The MILO Study (MEK Inhibitor in Low-grade Serous Ovarian Cancer): A Multinational, Randomized, Open-label Phase 3 Study of MEK162 vs. Physician[Single Quote]s Choice Chemotherapy in Patients with Recurrent or Persistent Low-grade Serous Carcinomas of the Ovary, Fallopian Tube or Primary Peritoneum
This multinational, randomized, open-label Phase 3 study will evaluate MeK162 vs. physician's choice of selected chemotherapies in patients with LGS carcinomas of the ovary, fallopian tube or primary peritoneum who have recurrent or persistent disease following at least 1 prior platinum-based chemotherapy treatment and no more than
3 prior lines of chemotherapy. Patients who have achieved a CR following therapy and who subsequently experience a return of cancer cells after last therapy are said to have recurrent disease. Persistent disease refers to residual cancer growths or cells that persist during and following last therapy.
Prior to randomization, central pathology review of the patient's archival histological tumor specimen obtained at Screening will be required to confirm diagnosis of LGS carcinoma. if adequate archival tumor sample is not available for confirmation of LGS carcinoma diagnosis, a tumor biopsy will be required with additional consent.
only those patients with confirmed LGS carcinoma per central pathology review and meeting all eligibility criteria will be randomized.
* Progression-free survival as determined by the blinded independent central review (BiCR). The local investigator
assessments will be used as supportive analyses
* overall survival
* objective response rate (oRR) as defined by the Response evaluation Criteria in Solid Tumors (ReCiST), Version 1.1
* Duration of response (DoR)
* Disease control rate (DCR), defined as having achieved a best response of complete response (CR) or partial response (PR), or stable disease (SD) documented at Week 24 or later
* incidence and severity of adverse events (aes), graded according to the national Cancer institute Common
Terminology Criteria for adverse events (nCi CTCae), Version 4.03
* Changes in clinical laboratory parameters
* assessment by the quality-of-life (QoL) questionnaires european organization for Research and Treatment of Cancer (eoRTC) QLQ-C30, eoRTC QLQ-oV28 and Functional assessment of Cancer Therapy (FaCT)/Gynecologic oncology Group (GoG)-neurotoxicity (nTX)
* Plasma concentration-time profiles and model-based PK parameters of MeK162 (and metabolite aR00426032, if
feasible) in a subset of the patients randomized to receive MeK162
* in tumor tissue, if available and as feasible:
o Mutations in cancer-associated and chemotherapy-metabolism-related genes
o Levels and activation states of apoptosis-related proteins and associated messenger ribonucleic acid (mRna)
o Levels and activation states of rat sarcoma viral oncogene (RaS)/v-Raf murine sarcoma viral oncogene
(RaF)/mitogen-activated protein kinase kinase (MeK)/extracellular signal-regulated kinase (eRK)
Patients must meet all of the following criteria at Screening to be eligible for randomization into
1. 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.
2. Recurrent or persistent 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[Single Quote]s treating physician.
Patients who have achieved a CR following last therapy and who subsequently
experience a return of cancer cells after treatment are said to have recurrent disease.
Persistent disease refers to residual cancer growths or cells that persist during and
following last therapy.
3. 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.e.; 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 regiment that it follows.
4. Measurable disease, as defined by RECIST, Version 1.1, per BICR.
5. Availability of 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.
6. Suitable for treatment with at least one of the physician[Single Quote]s choice chemotherapy options
(liposomal doxorubicin, paclitaxel or topotecan) as determined by the Investigator, given
the patient[Single Quote]s medical history, prior treatment(s), availability and approval of the
physician[Single Quote]s choice chemotherapy options for treatment of ovarian cancer within a given
country, and other relevant factors.
7. Female >= 18 years of age at time of informed consent.
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
9. Recovery from any clinically significant toxicity from prior chemotherapy, radiotherapy,
hormonal therapy or immunotherapy (excluding infertility, alopecia or Grade 1
10. Adequate hematopoietic, hepatic and renal function defined as follows:
a. Absolute neutrophil count (ANC) >= 1.5 x 109/L;
b. Hemoglobin >= 9.0 g/dL;
c. Platelet count >= 100 x 109/L;
d. Alanine aminotransfe and AST <= 2.5 x the upper limit of normal (ULN) or, if
patient has documented liver metastases, <= 5 x ULN;
e. Total bilirubin <= 2 x ULN;
f. Serum creatinine <= 1.5 x ULN.
11. Adequate cardiac function:
a. Left ventricular ejection fraction >= 50% as determined by a MUGA scan or
b. Mean triplicate QT interval corrected for heart rate using Fridericia[Single Quote]s formula
(QTcF) value <= 480 msec.
12. Patients of childbearing potential must have a negative serum beta-human chorionic
gonadotropin ([BETA]-HCG) test (women who are considered postmenopausal and not of
childbearing potential are defined in Section 5.3.1).
13. Patients of childbearing potential must agree to use a highly effective method of
contraception as defined in Section 5.3.1.
14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests
and other study procedures.
15. Provide a personally signed and dated informed consent form (ICF) prior to initiation of
any study-related procedures that are not considered standard of care.