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

NCT01849874TerminatedPHASE3INTERVENTIONAL

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.

Key Facts

Lead Sponsor

Pfizer

Enrollment

341

Start Date

2013-06-27

Completion Date

2016-01-20

Study Type

INTERVENTIONAL

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

Interventions

MEK162MEK inhibitor; oralPhysician's choice chemotherapy

Conditions

Low-grade Serous Ovarian CancerLow-grade Serous Fallopian Tube CancerLow-grade Serous Peritoneal Cancer

Eligibility

Age Range

18 Years+

Sex

FEMALE

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.

Outcome Measures

Primary Outcomes

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.

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 Outcomes

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.

Time frame: 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.

Time frame: 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.

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)

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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

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.

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

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.

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

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.

Time frame: 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.

Time frame: 2 hours ± 10 minutes postdose on Study Days 1, 57, and 113.

Locations

University of Arizona Cancer Center, Phoenix, United States

Associated Retina Consultants, Ltd., Phoenix, United States

Oncology Research Associates, PLLC d/b/a Pinnacle Oncology Hematology, Scottsdale, United States

Keck Hospital of USC, Los Angeles, United States

LAC & USC Medical Center, Los Angeles, United States

USC Healthcare Consultation Center 1, Los Angeles, United States

USC Healthcare Consultation Center 2, Los Angeles, United States

USC Norris Comprehensive Cancer Center, Los Angeles, United States

USC/Norris Comprehensive Cancer Center, Los Angeles, United States

Admin.Office/Study Supplies Mailing Address: UCLA Medicine Hematology-Oncology, Los Angeles, United States

Doris Stein Research Center Building, Los Angeles, United States

University of California Los Angeles, Hematology-Oncology Clinic, Los Angeles, United States

Gynecologic Oncology Associates, Newport Beach, United States

University of California, Irvine/UC Irvine Health, Orange, United States

UCLA Hematology/Oncology Clinic - Santa Monica, Santa Monica, United States

UCLA Hematology Oncology Clinic Santa Clarita, Valencia, United States

UCLA Hematology - Oncology Clinic - Westlake Village, Westlake Village, United States

Rocky Mountain Lions Eye Institute, Aurora, United States

University of Colorado Cancer Center, Aurora, United States

University of Colorado Denver, University of Colorado Cancer Center, Aurora, United States

Smilow Cancer Hospital at Yale-New Haven, New Haven, United States

Eye Physicians of Central Florida, Maitland, United States

Florida Hospital, Orlando, United States

Florida Hospital Cancer Institute, Orlando, United States

Eye Physicians of Central, Orlando, United States

H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States

Florida Cancer Specialists, Wellington, United States

Florida Cancer Specialists, West Palm Beach, United States

Georgia Regents University Cancer Center, Augusta, United States

University of Chicago Medical Center, Chicago, United States

St. Vincent Cancer Care, Indianapolis, United States

St. Vincent Gynecologic Oncology, Indianapolis, United States

St. Vincent Gynecology Oncology, Indianapolis, United States

St. Vincent Hospital and Health Care Center, Inc., Indianapolis, United States

Associated Vitreoretinal and Uveitis Consultants, Indianapolis, United States

University of Iowa Hospitals and Clinics, Iowa City, United States

University of Maryland Greenebaum Cancer Center, Baltimore, United States

Massachusetts General Hospital, Boston, United States

Ophthalmic Consultants of Boston (OCB), Boston, United States

Karmanos Cancer Institute, Detroit, United States

Kresge Eye Institute, Detroit, United States

Karmanos Cancer Institute, Farmington Hills, United States

Barnes-Jewish Hospital, St Louis, United States

Center for Advanced Medicine, St Louis, United States

Center For Clinical Studies, St Louis, United States

Washington University, St Louis, United States

Billings Clinic, Billings, United States

University of New Mexico Cancer Center, Albuquerque, United States

Eye Associates of New Mexico, Albuquerque, United States

Memorial Sloan Kettering Cancer Center, New York, United States

Montefiore Medical Center - Einstein Center for Cancer Care, The Bronx, United States

