Patient case: 61-year-old male with Ampullary carcinoma. Genetic variant: KRAS. Other conditions: None.

Clinical trial: Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer

Summary: 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.

Detailed description: PRIMARY OBJECTIVES:
  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.
  SECONDARY OBJECTIVES:
  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.
  TERTIARY OBJECTIVES:
  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.

Eligibility: Inclusion Criteria:
  -  Patients with the following tumors are included in the study:
  -  Patients initially diagnosed with low-grade serous ovarian or peritoneal carcinoma that recur as low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas as defined by GOG, Federation of Obstetricians and Gynecologists [FIGO], World Health Organization [WHO] or Silverberg)
  -  Patients initially diagnosed with serous borderline ovarian or peritoneal carcinoma that recur as low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas as defined by GOG, FIGO WHO or Silverberg)
  -  At least 4 weeks must have elapsed since the patient underwent any major surgery (eg. 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)
  -  Patients must have documented low-grade serous carcinoma; confirmation must occur by prospective pathology review prior to study entry; the prospective pathology review can be done on tissue from the recurrent carcinoma or from original diagnostic specimen
  -  All patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one target lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by CT or MRI; all imaging studies must be performed within 28 days prior to registration
  -  Prior therapy
  -  Patients must have recurred or progressed following at least one platinum-based chemotherapy regimen
  -  Patients may have received an unlimited number of prior therapy regimens
  -  Patients may not have received all of the five choices in the "standard therapy" arm
  -  Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration
  -  Any other prior therapy directed at the malignant tumor, including chemotherapy and radiation therapy, must be discontinued at least 4 weeks prior to registration; any investigational agent must be discontinued at least 28 days prior to registration
  -  Women of childbearing potential (i.e. patients whose reproductive organs remain in place and who have not passed menopause) and men must agree to use a highly effective method of contraception (e.g. hormonal, intrauterine device or; abstinence*) prior to study entry, during the study participation, and for six months after the last dose of the drug; women of child-bearing potential must have a negative pregnancy test within 14 days prior to randomization, cannot be breast-feeding, and must agree to use a highly effective form of contraception throughout the treatment period and for 6 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; * abstinence is only acceptable when this is in line with the preferred and usual lifestyle of the patient
  -  Patients must have the ability to understand and sign an approved informed consent and authorization permitting release of personal health information
  -  Patients must have a GOG performance status of 0 or 1
  -  Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption, such as malabsorption syndrome, bowel obstruction, or major resection of the stomach or bowel
  -  All prior treatment-related toxicities must be CTCAE v4 grade =< 1 (except alopecia) at the time of randomization
  -  Patients must have a left ventricular ejection fraction >= lower limit of normal by echocardiogram (ECHO) or multigated acquisition scan (MUGA)
  -  Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min
  -  Bilirubin =< 1.5 times upper limit of normal
  -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 times upper limit of normal
  -  Albumin >= 2.5 g/dL
  -  Prothrombin time (PT) and activated partial thromboplastin time (APTT) =< 1.5 times upper limit of normal
  -  Neutrophil count >= 1.5 x 10^9/L
  -  Platelet count >= 100 x 10^9/L
  -  Hemoglobin >= 9.0 g/dL
  -  If letrozole is selected as the control therapy, patients must be postmenopausal, either following bilateral oophorectomy or at least 5 years after spontaneous menopause; patients within 5 years of spontaneous menopause or who have had a hysterectomy without bilateral oophorectomy must have postmenopausal luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels; patients on hormone replacement therapy (HRT) must agree to withdrawal of hormone therapy before letrozole is started
  Exclusion Criteria:
  -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  -  Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib or standard of care agent
  -  If patients have had a potential index lesion radiated, it must have progressed post radiation therapy to be used as a measurable eligibility lesion
  -  Patients may not have received prior MEK, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), or v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor therapy
  -  Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:
  -  Patients may not be receiving any other anti-cancer or investigational agents
  -  The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to St. John's Wort, kava, ephedra [ma huang], gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)
  -  Patients with known leptomeningeal or brain metastases or spinal cord compression should be excluded from this clinical trial
  -  Patients with a bowel obstruction or any other gastrointestinal condition that might affect absorption of the oral drug should be excluded; this would include patients with inability to swallow and retain orally-administered medication, malabsorption syndrome, or those with a major resection of the stomach or bowels
  -  Patients with a history of interstitial lung disease or pneumonitis
  -  Patients with a previous or current malignancy at other sites should be excluded, with the exception of:
  -  Curatively treated local tumors such as carcinoma-in-situ of the cervix, basal or squamous cell carcinoma of the skin
  -  Tumors for which no relapse has been observed within 5 years
  -  Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible); patients with human immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications
  -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients, or to dimethyl sulfoxide (DMSO), or to Cremophor EL (polyoxyethylated castor oil); please note, exclusion for Cremophor is unnecessary unless paclitaxel is the only agent available and the patient randomizes to the conventional therapy option
  -  Patients with a history or evidence of cardiovascular risk, including any of the following:
  -  Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN)
  -  Bazett's corrected QT (QTcB) >= 480 msec
  -  History or evidence of current clinically significant uncontrolled arrhythmias
  -  Exception: Subjects with controlled atrial fibrillation for > 30 days prior to randomization are eligible
  -  History of (within 6 months prior to randomization) acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting
  -  History or evidence of current >= class II congestive heart failure as defined by New York Heart Association (NYHA)
  -  Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy
  -  Patients with intra-cardiac defibrillators or permanent pacemakers
  -  Known cardiac metastases
  -  Patients with a history or current evidence/risk of retinal vein occlusion (RVO)
  -  Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures
  -  Patients who require use of a concomitant medication that can prolong the QT interval
  -  Animal reproductive studies have not been conducted with trametinib; therefore, the study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable)

Relevance to patient case: not relevant