Study of Enzastaurin Versus Placebo in the Treatment of Patients With Brain Metastases of Lung Cancer, After Whole Brain Radiation Therapy

Time to progression (TTP) of brain metastases is the time from randomization to first observation of brain metastases progression. Response Evaluation Criteria In Solid Tumors (RECIST; Version 1.0), using magnetic resonance imaging (MRI), until observation of objective progression, or clinically as the date of increased steroids dose (barring radiological confirmation), was used to assess progressive disease (PD) of brain metastases. TTP was right-censored with the date of last contact if the participant died without MRI-documented PD or symptomatic deterioration or was lost to follow-up or received post therapy (Radio, Systemic, Surgery) before documented PD of the brain metastases.

Time frame: Baseline to measured progressive disease (up to 21.2 months)

Population: Time to progressive disease (TTP) was analyzed on all randomized patients. Participants censored: Enzastaurin = 35 and Placebo = 32.

Best overall tumor response on brain metastases (BOR) according to RECIST V1.0 response criteria. For complete response (CR) or partial response (PR), BOR was to be confirmed. Response criteria were * CR: Disappearance of all tumor lesions. * PR: Either a) at least a 30% decrease in sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LDs or b) complete disappearance of target lesions, with persistence (but not worsening) of one or more nontarget lesions. In either case, no new lesions may have appeared. * Stable Disease (SD) is defined as disease that does not meet the criteria for CR, PR, or progressive disease (PD), and has been evaluated at least 1 time, at least 6 weeks after baseline assessment.

Time frame: Baseline to measured progressive disease (up to 21.2 months)

Population: Best overall tumor response (BOR) on brain metastases and 95% confidence intervals were evaluated on all randomized patients who qualified by the following criteria:~* Presence of measurable disease in brain~* Treatment with at least one dose of study drug

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). Physical functioning was measured by items 1 to 5. Their sum score was linearly transformed to the range 0 - 100 as recommended by the EORTC (higher score is better).

Time frame: Baseline to 30 days after discontinuation (up to 17.6 months)

Population: EORTC QLQ-C30 scores from all randomized patients who filled in at least baseline and one post baseline questionnaire were evaluated and summarized by means of descriptive statistics.

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Diarrhea Scale is scored between 0 and 100 (lower score is better).

Time frame: Baseline to 30 days after discontinuation (up to 17.6 months)

Population: EORTC QLQ-C30 scores from all randomized patients who filled in at least baseline and one post baseline questionnaire were evaluated and summarized by means of descriptive statistics. Median differences between treatment groups in change from baseline to every 4 weeks and the inter-quartile range are reported.

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100 (lower score is better).

Time frame: Baseline to 30 days after discontinuation (up to 17.6 months)

Population: EORTC QLQ-C30 scores from all randomized patients who filled in at least baseline and one post baseline questionnaire were evaluated and summarized by means of descriptive statistics.

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Nausea/Vomiting Scale is scored between 0 and 100 (lower score is better).

Time frame: Baseline to 30 days after discontinuation (up to 17.6 months)

Population: EORTC QLQ-C30 scores from all randomized patients who filled in at least baseline and one post baseline questionnaire were evaluated and summarized by means of descriptive statistics. Median differences between treatment groups in change from baseline to every 4 weeks and the inter-quartile range are reported.

Health-related quality of life is measured using an EORTC quality of life questionnaire designed specifically for participants with brain tumors (BN-20). Questionnaires may be completed by the participant or with the assistance of the examiner at baseline prior to initiation of study therapy, and then approximately every 8 weeks while on study treatment (prior to discussing treatment response at each visit, whenever possible). All single questions are answered using a categorical scale (e.g., 1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much) and linearly transformed to 0 to 100 scales with 1) higher scores for a functional scale representing higher levels of functioning, 2) higher scores for the global health status/quality of life representing higher levels of global health status/quality of life, 3) and higher scores for a symptom scale representing higher level of symptoms. For Headache lower score is better.

Time frame: Baseline to 30 days after discontinuation (up to 17.6 months)

Population: QLQ-BN20 scores were evaluated in all randomized patients who filled in at least baseline and one post baseline questionnaire. Scores were summarized by means of descriptive statistics. Median differences between treatment groups in change from baseline to every 4 weeks and the inter-quartile range are reported.

A summary of serious adverse events (SAEs) and all other non-serious adverse events is located in the Reported Adverse Event Module.

Time frame: every 6 weeks (up to 27.2 months)

Population: Safety population of all participants who received at least one dose of study drug. All serious adverse events are reported. Other adverse events are reported with a threshold that they occurred in greater than 5% of patients.

Overall progression-free survival (PFS) is defined as the time from the date of study enrollment to the first date of progressive disease or death from any cause. For participants not known to have died as of the data cut-off date and who did not have progressive disease, PFS was censored at last contact date. For those who received subsequent systemic anticancer therapy (after discontinuation from study therapy) prior to objectively determined progression of brain metastases, PFS was censored at the start of radiotherapy for extracranial lesions or the date of starting chemotherapy.

Time frame: Baseline to measured progressive disease (up to 14.4 months)

Population: Progression-free survival was analyzed on all randomized participants.

Overall Response (OR) was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST v1.0). OR on extra-cranial tumors was assessed by response sequences. Complete response (CR) or partial response (PR), was confirmed by second assessment performed \>= 28 days after first response. Two CRs before progression required for best response of CR. Two PRs or better not qualifying for a CR, for best response of PR. * CR: Disappearance of all tumor lesions. * PR: 30% decrease from baseline in sum of the longest diameter of target lesions or complete disappearance of target lesions, without worsening of one or more nontarget lesions. In either case, no new lesions may have appeared. * Stable Disease (SD) is defined as disease that does not meet the criteria for CR, PR, or progressive disease (PD), and has been evaluated at least 1 time, at least 6 weeks after baseline assessment.

Time frame: Baseline to measured progressive disease (up to 27.2 months)

Population: Rate and 95% confidence intervals of overall response to treatment of extra-cranial tumor lesions were evaluated on all randomized participants who qualified for tumor response analysis by the following criteria:~* Presence of measurable disease in at least one site other than brain~* Treatment with at least one dose of study drug.

Overall survival (OS) was defined as the time from randomization to the date of death from any cause. For participants not known to have died as of the data cut-off date, OS was censored at the last contact date.

Time frame: Baseline to date of death from any cause (up to 27.2 months)

Population: OS was analyzed on all randomized patients.

Time to objective progression (TTOP) of brain metastases is the time from randomization to the first observation of objective progression of brain metastases assessed by MRI. TTOP was right-censored with the date of the last objective progression-free disease assessment if the participant died or did not have objective PD as of the cut-off date. For participants receiving post-discontinuation therapy prior to PD of brain metastases, TTOP was censored at the last assessment before post-discontinuation therapy. Kaplan-Meier estimated the median survival times and confidence intervals.

Time frame: Baseline to measured progressive disease (up to 21.2 months)

Population: TTOP was analyzed on randomized patients.