ENGOT-ov11/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

Low-grade serous carcinomas of the overay, fallopian tube and primary
peritoneum are rare tumors for which current therapies have limited efficacy.
A Phase 2 study evaluating the MEK inhibitor selumetinib showed an objective
response rate of 15%, a clinical benefit rate of 81% and a median
progression-free survival of 11 months. This Phase 3 is designed to evaluate
the efficacy of the MEK inhibitor MEK162 in patients with recurrent or
persisten LGS carcinoma of the ovary, fallopian tube or primary peritoneum.
Previous studies with this inhibitor in patients with other types of cancer
have shown that there is more chance of longer progression-free survival or
longer overall survival

Primary:
• Demonstrate superior efficacy (increased progression-free survival [PFS]) of
MEK162 vs. physician*s choice of selected chemotherapies (liposomal
doxorubicin, paclitaxel and topotecan)

Key Secondary:
• Demonstrate superior efficacy (increased overall survival [OS]) of MEK162 vs.
physician*s choice of selected chemotherapies

Other Secondary:
• Obtain additional estimates of the efficacy of MEK162 vs. physician*s choice
of selected chemotherapies
• Characterize the safety profile of MEK162 vs. physician*s choice of selected
chemotherapies
• Assess the effect on global health status of MEK162 vs. physician*s choice of
selected chemotherapies
• Characterize the plasma pharmacokinetics (PK) of MEK162 in this patient
population

Exploratory:
• Assess possible predictive biomarkers of clinical activity for MEK162

Note: As of 01 April 2016, screening and randomization into the study were
discontinued
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.
This study will have 2 periods, a randomized period and a crossover period to
MEK162 treatment after failure of physician*s choice chemotherapy treatment in
the randomized period.

Randomized Period
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. All patients must have measurable disease as defined by RECIST,
Version 1.1, per the BICR.
Patients will be stratified by their last platinum-free interval (PFI; <= 182
days vs. > 182 days) and number of prior systemic regimens (1 to 2 vs. > 2) and
then randomized 2:1 to receive MEK162 or physician*s choice chemotherapy
(liposomal doxorubicin, paclitaxel or topotecan). Platinum-free interval is the
period of time from the date of last platinum dose to the date of progressive
disease (PD) on that regimen (defined as radiological and/or clinical
progression; an increase in cancer antigen [CA]-125 alone is not sufficient) or
initiation of subsequent therapy, whichever occurred first. Non-platinum
maintenance therapy (e.g., extending taxane treatment) is not counted as
another subsequent therapy. Platinum-free interval for the most recent platinum
therapy will need to be calculated prior to randomization for stratification
purposes. Prior systemic regimens include both chemotherapy regimens and
hormonal therapy regimens given by all routes of administration. For the
purpose of stratification, front-line therapy may include neoadjuvant and
adjuvant therapy and will be counted as 1 prior systemic regimen. The
randomization schedule will be created and managed by an independent
statistician not assigned to support the study and will be implemented via an
external Interactive Web Response System (IWRS).
Once a patient is randomized, efficacy, safety and global health status will be
assessed at specified time points. Tumor tissue, if available after central
pathology review and with patient consent, will be assessed for mutations and
copy number variations in cancer-associated (including RAS/RAF) and
chemotherapy-metabolism-related genes. With patient consent, tumor tissue may
also be analyzed for exploratory biomarkers. In addition, a subset of patients
randomized to receive MEK162 will have pre- and postdose blood samples
collected on specified days in order to characterize the plasma PK of MEK162 in
this patient population. This same subset of patients, with patient consent,
will also have a predose blood sample drawn for genetic variant analysis of the
UDP-glucuronosyl transferase (UGT)1A1 gene to investigate the effect of UGT1A1
genetic variant on MEK162 exposure. With patient consent, these blood samples
may also be analyzed for exploratory biomarkers.
As of Protocol Version 6 (date 15 March 2017), BICR review of tumor assessments
will no longer be performed; tumor assessments in both the randomized and
crossover periods will be conducted by the study sites according to
institutional standards. Results of tumor assessments will be retained in
patient files only and no longer be entered into the eCRFs. All laboratory
assessments will be performed by a central laboratory as well as the local
laboratory if more rapid results are required for treatment decisions or
patient safety. All patients will be followed for approximately 30 days after
the last dose of study drug for safety. After the Safety Follow-up period,
patients will be discontinued from the study

Crossover Period
As of Protocol Version 6, crossover from physician*s choice chemotherapy
treatment to MEK162 treatment will no longer be permitted.
The study will have an independent Data Monitoring Committee (DMC) to review
safety data at regular intervals, as well as to perform the interim efficacy
analysis. An interim efficacy analysis for futility will be conducted following
a prespecified number of events.

Patients randomized to MEK162 treatment will take 45 mg orally (PO) twice daily
(BID) with water, continuously, starting on Day 1. Patients should be fasted 1
hour before and 1 hour after each dose.

Patients randomized to the physician*s choice chemotherapy arm will receive one
of the following therapies, if available and if approved for treatment of
ovarian cancer within a given country:
• Liposomal doxorubicin 40 mg/m2 intravenously (IV) on Day 1 of every 28 day
cycle
• Paclitaxel 80 mg/m2 IV on Days 1, 8 and 15 of every 28 day cycle
• Topotecan 1.25 mg/m2 IV on Days 1 through 5 of every 21 day cycle

Patients randomized to the physician*s choice chemotherapy arm should receive a
therapy considered appropriate by the Investigator given the patient*s medical
history, prior treatment(s) and other relevant factors. At least 3 days prior
to randomization, the Investigator must declare which physician*s choice
chemotherapy the patient will receive if randomized to this treatment arm.

Patients must receive their first dose of study drug within 5 days of
randomization.
Patients will receive premedication prior to chemotherapy infusions per
institutional standards. Hematologic growth factors may be given per
institutional standards.
For an individual patient, the dose of study drug may be reduced or interrupted
as appropriate based on protocol defined treatment modifications.

The benefits of treatment is to increase progression-free survival of the
patient.