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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2016 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02101788
First received: March 28, 2014
Last updated: August 29, 2016
Last verified: July 2016
  Purpose
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.

Condition Intervention Phase
Micropapillary Serous Carcinoma
Ovarian Serous Adenocarcinoma
Primary Peritoneal Serous Adenocarcinoma
Recurrent Ovarian Carcinoma
Recurrent Primary Peritoneal Carcinoma
Other: Laboratory Biomarker Analysis
Drug: Letrozole
Drug: Paclitaxel
Drug: Pegylated Liposomal Doxorubicin Hydrochloride
Other: Pharmacological Study
Other: Quality-of-Life Assessment
Drug: Tamoxifen Citrate
Drug: Topotecan Hydrochloride
Drug: Trametinib
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Progression-free survival (PFS) [ Time Frame: Time from study entry to time of progression or death, whichever occurs first, assessed up to 10 years ] [ Designated as safety issue: No ]
    Patients will be grouped by their randomized treatment for intention-to-treat analyses.


Secondary Outcome Measures:
  • Incidence of adverse events (AEs) assessed using the National Cancer Institute CTCAE version 4 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    The severity of each AE will be assessed. Patients will be tabulated according to their maximum severity for each organ system or preferred term. Summarized with descriptive statistics for the patients in the safety analysis dataset.

  • Objective tumor response rate (complete response and partial response) using the RECIST 1.1 [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Compared between the arms using logistic regression via a model incorporating study arm and the factors used in the minimization algorithm. The p-value associated with study arm will be obtained from this model. An 80% confidence interval for the odds ratio will be provided.

  • Overall survival [ Time Frame: Time from study entry to time of death or date of last contact, assessed up to 10 years ] [ Designated as safety issue: No ]
    Based on a log-rank test. Characterized by treatment group with Kaplan-Meier plots and estimates of the median time until death. The log rank test will be used to compare treatment groups with respect to overall survival.

  • Quality of life as measured by FACT-GOG-NTX [ Time Frame: Up to 52 weeks ] [ Designated as safety issue: No ]
    Examined with a mixed model, adjusting for pretreatment TOI score, age, and treatment option (PLD, weekly topotecan hydrochloride, or weekly paclitaxel). The overall type I error for the two primary QoL hypotheses (1 and 2) will be controlled at alpha=0.10 by using a Bonferroni adjustment: each will be tested at alpha=0.0513. The overall alpha for the QoL hypotheses will be controlled by testing the secondary hypothesis only if one or both of the two primary hypotheses are rejected. All tests will be two-sided.

  • Quality of life as measured by FACT-O-TOI [ Time Frame: Up to 52 weeks ] [ Designated as safety issue: No ]
    Examined with a mixed model, adjusting for pretreatment TOI score, age, and treatment option (PLD, weekly topotecan hydrochloride, or weekly paclitaxel). The overall type I error for the two primary quality of life (QoL) hypotheses (1 and 2) will be controlled at alpha=0.10 by using a Bonferroni adjustment: each will be tested at alpha=0.0513. The overall alpha for the QoL hypotheses will be controlled by testing the secondary hypothesis only if one or both of the two primary hypotheses are rejected. All tests will be two-sided.


Other Outcome Measures:
  • Cell-free DNA (cfDNA) in plasma (translational research) [ Time Frame: Up to day 1 of course 3 ] [ Designated as safety issue: No ]
    Total plasma cell-free DNA will be quantified. Tumor response will be correlated with concentrations of cfDNA.

  • Changes in DUSP6 protein levels (translational research) [ Time Frame: Baseline to up to day 1 of course 3 ] [ Designated as safety issue: No ]
    Protein levels will be analyzed and their relationship with tumor response will be explored. Testing will be done using one-sided tests with alpha=0.05.

  • Changes in ER protein levels (translational research) [ Time Frame: Baseline to up to day 1 of course 3 ] [ Designated as safety issue: No ]
    Protein levels will be analyzed and their relationship with tumor response will be explored. Testing will be done using one-sided tests with alpha=0.05.

  • Changes in pERK protein levels (translational research) [ Time Frame: Baseline to up to day 1 of course 3 ] [ Designated as safety issue: No ]
    Protein levels will be analyzed and their relationship with tumor response will be explored. Testing will be done using one-sided tests with alpha=0.05.