Montefiore Medical Center, The Bronx, United States

Montefiore Medical Center - Centennial Women's Health, The Bronx, United States

Montefiore Medical Center, Green Medical Arts Pavilion, The Bronx, United States

University of Cincinnati Medical Center, Cincinnati, United States

Fairview Hospital Moll Pavilion Cancer Center, Cleveland, United States

Cleveland Clinic Taussig Cancer Center, Cleveland, United States

Cleveland Clinic-Main Campus, Cleveland, United States

James Cancer Hospital & Solove Research Institute, Columbus, United States

OSU Wexner Medical Center, Columbus, United States

Stefanie Spielman Comprehensive Breast Cancer, Columbus, United States

OSU Gynecologic Oncology at Mill Run, Hilliard, United States

Hillcrest Hospital, Mayfield Heights, United States

University of Cincinnati Physicians Company, West Chester, United States

Dean McGee Eye Institute, Oklahoma City, United States

Stephenson Cancer Center(clinic location), Oklahoma City, United States

Stephenson Cancer Center, Oklahoma City, United States

Fox Chase Cancer Center, Philadelphia, United States

Jeanes Hospital, Philadelphia, United States

Magee-Womens Hospital of UPMC, Pittsburgh, United States

University of Pittsburgh Medical Center, Pittsburgh, United States

Parkland Health and Hospital System, Dallas, United States

UT Southwestern Medical Center-Zale Lipshy University Hospital, Dallas, United States

UT Southwestern Medical Center-Clements University Hospital, Dallas, United States

UT Southwestern Medical Center, Dallas, United States

University of Texas MD Anderson Cancer Center, Houston, United States

University of Virginia, Charlottesville, United States

Dr Anil Arora, Wahroonga, Australia

Sydney Adventist Hospital, Wahroonga, Australia

Westmead Hospital, Westmead, Australia

Mater Misericordiae Health Services Brisbane Limited, South Brisbane, Australia

Adelaide Cardiology, Adelaide, Australia

Adelaide Eye and Retina Centre, Adelaide, Australia

Royal Adelaide Hospital, Adelaide, Australia

Thomas and Delaney Optometrists, Norwood, Australia

Burnside War Memorial Hospital, Toorak Gardens, Australia

Sunshine Hospital, St Albans, Australia

Sir Charles Gairdner Hospital, Nedlands, Australia

Innsbruck Medical University, Innsbruck, Austria

Centre Hospitalier de l'ardenne, Libramont, Belgium

Private practice Ophthalmology, Libramont, Belgium

University Hospital Leuven, Leuven, Belgium

Cliniques Universitaires Saint-Luc, Brussels, Belgium

Ghent University Hospital, Ghent, Belgium

University Hospital Gent, Ghent, Belgium

CHR de la Citadelle, Liège, Belgium

Clinique et Maternite Sainte-Elisabeth Namur, Namur, Belgium

Sint-Augustinus, Wilrijk, Belgium

Tom Baker Cancer Centre, Calgary, Canada

British Columbia Cancer Agency - Vancouver Centre, Vancouver, Canada

CancerCare Manitoba, Winnipeg, Canada

Juravinski Cancer Center, Department of Oncology, Hamilton, Canada

Princess Margaret Cancer Centre, Toronto, Canada

Centre Hospitalier de l'Universite de Montreal (Chum) - Hopital Notre-Dame, Montreal, Canada

Jewish General Hospital, Montreal, Canada

Teaching Hospital Hradec Kralove, Hradec Králové, Czechia

Fakultni nemocnice Olomouc, Olomouc, Czechia

Fakultni nemocnice Ostrava, Ostrava - Poruba, Czechia

Fakultni Nemocnice Ostrava, Ostrava - Poruba, Czechia

Fakultni nemocnice Ostrava, Ostrava-Poruba, Czechia

General University Hospital in Prague, Prague, Czechia

Aalborg Sygehus Apotek, Aalborg, Denmark

Aalborg University Hospital, Aalborg, Denmark

Herlev Hospital Onkologisk AFD, Herlev, Denmark

Ojenklinikken 2061, København Ø, Denmark

Radiologisk Afdeling 2023, København Ø, Denmark

Region Hovedstadens Apotek, København Ø, Denmark

Rigshospitalet, København Ø, Denmark

Tampere University Hospital, Tampere, Finland

CHU Jean Minjoz, Besançon, France

Centre Oscar Lambret, Lille, France

Hopital Prive La Louviere, Lille, France

Hopital Edouard Herriot, Lyon, France

Centre Leon Berard, Lyon, France

Centre Paradis Monticelli, Marseille, France

Institut Paoli Calmettes - Departement d'Oncologie Medicale, Marseille, France

Centre d'Ophtalmologie du LEZ Centre Medical Les Roques, Montferrier S/lez, France

