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

Study Objectives

Primary objective:

Demonstrate superior efficacy (increased progression-free
survival [PFS]) of MEK162 vs physician’s choice of selected chemotherapies (liposomal doxorubicin, paclitaxel and topotecan) in patients with recurrent or persistent low-grade serous (LGS) carcinomas of the ovary, fallopian tube or primary peritoneum.

Key Secondary objective:

Demonstrate superior efficacy of MEK162 (increased overall survival [OS]) vs physician’s choice of selected chemotherapies (liposomal doxorubicin, paclitaxel and topotecan) in patients with recurrent or persistent low-grade serous (LGS) carcinomas of the ovary, fallopian tube or primary peritoneum.

Participation conditions

Inclusion criteria

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‘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.

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’s choice chemotherapy options (liposomal doxorubicin, paclitaxel or topotecan) as determined by the Investigator, given the patient’s medical history, prior treatment(s), availability and approval of the Physician’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 neuropathy).

10. Adequate hematopoietic, hepatic and renal function defined as follows:

a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L;
b. Hemoglobin ≥ 9.0 g/dL;
c. Platelet count ≥ 100 × 109/L;
d. Alanine aminotransferase and AST ≤ 2.5 × the upper limit of normal (ULN) or, if patient has documented liver metastases, ≤ 5 × ULN;
e. Total bilirubin ≤ 2 × ULN;
f. Serum creatinine ≤ 1.5 × ULN.

11. Adequate cardiac function:

a. Left ventricular ejection fraction ≥ 50% as determined by a MUGA scan or ECHO;
b. Mean triplicate QT interval corrected for heart rate using Fridericia’s formula(QTcF) value ≤ 480 msec.

12. Patients of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-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.

Exclusion criteria

Patients meeting any of the following criteria at Screening are ineligible for randomization into the study:

1. History or current evidence of CSR or retinal vein occlusion (RVO), or predisposing factors to CSR or RVO (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, history of hyperviscosity or hypercoagulability syndromes).

2.. Prior therapy with a MEK inhibitor or BRAF inhibitor.

3. History of Gilbert’s syndrome.

4.Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:

a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft [CABG], coronary angioplasty or stenting) within 6 months prior to Screening;

b. Symptomatic congestive heart failure, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality within 6 months prior to Screening except atrial fibrillation and paroxysmal supraventricular tachycardia.

5. Uncontrolled arterial hypertension despite medical treatment.

6. Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).

7. Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment (i.e., muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels).

8. Uncontrolled or symptomatic brain metastases that are not stable, require steroids or enzyme inducing anti-epileptic drugs, are potentially life-threatening or have required radiation within 28 days prior to starting study drug.

9. Concomitant malignancies or previous malignancies with less than a 5-year disease-free interval at the time of randomization; 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.

10. Medical, psychiatric, cognitive or other conditions that compromise the patient's ability to understand the patient information, provide informed consent, comply with the study protocol or complete the study.

11. Any severe concurrent disease or condition (e.g., active systemic infection, cardiac arrhythmia) that, in the judgment of the Investigator, would make the patient inappropriate for study participation.

12. Gastrointestinal abnormalities including an inability to take oral medication, requirement for IV alimentation, active peptic ulcer, or prior surgical procedures affecting absorption.

13. Known positive serology for the human immunodeficiency virus (HIV), active hepatitis B and/or active hepatitis C.

14. Treatment with a cyclical chemotherapy within a period of time that is less than the cycle length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin C) prior to starting study drug.

15. Treatment with a biologic therapy (e.g., antibodies) or anticancer hormonal therapy within 28 days prior to starting study drug.

16. Treatment with continuous or intermittent small-molecule therapeutics within 5 half-lives (t1/2) of the agent, or within 28 days prior to starting study drug where t1/2 is unknown.

17. Treatment with any investigational agent(s) within a period of time that is less than the cycle length used for that treatment or within 28 days prior to starting study drug, whichever is shorter.

18. Treatment with prior radiotherapy within 21 days prior to starting study drug; however, if the radiation portal covered ≤ 10% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy.

29. Any major surgery where adequate wound healing has not occurred prior tor andomization.

20. Pregnancy or breast feeding.

21. Prior randomization into this clinical study.
 

CHL Centre Hospitalier de Luxembourg