Brief Summary
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.
Brief Title
A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer
Completion Date
Completion Date Type
Actual
Conditions
Low-grade Serous Ovarian Cancer
Low-grade Serous Fallopian Tube Cancer
Low-grade Serous Peritoneal Cancer
Eligibility Criteria
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.
* 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.
Inclusion Criteria
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.
* 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.
Gender
Female
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT01849874
Org Class
Industry
Org Full Name
Pfizer
Org Study Id
ARRAY-162-311
Overall Status
Terminated
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
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
Primary Outcomes
Outcome Description
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.
Outcome Measure
Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR)
Outcome Time Frame
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 Ids
Secondary Id
C4211003
Secondary Id
2013-000277-72
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
From randomization date to the date of death, for censored participants at their last contact date (up to 24 months)
Outcome Measure
Overall Survival (OS)
Outcome Description
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.
Outcome Time Frame
From randomization until disease progression or death (up to 24 months)
Outcome Measure
Objective Response Rate Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 (RECIST V1.1)
Outcome Description
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.
Outcome Time Frame
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)
Outcome Measure
Duration of Response (DOR)
Outcome Description
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.
Outcome Time Frame
Week 24
Outcome Measure
Disease Control Rate (DCR)
Outcome Description
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.
Outcome Time Frame
From the first dose of study intervention until 30 days after the last dose (up to 9 years)
Outcome Measure
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Outcome Description
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.
Outcome Time Frame
From the first dose of study intervention until 30 days after the last dose (up to 9 years)
Outcome Measure
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
Outcome Description
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.
Outcome Time Frame
Screening, every 8 weeks from randomization for the first 72 weeks (while on treatment), treatment discontinuation visit, 30-day safety follow-up visit
Outcome Measure
Quality of Life Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30)
Outcome Description
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.
Outcome Time Frame
Screening, every 8 weeks from randomization for the first 72 weeks (while on treatment), treatment discontinuation visit, 30-day safety follow-up visit
Outcome Measure
Quality of Life Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Ovarian Cancer Module (QLQ-OV28)
Outcome Description
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.
Outcome Time Frame
Screening, every 8 weeks from randomization for the first 72 weeks (while on treatment), treatment discontinuation visit, 30-day safety follow-up visit
Outcome Measure
Quality of Life Per Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT/GOG-NTX)
Outcome Description
Ctrough of MEK162 is defined as the predose plasma concentration of MEK162. Ctrough of MEK162 was observed directly from data.
Outcome Time Frame
Predose on Study Days 1, 57, and 113.
Outcome Measure
Predose Plasma Concentration (Ctrough) of MEK162
Outcome Description
Cmax is maximum observed plasma concentration. Cmax of MEK162 was observed directly from data.
Outcome Time Frame
2 hours ± 10 minutes postdose on Study Days 1, 57, and 113.
Outcome Measure
Maximum Observed Plasma Concentration (Cmax) of MEK162
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Nicole Nevadunsky
Investigator Email
nnevadun@montefiore.org
Investigator Phone
718-405-8082
MeSH Terms
BINIMETINIB