Institut Regional du Cancer Montpellier, Montpellier, France

Cabinet Liberal du Dr Xavier Zanlonghi, Nantes, France

Clinique Sourdille, Nantes, France

L'Hopital Prive du Confluent SAS, Nantes, France

Centre d'Investigations Cliniques 1423, Paris, France

Hopital Europeen Georges Pompidou, Paris, France

Centre Investigateur CARIO - HPCA, Plérin, France

Institut de Cancerologie de I'Ouest - Rene Gauducheau, Saint-Herblain, France

Institut Gustave Roussy, Villejuif, France

Universitaets-Brustzentrum, Tübingen, Germany

Universitätsfrauenklinik Ulm, Ulm, Germany

Klinikum rechts der Isar, Munich, Germany

Klinik fur Frauenheilkunde und Geburtshilfe, Kassel, Germany

Universitätsklinikum Bonn, Bonn, Germany

Kliniken Essen-Mitte, Essen, Germany

Uni Carl Gustav Carus, Dresden, Germany

Universitätsklinikum Schleswig-Holstein, Kiel, Germany

Charité Universitaetsmedizin Berlin, Berlin, Germany

Universitaetsklinik Freiburg, Freiburg im Breisgau, Germany

Frauenheilkunde und Geburtshilfe, Greifswald, Germany

NCT Nationales Centrum für Tumorerkrankungen Heidelberg, Heidelberg, Germany

Euromedic Diagnostics Magyarorszag Kft., Győr, Hungary

Petz Aladar Korhaz Kardiologiai Osztaly, Győr, Hungary

Petz Aladar Korhaz Szemeszeti Osztaly, Győr, Hungary

Magyar Honvedseg Egeszsegugyi Kozpont, Onkologiai Osztaly, Budapest, Hungary

Magyar Honvedseg Egeszsegugyi Kozpont, Budapest, Hungary

Semmelweis Egyetem AOK Szemeszeti Klinika, Budapest, Hungary

Orszagos Onkologiai Intezet Kozponti Aneszteziologiai es Intenzivterapias Osztaly, Budapest, Hungary

Orszagos Onkologiai Intezet, Nogyogyaszati Osztaly, Budapest, Hungary

Orszagos Onkologiai Intezet, Budapest, Hungary

Magyar Honvedseg Egeszsegugyi Kozpont, Budapest, Hungary

St James's Hospital, Dublin, Ireland

Istituto Clinico Humanitas, Rozzano, Italy

Centro di Riferimento Oncologico - Struttura Operativa Complessa (SOC)- Oncologia Medica C, Aviano, Italy

Ospedale Civile degli Infermi - Servizio di Oculistica, Faenza, Italy

Ospedale Civile degli Infermi - Unita Operativa di Oncologia Medica, Faenza, Italy

Ospedale Umberto I - Unita Operativa di Oncologia, Lugo, Italy

Istituto Nazionale Tumori Regina Elena - Oncologia Medica A, Roma, Italy

Policlinico Umberto I - Università Sapienza, Roma, Italy

Azienda Ospedaliera Sant' Andrea - Unita Operativa Semplice di Patologia Vitreo-Retinica, Roma, Italy

SSD Oncologia Medica Addarii-Zamagni - Policlinico S. Orsola-Malpighi, Bologna, Italy

Struttura Complessa di Oftalmologia Policlinico S. Orsola-Malpighi, Bologna, Italy

Spedali Civili di Brescia - Struttura Complessa Clinicizzata - U.O.di Oculistica, Brescia, Italy

Spedali Civili Di Brescia, Brescia, Italy

Azienda Ospedaliera Cannizzaro, Catania, Italy

Ospedale San Raffaele - Unita Operativa di Oculistica, Milan, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori - SC Oncologia Ginecologica, Milan, Italy

Istituto Europeo Oncologico, Milan, Italy

Azienda Ospedaliera Vincenzo Monaldi di Napoli - U.O.C. di Oculistica, Naples, Italy

Istituto Nazionale Tumori di Napoli, "G.Pascale" , Oncologia Medica, Dipartimento Uro-Ginecologico, Naples, Italy

Universita degli Studi Federico II di Napoli Dipartimento di Neuroscienze Scienze, Naples, Italy

Universita degli Studi Federico II di Napoli Oncologia Medica, Naples, Italy

Azienda Opsedaliera S. Maria Degli Angeli Pordenone-Dipartimento di Chirurgia Specialistica -, Pordenone, Italy

Ospedale Santa Maria delle Croci - Oculistica, Ravenna, Italy

Ospedale Santa Maria delle Croci - Unita Operativa di Oncologia, Ravenna, Italy

Dipartimento Organi di Senso, Roma, Italy

Dipartimento di Scienze Chirurgiche per le Patologie della Testa e del Collo - UOC di Oculistica, Roma, Italy

