A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer

Study Overview
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Brief Summary
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The MILO Study (MEK Inhibitor in Low-grade Serous Ovarian Cancer) is a Phase 3 study during which patients with recurrent or persistent low-grade serous (LGS) carcinomas of the ovary, fallopian tube or primary peritoneum will receive either investigational study drug MEK162 or a chemotherapy chosen by the physician (liposomal doxorubicin, paclitaxel or topotecan). Patients will be followed to compare the effectiveness of the study drug to that of the selected chemotherapies. Patients may be eligible to crossover from physician's choice chemotherapy to MEK162 if they meet certain inclusion criteria including centrally confirmed disease progression. Approximately 360 patients from North America, Europe and Australia will be enrolled in this study.

Official Title
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The MILO Study (MEK Inhibitor in Low-grade Serous Ovarian Cancer): A Multinational, Randomized, Open-label Phase 3 Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Recurrent or Persistent Low-grade Serous Carcinomas of the Ovary, Fallopian Tube or Primary Peritoneum

Conditions
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Low-grade Serous Ovarian Cancer, Low-grade Serous Fallopian Tube Cancer, Low-grade Serous Peritoneal Cancer

Intervention / Treatment
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* Drug: MEK162, MEK inhibitor; oral
* Drug: Physician's choice chemotherapy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of LGS carcinoma of the ovary, fallopian tube or primary peritoneum (invasive micropapillary serous carcinoma or invasive grade 1 serous carcinoma), confirmed histologically and verified by central pathology review. Recurrent or persistent measurable disease that has progressed (defined as radiological and/or clinical progression; an increase in cancer antigen [CA]-125 alone is not sufficient) on or after last therapy (i.e., chemotherapy, hormonal therapy, surgery) and is not amenable to potentially curative intent surgery, as determined by the patient's treating physician. Must have received at least 1 prior platinum-based chemotherapy regimen but have received no more than 3 lines of prior chemotherapy regimens, with no limit to the number of lines of prior hormonal therapy. Front-line therapy may include neoadjuvant and adjuvant therapy and will be counted as 1 prior systemic regimen. Biological therapy (e.g. bevacizumab) administered as a single agent is considered a prior systemic regimen and not a prior chemotherapy regimen. Maintenance therapy is not considered its own regimen but should be included with the regimen that it follows. Available archival tumor sample (excisional or core biopsy) for confirmation of LGS carcinoma diagnosis. If adequate archival tumor sample is not available, willingness to consent to tissue biopsy. Suitable for treatment with at least one of the physician's choice chemotherapy options (liposomal doxorubicin, paclitaxel or topotecan) as determined by the Investigator. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Additional criteria exist. Key Exclusion Criteria: History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes). Prior therapy with a MEK or BRAF inhibitor. History of Gilbert's syndrome. Impaired cardiovascular function or clinically significant cardiovascular diseases. Uncontrolled or symptomatic brain metastases that are not stable or require steroids, are potentially life-threatening or have required radiation within 28 days prior to first dose of study treatment. Concomitant malignancies or previous malignancies with less than a 5-year disease-free interval at the time of first dose of study treatment; patients with adequately resected basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or ductal carcinoma in situ may be enrolled irrespective of the time of diagnosis. Known positive serology for the human immunodeficiency virus (HIV), active hepatitis B and/or active hepatitis C. Prior randomization into this clinical study. Additional criteria exist.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: MEK162<br> | Drug: MEK162, MEK inhibitor; oral<br>* multiple dose, single schedule<br>|
| Active Comparator: Physician's choice chemotherapy<br> | Drug: Physician's choice chemotherapy<br>* Patients will receive one of the following chemotherapies as determined by the physician: Liposomal doxorubicin, anthracycline antibiotic; intravenous (multiple dose, single schedule) Paclitaxel, mitotic inhibitor; intravenous (multiple dose, single schedule) Topotecan, topoisomerase 1 inhibitor; intravenous (multiple dose, single schedule)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) | PFS was defined as the time from randomization to the earliest documented disease progression date or death due to any cause whichever occurred first. Disease progression was defined as at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including Baseline) and an absolute increase of greater than or equal to (>=) 5 millimeter (mm). Appearance of new lesions >=10 mm in diameter also constituted PD. If a participant did not have an event at the time of the analysis cutoff or at the start of any new therapy, PFS was censored at the date of last adequate tumor assessment. | From randomization until documented progressive disease (PD) or death, whichever occurred first, for censored participants at the date of last adequate tumor assessment (up to 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. Participants who were alive at the data cutoff date were censored for overall survival at their last contact date. | From randomization date to the date of death, for censored participants at their last contact date (up to 24 months) | 
| Objective Response Rate Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (RECIST V1.1) | ORR was defined as the percentage of participants achieving an overall best response of complete response (CR) or partial response (PR) (responders). CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures less than (<) 10 mm, PR was defined as at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the Baseline sum of diameters. Non-target lesions must be non-progressive disease. | From randomization until disease progression or death (up to 24 months) | 
