| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent low grade serous ovarian or peritoneal cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Ovarian or peritoneal cancer which has came back or started to grow again |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine if treating patients with recurrent or progressive low grade serous ovarian or peritoneal cancer (previously treated with platinum-based chemotherapy) with Trametinib improves progression free survival compared to current treatment options. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
- To determine the nature, frequency and maximum degree of toxicities experienced by patients in each treatment arm of study.
- To determine the quality of life of patients, as assessed by Functional Assessment of Cancer Therapy- Ovarian (FACT-0)
: 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-TOI
: To compare Trametinib to the control arm with regard to patients self reported acute (up to post cycle 6) neurotoxicity as measured by FACT-GOG-NTX
- To estimate the objective response rate in patients in each treatment arm of study.
Exploratory Objectives:
- To estimate the overall survival of patients in each treatment arm.
- To estimate the tumour response rate in patients receiving trametinib after crossover from standard of care.
- To estimate the progression free survival in patients receiving trametinib after crossover from standard of care.
- To c |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Patients age greater than 18 years of age.
- Patients initially diagnosed with low grade serous ovarian or peritoneal carcinoma that as recur as low grade serous carcinoma.
- Patients initially diagnosed with serous borderline ovarian or peritoneal carcinoma.
- Patients must have documented low grade serous carcinoma . Confirmation must occur by prospective pathology review prior to study entry.
- Patients must have measurable disease according Response Evaluation Criteria in Solid Tumours (RECIST 1.1)
- 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 five choices in the "standard therapy" arm.
- An image guided core biopsy of fresh tissue must be obtained prior to randomisation and submitted for translational research purposes.
- Patients of childbearing potential must have a negative pregnancy test, cannot be breast feeding, and must agree to practice a highly effective means of birth control prior to study entry, for the duration of the study participation, and for six months after last dose of study treatment.
- Patient has given written informed consent
- Patient must have performance status of 0 or 1.
- Patient must be 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 or major resection of the stomach or bowels.
- Patients must have a left ventricular ejection fraction > = lower limit of normal by echocardiogram (ECHO) of multigated acquistion scan (MUGA).
- Patients must have adequate bone marrow function, renal function, endocrine and hepatic function as defined by study protocol.
- If letrozole is selected as the control therapy, patients must be menopausal, either following bilateral oophorectomy or least 5 years 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 follical stimulating hormone (FSH) levels; patients on hormone replacement therapy must agree to withdrawal of hormone therapy before letrozole is started.
- All prior treatment-related toxicities must be CTCAE v4 grade <1 (except alopecia) at the time of randomization
- At least 4 weeks must have elapsed since the patient underwent any major surgery.
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| E.4 | Principal 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.
- If patients have received 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 they will be excluded.
- If patients have had a potential index lesion radiated, it must have progressed post radiation therapy to be used a measurable eligibility lesion.
- Patients may not have received prior MEK, KRAS, or 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.
Tumours for which no relapse has been observed within 5 years.
- Patients with active hepatitis B or C; human immunodeficiency virus (HIV) infected patients with adequate CD4 counts (> 350 cells/mm3) will be eligible; HIV-positive patients on combination antiretroviral therapy are ineligible
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug, 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 randomisation are eligible
: History of (within 6 months prior to randomisation) 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) or central serous retinopathy (CSR)
- Patients with any psychological, familial, sociological, or geographical condition that may potentially hamper compliance with the study protocol and follow-up schedule
- Patients who require use of a concomitant medication that can prolong the QT interval.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure is to estimate the progression free survival (PFS) as defined by RECIST 1.1 criteria, in women with recurrent low grade serous carcinoma of the ovary or peritoneum treated with Trametinib and compare this to PFS in women treated with commercially available agents consisting of one of five possible agents. PFS is defined as the duration of time from date of randomisation to date of progression or death, which ever occurs earlier. CA125 progression alone will not be considered as progressive disease. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Disease evaluation will be performed based on tumour imaging. All patients will undergo baseline evaluation tumour assessment with a CT scan or MRI of abdomen, chest and pelvis within 28 days prior to starting study treatment. The same modality should be used for the duration of the study. From date of randomisation for 15 months or until progressive disease occurs, patients will undergo imaging every 8 weeks. Patients who have not progressed at the end of 15 months will have subsequent imaging performed only if clinically indicated. Patients that come off treatment for reasons other than progression continue to have imaging scans at the specified time points. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints
- To determine the nature, frequency and maximum degree of toxicities experienced by patients in each treatment arm of study.
- To determine the quality of life of patients, as assessed by Functional Assessment of Cancer Therapy- Ovarian (FACT-0)
: 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-TOI
: To compare Trametinib to the control arm with regard to patients self reported acute (up to post cycle 6) neurotoxicity as measured by FACT-GOG-NTX
- To estimate the objective response rate in patients in each treatment arm of study.
Exploratory Objectives:
- To estimate the overall survival of patients in each treatment arm.
- To estimate the tumour response rate in patients receiving trametinib after crossover from standard of care.
- To estimate the progression free survival in patients receiving trametinib after crossover from standard of care.
- 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.
In addition to secondary and exploratory endpoints for the study there are Translational research objectives
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Toxicity: day 1 of each cycle of treatment assessed using NCI CTCAE Version 4.
- Quality of Life (QOL) as measured by FACT and FACT NTX, QOL questionnaires will be completed at screening, prior to cycle 4, post 4 weeks after cycle 6, 36 weeks and 52 weeks after starting treatment.
- Objective response rates (complete response and partial response) using RECIST 1.1 criteria
Exploratory Endpoints:
- Overall survival, patients will be followed up for survival after progressions
- Tumour response rate in patients receiving trametinib after crossover from standard treatment arm following progression using RECIST 1.1
- Comparison of trametinib to endocrine standard therapy via Quality of Life (QOL)as measured by FACT-O-TOI and FACT-GOG-NTX. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 24 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
For the purposes of the clinical trial authorisation the trial is deemed to have ended 30 days after the last patient remaining on treatment receives the last dose of Trametinib.
For the purposes of the main REC approval, the study end date is deemed to be the date of last data capture. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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