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
Overview
- Phase
- Phase 2
- Intervention
- Letrozole
- Conditions
- Borderline Ovarian Serous Tumor
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 260
- Locations
- 499
- Primary Endpoint
- Progression-free Survival (PFS)
- Status
- Completed
- Last Updated
- 5 months ago
Overview
Brief Summary
This phase II/III trial studies how well trametinib works and compares it to standard treatment with either letrozole, tamoxifen, paclitaxel, pegylated liposomal doxorubicin, or topotecan in treating patients with low-grade ovarian cancer or peritoneal cavity cancer that has come back (recurrent), become worse (progressive), 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 OBJECTIVE: 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). IIa. 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). IIb. 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). III. To estimate the objective response rate (RR) of patients in each treatment arm. IV. To test whether high expression of pERK, as quantified by immunohistochemistry (IHC), is associated with better prognosis (RR or PFS) among patients receiving the randomized treatment. V. To test whether genetic changes associated with MAPK pathway activation (KRAS, NRAS, HRAS, BRAF, MEK, ERBB2 or NF1) are associated with improved prognosis (RR or PFS) among patients receiving the randomized treatment. 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 IV over 30 minutes on days 1, 8, and 15. Cycles 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. Cycles 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients age greater than 18 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 (e.g. MAJOR: laparotomy, laparoscopy, thoracotomy, VATS \[video assisted thorascopic surgery\]); there is no restriction on MINOR procedures: (e.g. 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
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
- •Because the composition, PK, and metabolism of many herbal supplements are unknown, 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 because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
- •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
Arms & Interventions
Arm A (letrozole, tamoxifen, paclitaxel, PLD, topotecan)
Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.
Intervention: Letrozole
Arm A (letrozole, tamoxifen, paclitaxel, PLD, topotecan)
Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.
Intervention: Paclitaxel
Arm A (letrozole, tamoxifen, paclitaxel, PLD, topotecan)
Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.
Intervention: Pegylated Liposomal Doxorubicin Hydrochloride
Arm A (letrozole, tamoxifen, paclitaxel, PLD, topotecan)
Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.
Intervention: Quality-of-Life Assessment
Arm A (letrozole, tamoxifen, paclitaxel, PLD, topotecan)
Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.
Intervention: Questionnaire Administration
Arm A (letrozole, tamoxifen, paclitaxel, PLD, topotecan)
Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.
Intervention: Tamoxifen Citrate
Arm A (letrozole, tamoxifen, paclitaxel, PLD, topotecan)
Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.
Intervention: Topotecan
Arm B (trametinib)
Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Arm B (trametinib)
Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Trametinib Dimethyl Sulfoxide
Outcomes
Primary Outcomes
Progression-free Survival (PFS)
Time Frame: Time from study entry to time of progression or death, an average of 7 months for arm A and 13 months for arm B
Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the PFS endpoint definition.
Secondary Outcomes
- Overall Survival(Time from study entry to time of death or date of last contact, an average of 29 months for arm A and 37 months for arm B)
- Incidence of Adverse Events (AEs)(During treatment period and up to 100 days after stopping the study treatment)
- Patients Reported Acute Quality of Life(1. baseline (prior to cycle 1), 12 weeks (prior to cycle 4), 24 weeks (4 weeks post cycle 6), 36 weeks post cycle 1, 52 weeks post cycle 1.)
- Progression Free Survival(Time from study entry to time of progression or death, an average of 7 months for SOC and 13 months for the treatment (Trametinib) arm.)
- pERK Expression(Baseline)
- Objective Tumor Response Rate (Complete Response and Partial Response)(Time from study entry to time of progression or death, an average of 7 months for arm A and 13 months for arm B)
- Patient Reported Acute Peripheral Neuropathy Symptoms(Up to 52 weeks)