  • Changes in PR protein levels (translational research) [ Time Frame: Baseline to up to day 1 of course 3 ] [ Designated as safety issue: No ]
    Protein levels will be analyzed and their relationship with tumor response will be explored. Testing will be done using one-sided tests with alpha=0.05.

  • KRAS mutations, determined by Next-Generation sequencing mutational analysis (translational research) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The association between KRAS mutations and tumor response and PFS will be explored using Cox proportional hazards models.

  • Mutations in genetic pathways, determined by Next-Generation sequencing mutational analysis (translational research) [ Time Frame: Up to day 1 of course 3 ] [ Designated as safety issue: No ]
    Mutations of genes in the MAPK and PI3K/AKT/mTOR pathways will be analyzed. Testing will be done using one-sided tests with alpha=0.05.

  • Pharmacokinetic parameters of trametinib (translational research) [ Time Frame: Pre-dose and 4-8 hours post-dose on course 1, day 15; pre-dose and 2 hours post-dose on course 1, day 28; 30 minutes post-dose on course 2, day 1; pre-dose and 30 minutes on course 3, day 1 ] [ Designated as safety issue: No ]
    Plasma-time concentration data trametinib will be displayed in tables and/or graphs. Population pharmacokinetic parameters of trametinib and combination therapies such as clearance (CL) and volume of distribution (V) will be determined. In addition, the influence of various covariates (e.g. age, weight, and race) on the pharmacokinetic parameters will be examined.

  • Transcriptional signatures that will predict MEK addiction and sensitivity to trametinib (translational research) [ Time Frame: Up to day 1 of course 3 ] [ Designated as safety issue: No ]
    Identified by RNASeq. Testing will be done using one-sided tests with alpha=0.05.


Estimated Enrollment: 250
Study Start Date: February 2014
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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 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.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Letrozole
Given PO
Other Names:
  • CGS 20267
  • Femara
Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat
Drug: Pegylated Liposomal Doxorubicin Hydrochloride
Given IV
Other Names:
  • ATI-0918
  • Caelyx
  • DOX-SL
  • Doxil
  • Doxilen
  • Doxorubicin HCl Liposome
  • Doxorubicin Hydrochloride Liposome
  • Duomeisu
  • Evacet
  • LipoDox
  • Liposomal Adriamycin
  • Liposomal Doxorubicin Hydrochloride
  • Liposomal-Encapsulated Doxorubicin
  • Pegylated Doxorubicin HCl Liposome
  • S-Liposomal Doxorubicin
  • Stealth Liposomal Doxorubicin
  • TLC D-99
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Drug: Tamoxifen Citrate
Given PO
Other Names:
  • Apo-Tamox
  • Clonoxifen
  • Dignotamoxi
  • Ebefen
  • Emblon
  • Estroxyn
  • Fentamox
  • Gen-Tamoxifen
  • Genox
  • ICI 46,474
  • ICI-46474
  • Jenoxifen
  • Kessar
  • Ledertam
  • Lesporene
  • Nolgen
  • Noltam
  • Nolvadex
  • Nolvadex-D
  • Nourytam
  • Novo-Tamoxifen
  • Novofen
  • Noxitem
  • Oestrifen
  • Oncotam
  • PMS-Tamoxifen
  • Soltamox
  • TAM
  • Tamax
  • Tamaxin
  • Tamifen
  • Tamizam
  • Tamofen
  • Tamoxasta
  • Tamoxifeni Citras
  • Zemide
Drug: Topotecan Hydrochloride
Given IV
Other Names:
  • Hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • Topotecan HCl
  • topotecan hydrochloride (oral)
Experimental: Arm B (trametinib)
Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Drug: Trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   19 Years and older   (Adult, Senior)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02101788

  Show 419 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: David Gershenson NRG Oncology
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02101788     History of Changes
Other Study ID Numbers: NCI-2014-00629  NCI-2014-00629  GOG-0281  GOG-0281  U10CA180868 
Study First Received: March 28, 2014
Last Updated: August 29, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Adenocarcinoma
Ovarian Neoplasms
Cystadenocarcinoma, Serous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Paclitaxel
Liposomal doxorubicin
Letrozole
Trametinib
Albumin-Bound Paclitaxel
Doxorubicin
Topotecan
Tamoxifen
Citric Acid
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators

ClinicalTrials.gov processed this record on August 29, 2016