Policlinico Agostino Gemelli, Roma, Italy

Academic Medical Center (AMC), Amsterdam, Netherlands

University Medical Center Groningen, Medical Oncology, Groningen, Netherlands

Maastricht University Medical Centre, Maastricht, Netherlands

Aleris, Oslo, Norway

Avd. for gynekologisk kreft, Radiumhospitalet, Oslo, Norway

Oslo Universitetssykehus HF, Oslo, Norway

Centralny Szpital Kliniczny MON, Warsaw, Poland

Hospital Duran i Reynals, L'Hospitalet de Llobregat, Spain

Hospital Universitario Reina Sofía/ Provincial, Córdoba, Spain

Centro de Salud Anoeta, Anoeta, Spain

Hospital Universitario Donostia, Donostia / San Sebastian, Spain

Ophthalmology at Instituto Oftalmologico Integral, Barcelona, Spain

Hospital Clinic Barcelona, Barcelona, Spain

Hospital de Sant Joan Despi Moises Broggi, Barcelona, Spain

Cardiology at Consulta de Cardiologia, Córdoba, Spain

Centro Medico Sanitas Ressalta, Córdoba, Spain

Instituto de Oftalmologia y Hospital La Arruzafa, Córdoba, Spain

Radiology at Centro Medico Sanitas Ressalta, Córdoba, Spain

Radiology at Hospital Univeristari de Bellvitge, L'Hospitalet de Llobregat, Spain

Hospital Ramón Y Cajal, Madrid, Spain

Hospital Universitario 12 de Octubre, Madrid, Spain

Hospital Son Llatzer, Palma de Mallorca, Spain

Hospital Universitario Virgen Macarena, Seville, Spain

Hospital Virgen de la Salud, Toledo, Spain

Fundacion IVO-Instituto Valenciano de Oncologia, Valencia, Spain

Ophthalmology at Hospital Universitari i Politecnic La Fe de Valencia, Valencia, Spain

Karolinska Universitetssjukhuset, Stockholm, Sweden

Onkologkliniken Akademiska Sjukhuset, Uppsala, Sweden

Sarah Cannon Research Institute UK, London, United Kingdom

Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

University of Nottingham, Nottingham, United Kingdom

Ashtead Hospital, Ashtead, United Kingdom

The Clock House Medical Practice, Epsom, United Kingdom

The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom

St. Anthony's Hospital, North Cheam, United Kingdom

City Hospital, Birmingham, United Kingdom

Royal Marsden NHS Foundation Trust, London, United Kingdom

The Harley Street Clinic, London, United Kingdom

London Eye Diagnostic Centre, London, United Kingdom

The Christie NHS Foundation Trust, Manchester, United Kingdom

Linked Papers

2020-08-21

MILO/ENGOT-ov11: Binimetinib Versus Physician’s Choice Chemotherapy in Recurrent or Persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum

PURPOSE Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. METHODS This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician’s choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. RESULTS A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. CONCLUSION Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.

Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer

Abstract Purpose: We present the results of a post hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874). Patients and Methods: Mutation/copy-number analysis was performed on tissue obtained pre-randomization. The Kaplan–Meier method was used to estimate progression-free survival (PFS). Unbiased univariate analysis, Cox regression, and binary logistic regression were used to test associations between mutation status and outcomes, including PFS and binary response by local RECIST 1.1. Results: MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22 to 79, from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or physician's choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%). In 135 patients treated with binimetinib with response rate (RR) data, other detected MAPK pathway alterations included: NRAS (n = 11, 8.1%), BRAF V600E (n = 8, 5.9%), RAF1 (n = 2, 1.5%), and NF1 (n = 7, 5.2%). In those with and without MAPK pathway alterations, the RRs with binimetinib were 41% and 13%, respectively. PFS was significantly longer in patients with, compared with those without, MAPK pathway alterations treated with binimetinib [HR, 0.5; 95% confidence interval (CI) 0.31–0.79]. There was a nonsignificant trend toward PFS improvement in PCC-treated patients with MAPK pathway alterations compared with those without (HR, 0.82; 95% CI, 0.43–1.59). Conclusions: Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with low-grade serous ovarian cancer (LGSOC) treated with binimetinib, and to a lesser extent in those treated with PCC, who harbored MAPK pathway alterations. Somatic tumor testing should be routinely considered in patients with LGSOC and used as a future stratification factor.

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

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