This randomized phase II/III trial studies how well trametinib works and compares it to standard treatment with either letrozole, tamoxifen citrate, paclitaxel, pegylated liposomal doxorubicin hydrochloride, or topotecan hydrochloride in treating patients with low-grade ovarian cancer or peritoneal cavity cancer that has come back, become worse, or spread to other parts of the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trametinib is more effective than standard therapy in treating patients with ovarian or peritoneal cavity cancer.
A Randomized Phase II/III Study to Assess the Efficacy of Trametinib (GSK 1120212) in Patients With Recurrent or Progressive Low-Grade Serous Ovarian Cancer or Peritoneal Cancer
I. To estimate the progression-free survival (PFS) hazard ratio of trametinib compared to that of "commercially available therapies" consisting of one of five commercially available agents in women with recurrent low-grade serous carcinoma of the ovary or peritoneum previously treated with platinum-based chemotherapy.
I. To determine the nature, frequency and maximum degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 for each treatment arm.
II. To determine the quality of life, as assessed by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O).
III. To compare trametinib to the control arm with regard to patients' self-reported acute (up to post-cycle 6) quality of life as measured by the FACT-O-Trial Outcome Index (TOI).
IV. To compare trametinib to the control arm with regard to patients' self-reported acute (up to post-cycle 6) neurotoxicity as measured by the FACT-Gynecologic Oncology Group (GOG)-Neurotoxicity (NTX).
V. To estimate the objective response rate (RR) of patients in each treatment arm.
I. To estimate the overall survival (OS) of patients in each treatment arm. II. To estimate the tumor response rate in patients receiving trametinib after crossover from standard of care.
III. To estimate the PFS in patients receiving trametinib after crossover from standard of care.
IV. To compare trametinib to "endocrine standard therapy" (i.e., letrozole, tamoxifen) with regard to patients' self-reported acute quality of life and neurotoxicity, as measured by the FACT-O-TOI, and FACT-GOG-NTX, respectively.
V. To examine deoxyribonucleic acid (DNA) isolated from formalin-fixed, paraffin-embedded sections of tissue from primary diagnosis, recurrence, and fine needle aspiration/core biopsies with next generation sequencing mutational analyses of genes in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog 1 (AKT)/mammalian target of rapamycin (mTOR) pathways and to explore their relationship with tumor response in patients treated with trametinib. (Translational research objectives) VI. To examine protein levels of estrogen receptor (ER), progesterone receptor (PR), phosphorylated (p)mitogen-activated protein kinase 1 (ERK), and dual specificity phosphatase 6 (DUSP6) and explore their relationship with tumor response in patients treated with trametinib. (Translational research objectives) VII. To identify transcriptional signatures by ribonucleic acid sequencing (RNAseq) that will predict mitogen-activated protein kinase kinase (MEK) addiction and sensitivity to trametinib. (Translational research objectives) VIII. To conduct studies of specific genes in cell-free DNA in plasma of patients and to explore their relationship with tumor response to trametinib. (Translational research objectives) IX. To examine the pharmacokinetics of trametinib. (Translational research objectives)
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM A: Patients receive clinician's choice of either letrozole orally (PO) once daily (QD) on days 1-28, tamoxifen citrate PO twice daily (BID) on days 1-28, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride (PLD) IV over 1 hour on day 1, or topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.
ARM B: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.
Micropapillary Serous Carcinoma Ovarian Serous Adenocarcinoma Primary Peritoneal Serous Adenocarcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Paclitaxel Liposomal doxorubicin Letrozole Trametinib Albumin-Bound Paclitaxel Doxorubicin Topotecan Tamoxifen Citric Acid
Open to females ages 19 years and up
MAJOR: laparotomy, laparoscopy, thoracotomy, VATS [video assisted thorascopic surgery]); there is no restriction on MINOR procedures: (eg. central venous catheter placement, ureteral stent placement or exchange, tumor core or fine-needle aspirate[FNA] biopsy)
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