-mm horizontal line). Participants indicate intensity of response to the items in question (0 = lowest rating, 100 = highest rating). The LCSS total score ranges from 0 (lowest rating) to 100 (highest rating) and was defined as the mean over all 9 items. | Cycle 2 Day 1 |