Last updated: 11/03/2018 21:18:21
Updated analyses adjusting for treatment crossover in Part C of a Phase 2 trial (BRF113220) of dabrafenib and trametinib combination therapy in patients with metastatic melanoma based on recent dataset (March 2013)
Clinicaltrials.gov ID
Not applicable
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Trial overview
Official title: Updated analyses adjusting for treatment crossover in Part C of a Phase 2 trial (BRF113220) of dabrafenib and trametinib combination therapy in patients with metastatic melanoma based on recent dataset (March 2013)
Trial description: Treatment crossover occurs when patients in the control group of a clinical trial are allowed to switch onto the experimental treatment at some point during follow-up. Crossover is becoming more commonplace in clinical trials of cancer treatments. Generally crossover is permitted when the new intervention has been shown to be effective in interim analyses (often based upon an outcome measure such as time to disease progression), and therefore it is deemed unethical to deny treatment to control group patients. In these circumstances if an “intention to treat” analysis is conducted – that is, the survival data are analyzed according to the arms to which patients were randomized – the estimate of the overall survival (OS) advantage associated with the new treatment could be biased. If control group patients that cross over benefit from the new treatment measures of average OS in the control group (for example means, or medians) will be higher than would have been observed if treatment crossover had not occurred. This will result in the OS advantage of the new treatment being underestimated. This is particularly important in the context of economic evaluation because survival estimates are used in cost-effectiveness analyses used to support health technology assessment submissions, and treatment crossover is likely to cause the cost-effectiveness of the new treatment to be underestimated. The objective of this study is to analyze updated survival data (March 2013 dataset) from Part C (only for dabrafenib (150mg) plus trametinib (2mg) vs. dabrafenib monotherapy (150mg)) of a phase 2 study (BRF113220) investigating the combination of dabrafenib and trametinib compared to dabrafenib alone to estimate an adjusted treatment effect that attempts to control for the potential consequence of treatment crossover. Two statistical methods (rank preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE)) will be applied to adjust for treatment crossover using Part C patient level data from the trial.
Primary purpose:
Not applicable
Trial design:
Not applicable
Masking:
Not applicable
Allocation:
Not applicable
Primary outcomes:
Overall survival data from Part C of the Ph2 trial (BRF113220) will be reported based on various analyses that control for the effect of treatment crossover.
Timeframe: Overall survival data will be based on time from randomization to date of death or censoring. Data cut-off of March 29, 2013
Secondary outcomes:
Not applicable
Interventions:
Enrollment:
162
Primary completion date:
Not applicable
Observational study model:
Case-Control
Time perspective:
Retrospective
Clinical publications:
Not applicable
Medical condition
Melanoma
Product
dabrafenib, dabrafenib/trametinib, trametinib
Collaborators
Not applicable
Study date(s)
October 2013 to October 2013
Type
Observational
Phase
Not applicable
Participation criteria
Sex
Female & Male
Age
18 - 85 Year
Accepts healthy volunteers
none
- Male or female of non-childbearing potential; > or = 18 years of age
- Tumor type criteria:
- Prior exposure to BRAF or MEK inhibitors. Prior anti-cancer therapy in the metastatic setting, with the exception of up to one regimen of chemotherapy and/or interleukin-2.
- History of retinal vein occlusion (RVO) or central serous retinopathy (or chorioretinopathy [CSR]), or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).
Inclusion and exclusion criteria
Inclusion criteria:
- Male or female of non-childbearing potential; > or = 18 years of age
- Tumor type criteria: BRAF mutation-positive melanoma or colorectal cancer (i.e., V600E, V600K or V600D) as determined via genetic testing (other BRAF mutation-positive tumor types could be enrolled in Parts A and B with approval of the GSK medical monitor; Part C only enrolled melanoma subjects). Testing with the GSK BRAF mutation assay could be required for enrolment.
- Archived tissue was required; a fresh biopsy was required if archived tissue was not available, with a BRAF mutation (V600E, V600K or V600D). Only melanoma subjects can be enrolled;
- Measurable disease per RECIST criteria
Exclusion criteria:
- Prior exposure to BRAF or MEK inhibitors. Prior anti-cancer therapy in the metastatic setting, with the exception of up to one regimen of chemotherapy and/or interleukin-2.
- History of retinal vein occlusion (RVO) or central serous retinopathy (or chorioretinopathy [CSR]), or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).
- Visible retinal pathology as assessed by ophthalmic exam that was considered a risk factor for RVO or CSR such as evidence of new optic disc cupping, new visual field defects and intraocular pressure >21 mm Hg as measured by tonography
- Subjects with brain metastases were excluded, unless a. All known lesions were previously treated with surgery or stereotactic radiosurgery, and b. Brain lesion(s), if still present, were confirmed stable (i.e. no increase in lesion size) for ≥90 days prior to first dose on study (documented with two consecutive magnetic resonance imaging [MRI] or computed tomography [CT] scans using contrast), and c. Asymptomatic with no corticosteroids requirement for ≥ 30 days prior to first dose on study, and d. No enzyme-inducing anticonvulsants for ≥ 30 days prior to first dose on study.
- Subjects with a history of pneumonitis or interstitial lung disease.
- History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 6 months.
- QTc interval ≥480 msec (≥500 msec for subjects with Bundle Branch Block).
- Uncontrolled arrhythmias. Subjects with controlled atrial fibrillation for >1 month prior to study Day 1 were eligible.
- Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
- Abnormal cardiac valve morphology (subjects with minimal abnormalities, could be entered on study with approval from the GSK Medical Monitor).
- Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg and/or diastolic > 90 mm Hg which could not be controlled by anti-hypertensive therapy.
- Subjects with intra-cardiac defibrillators or permanent pacemakers
- Cardiac metastases
Trial location(s)
This study does not involve prospective enrollment of participants.
Study documents
Clinical study report
Available language(s): English
Scientific result summary
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Refer to study documents
Recruitment status
Study complete
Actual primary completion date
Not applicable
Actual study completion date
2013-25-10
Plain language summaries
Not applicable. GSK’s transparency policy provides for Plain Language Summaries for Interventional studies.
Additional information about the trial
Not applicable
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