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

Study Overview
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Brief Summary
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This study is a multinational study to compare enzastaurin versus placebo in the treatment of patients with brain metastases of lung cancer. Approximately 108 patients will be randomly assigned to receive either enzastaurin or placebo after having completed whole brain radiotherapy.

Official Title
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A Double-blind, Randomized, Placebo-controlled Multicentre Phase II Study of Maintenance Enzastaurin Following Whole Brain Radiation Therapy in the Treatment of Brain Metastases From Lung Cancer

Conditions
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Non Small Cell Lung Cancer, Small Cell Lung Cancer

Intervention / Treatment
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* Drug: enzastaurin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Having radiologically proven brain metastases of lung cancer Having received whole brain radiotherapy with either 30 grays in 2 weeks or 20 grays in one week. Treatment with enzastaurin must start within 14 days after the last fraction of the whole brain radiotherapy No other previous radiotherapy to the brain except for radiosurgery at one occasion Adequate organ function as measured by appropriate laboratory tests. Age 18 years or older. Exclusion Criteria: Inability to swallow tablets or show conditions which could interfere with oral medication intake (e.g. vomiting, partial bowel obstruction). Inability to discontinue use of certain anti-epileptic drugs such as, carbamazepine, phenobarbital or phenytoin. Concurrent administration of warfarin Hemophilia Having had any systemic anti-cancer treatment within the last 2 weeks prior to enrolment.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: enzastaurin<br>* 1125 mg loading dose then 500 mg, oral, daily, until disease progression<br>* Other names: LY317615;|
| Placebo Comparator: B<br> | Drug: placebo<br>* oral, daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression of Brain Metastases | 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. | Baseline to measured progressive disease (up to 21.2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Objective Progression of Brain Metastases | 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. | Baseline to measured progressive disease (up to 21.2 months) | 
| Overall Progression-free Survival (Including Both Progression of Brain and Extracranial Tumor Lesion) | 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. | Baseline to measured progressive disease (up to 14.4 months) | 
| Overall Survival | 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. | Baseline to date of death from any cause (up to 27.2 months) | 
| Overall Response (OR) to Treatment of Extra-cranial Tumor Lesions by Percentage of 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. | Baseline to measured progressive disease (up to 27.2 months) | 
| Best Overall Tumor Response on Brain Metastases by Percentage of Participants | 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. | Baseline to measured progressive disease (up to 21.2 months) | 
| Health-related Quality of Life (HRQoL) EORTC QLQ-C30 Physical Functioning | 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). | Baseline to 30 days after discontinuation (up to 17.6 months) | 
| HRQoL Questionnaire - EORTC QLQ-C30 Fatigue | 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). | Baseline to 30 days after discontinuation (up to 17.6 months) | 
| HRQoL Questionnaire - EORTC QLQ-C30 Nausea/Vomiting | 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). | Baseline to 30 days after discontinuation (up to 17.6 months) | 
| HRQoL Questionnaire - EORTC QLQ-C30 Diarrhea | 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). | Baseline to 30 days after discontinuation (up to 17.6 months) | 
| HRQoL Questionnaire - QLQ-BN20 Headache | 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. | Baseline to 30 days after discontinuation (up to 17.6 months) | 
| Number of Participants With Adverse Events | A summary of serious adverse events (SAEs) and all other non-serious adverse events is located in the Reported Adverse Event Module. | every 6 weeks (up to 27.2 months) |