| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Recurrent or persistent low-grade serous (LGS)
carcinomas of the ovary, fallopian tube or primary peritoneum |
|
| E.1.1.1 | Medical condition in easily understood language |
| Recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube or primary peritoneum |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether treatment with MEK162 prolongs Progression-free survival as compared to physician’s choice of selected chemotherapies (liposomal doxorubicin, paclitaxel and topotecan) in patients with recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube or primary peritoneum |
|
| E.2.2 | Secondary objectives of the trial |
Obtain additional estimates of the efficacy (including overall survival
[OS]) 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
• During the crossover period, after failure of physician's choice
chemotherapy in the randomized period:
o Assess the efficacy of MEK162
o Characterize the safety profile of MEK162
o Assess the effect on global health status of MEK162 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
•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.
•Other protocol-defined inclusion criteria exist. |
|
| E.4 | Principal exclusion criteria |
•History or current evidence of retinal vein occlusion (RVO), or current risk factors for RVO.
•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.
•Other protocol-defined exclusion criteria exist. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Progression-free survival as determined by the blinded independent central review (BICR). The local Investigator assessments will be used as supportive analyses. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumor assessments will be performed every 8 weeks from
randomization for the first 72 weeks, then every 12 weeks while the
patient is receiving study drug treatment, irrespective of the days of study drug administration. Patients who have locally
determined Progressive Disease (PD) confirmed by the BICR will discontinue study drug and cease tumor assessments. Patients who discontinue study drug for reasons other than PD per BICR will continue to have tumor assessments every 8 weeks from randomization for the first 72 weeks, then every 12 weeks for the remainder of the study until one of the following (whichever occurs first): locally determined PD is confirmed by the BICR, withdrawal of consent, initiation of subsequent anticancer therapy, lost to follow-up or death. |
|
| E.5.2 | Secondary end point(s) |
Overall survival
• Objective response rate (ORR) as defined by the Response Evaluation
Criteria in Solid Tumorso Assessment by the QOL questionnaires EORTC
QLQ-C30, EORTC QLQ-OV28 and FACT/GOG-NTX (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
• During the crossover period, after failure of physician's choice
chemotherapy in the randomized period:
o Progression-free survival as determined by local Investigator
assessments
o Objective response rate as defined by RECIST, Version 1.1
o Duration of response
o Incidence and severity of AEs, graded according to the NCI CTCAE,
Version 4.03
o Changes in clinical laboratory parameterso Assessment by the QOL
questionnaires EORTC QLQ-C30, EORTC QLQ-OV28 and FACT/GOG-NTX |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall Survival: All patients will be followed for survival until withdrawal of consent, lost to follow-up or death; or until the study ends.
ORR, DOR, DCR: Tumor assessments will be performed every 8 weeks from randomization for the first 72 weeks, then every 12 weeks for the remainder of the study
Safety:Continuously while on study drug and for 30 days after the last dose of study drug.
Patient Reported Outcomes: The EORTC QLQ-C30, EORTC QLQ-OV28 and FACT-GOG/NTX questionnaires will be completed within 7 days prior to randomization; every 8 weeks from randomization for the first 72 weeks; at the Treatment Discontinuation Visit;and at the 30-Day Safety Follow-up Visit.
PK:Pharmacokinetic samples will be drawn predose and
2 hours ± 10 minutes postdose on Days 1, 57 and 113. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 106 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Luxembourg |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study will be when all patients have been followed for 5
years after the last randomized patient's randomization date. Any
patients still receiving MEK162 at the end of the study will be allowed
to continue at the discretion of the Investigator and as long as none of
the treatment discontinuation criteria are met. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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