| Duration of Response (DOR) | DOR was defined as the time from first radiographic evidence of response to the earliest documented progression date or death due to any cause, and was calculated on responders only. Responders with no PD or death date or subsequent anticancer therapy by the data cutoff date, were censored for DOR at their last radiological assessment. Responders who received subsequent anticancer therapy prior to PD or death were censored at their last radiological assessment prior to initiation of subsequent anticancer therapy. | From the first radiographic evidence of response to the first documentation of PD or death, for censored participants at their last radiological assessment (up to 24 months) | 
| Disease Control Rate (DCR) | Disease control rate was defined as percentage of participants with disease control. Disease control was defined as a best response of CR or PR, or stable disease (SD) documented at Week 24 or later. CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures <10 mm, and PR is defined as at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the Baseline sum of diameters. Non-target lesions must be non-progressive disease. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters on study. | Week 24 | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship. SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial/prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | From the first dose of study intervention until 30 days after the last dose (up to 9 years) | 
| Number of Participants With Shift Greater Than or Equal to Grade 3 From Baseline in Laboratory Parameter Values Based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03 | Number of participants with shifts from normal Baseline values (Grade 0) to abnormal post-baseline values on-study (shift to greater than or equal to Grade 3) were reported as per NCI-CTCAE, v4.03 graded from Grade 1 to 5. Grade 1: Mild; asymptomatic/ mild symptoms; clinical/diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local/noninvasive intervention indicated. Grade 3: Severe/medically significant but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Shifts in lab parameter from Grade 0 to 3, Grade 0 to 4 and Grade 0 to Low 3 and 4 and Grade 0 to High 3 and 4 (for parameters total hemoglobin, lymphocytes, white blood cells, calcium, magnesium, potassium, and sodium) were reported. | From the first dose of study intervention until 30 days after the last dose (up to 9 years) | 
| Quality of Life Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30) | EORTC QLQ-C30 is a 30-item cancer-specific instrument that assesses participant reported outcomes, consisting of 5 functional scales, 3 symptoms scales, a global health status/quality of life (QOL) scale, and 6 single-item scales. The global health status/QOL scale has 7 possible scores of responses (1=very poor to 7=excellent). All other items have 4 possible scores (1=not at all, 2=a little, 3=quite a bit, 4=very much). A linear transformation was applied to the raw scores so that all transformed scores lie between 0 to 100, with 0 being the worst and 100 being the best for global health status/QOL and functional scales, and 0 being the best and 100 being the worst for symptoms scales. In this study, global health status/QOL scale score was identified as the primary patient-reported outcome variable of interest. Physical functioning, emotional functioning, and social functioning scale scores were considered as secondary. Higher scores indicate better quality of life. | Screening, every 8 weeks from randomization for the first 72 weeks (while on treatment), treatment discontinuation visit, 30-day safety follow-up visit | 
| Quality of Life Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Ovarian Cancer Module (QLQ-OV28) | EORTC QLQ-OV28 contains 28 items which assess a comprehensive range of relevant issues: abdominal/gastrointestinal (GI) symptoms, peripheral neuropathy, other chemotherapy side-effects, hormonal/menopausal symptoms, body image, attitude to disease/treatment and sexual functioning. The score for each domain and component score were scaled from 0 (minimum) to 100 (maximum). Higher scores indicate lower quality of life except for sexual functioning where higher scores indicate better quality of life. | Screening, every 8 weeks from randomization for the first 72 weeks (while on treatment), treatment discontinuation visit, 30-day safety follow-up visit | 
| Quality of Life Per Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT/GOG-NTX) | FACT/GOG-NTX questionnaire consists of questions for dimensions related to physical, social, emotional, and functional well-being which contains 11 items, with responses scored on a Likert scale from 0 (not at all) to 4 (very much) designed to capture the symptoms of chemotherapy-induced peripheral neuropathy (CIPN). The summed scores of each item were reverted into standardized scores ranging from 0 to 44, with a higher score indicating a lower level of neurological toxicity and less effect on quality of life (ie, higher scores indicate better quality of life). The trial outcome index consists of two subscales from the FACT-G: Physical Well Being (7 items) and Functional Well Being (7 items), plus the Cervix Cancer-specific subscale (15 items). Each item in the trial outcome index scored using a 5-point scale (0=not at all to 4=very much). The summed scores of each item were reverted into standardized scores ranging from 0 to 116. Higher scores indicate better quality of life. | Screening, every 8 weeks from randomization for the first 72 weeks (while on treatment), treatment discontinuation visit, 30-day safety follow-up visit | 
| Predose Plasma Concentration (Ctrough) of MEK162 | Ctrough of MEK162 is defined as the predose plasma concentration of MEK162. Ctrough of MEK162 was observed directly from data. | Predose on Study Days 1, 57, and 113. | 
| Maximum Observed Plasma Concentration (Cmax) of MEK162 | Cmax is maximum observed plasma concentration. Cmax of MEK162 was observed directly from data. | 2 hours ± 10 minutes postdose on Study Days 1, 57, and 113. |