Last updated: 02/04/2020 15:40:13

Adjusting for treatment crossover in the BREAK-3 and METRIC trials

GSK study ID
117385
Clinicaltrials.gov ID
Not applicable
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Overview
Eligibility
Locations
Study documents
Results summary
Plain language summaries
Additional information

Trial overview

Official title: Adjusting for treatment crossover in the BREAK-3 and METRIC trials
Trial description: Treatment crossover occurs when subjects 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 survival data from the BREAK-3 and METRIC trials (both trials are two-arm, open-label, randomized Phase III studies) to estimate an adjusted treatment effect that attempts to control for the potential consequence of treatment crossover. A two staged approach will be used to analyze patient level data from the BREAK-3 and METRIC trials and a range of statistical methods will be applied to adjust for treatment crossover at each stage. Analyses will be undertaken as a feasibility stage (to test the validity and appropriateness of the rank preserving structural failure time model (RPSFTM ) and iterative parameter estimation (IPE) methods), followed by a final analysis stage which may include the inverse probability of censoring weights (IPCW) method .
Stage 1 [Feasibility] – involves the application of two initial methods (RPSFT & IPE) for treatment crossover analyses using the trial data sets for BREAK-3 and METRIC trials. The respective treatment effects will be assessed and the methods validated.
Stage 2 [Final Analysis] – taking into account the economic model being developed and additional mature trial data to be provided in the future, this more comprehensive stage involves the application of additional methods for addressing treatment crossover, including the IPCW, if this is deemed appropriate given the crossover mechanism, dataset characteristics, and data availability.
Primary purpose:
Not applicable
Trial design:
Not applicable
Masking:
Not applicable
Allocation:
Not applicable
Primary outcomes:

Overall survival (OS) data from BREAK-3 and METRIC trials will be reported based on various analyses that control for the effect of treatment crossover.

Timeframe: OS data will be based on time from randomization to date of death or censoring. For feasibility analyses data cut-off of June 2012 for BREAK-3 trial and October 2011 for METRIC trial will be used.

Secondary outcomes:
Not applicable
Interventions:
  • Drug: dacarbazine
  • Drug: dabrafenib
  • Drug: trametinib
  • Drug: paclitaxel
    • Enrollment:
    0
    Primary completion date:
    2015-20-03
    Observational study model:
    Cohort
    Time perspective:
    Retrospective
    Clinical publications:
    Not applicable
    Medical condition
    Cancer, Neoplasms
    Product
    dabrafenib, dabrafenib/trametinib, trametinib
    Collaborators
    Not applicable
    Study date(s)
    October 2012 to March 2015
    Type
    Observational
    Phase
    Not applicable

    Participation criteria

    Sex
    Female & Male
    Age
    18+ years
    Accepts healthy volunteers
    none
    • For BREAK-3 trial key inclusion criteria included:
    • Histologically confirmed advanced (unresectable Stage III) or metastatic (Stage IV) BRAF V600E mutation positive melanoma as determined by central laboratory testing
    • For BREAK-3 trial key exclusion criteria included:
    • Ocular or primary mucosal melanoma
    Inclusion and exclusion criteria
    Inclusion criteria:
    • For BREAK-3 trial key inclusion criteria included:
    • Histologically confirmed advanced (unresectable Stage III) or metastatic (Stage IV) BRAF V600E mutation positive melanoma as determined by central laboratory testing
    • Treatment naïve for advanced/metastatic disease, with the exception of IL-2, surgery, and radiotherapy, which were allowed
    • Measurable disease according to RECIST Version 1.1
    • Age at least 18 years of age
    • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
    • Adequate organ function For METRIC trial key inclusion criteria included:
    • Histologically confirmed, Stage III unresectable (Stage IIIC) or metastatic (Stage IV) cutaneous melanoma, which is also determined to be BRAF V600E/K mutation positive by the central reference laboratory.
    • Subjects may have received no prior treatment or up to 1 prior regimen of chemotherapy for advanced or metastatic melanoma.
    • Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
    • Adequate screening organ function
    • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
    Exclusion criteria:
    • For BREAK-3 trial key exclusion criteria included:
    • Ocular or primary mucosal melanoma
    • Currently receiving anti-cancer therapy, or use of any investigational anti-cancer or other drug within 28 days of receipt of first dose of GSK2118436
    • Major surgery, radiotherapy, or immunotherapy within last 4 weeks
    • History of other malignancy. Subjects who had been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma were eligible.
    • History of human immunodeficiency virus infection or glucose-6-phosphate dehydrogenase deficiency
    • Evidence of active central nervous system (CNS) disease or cardiac metastases
    • Cardiac abnormalities, including: QTc ≥480 msec; history of acute coronary syndrome (including unstable angina), coronary angioplasty, stenting, or cardiac arrhythmias (except sinus arrhythmia) within past 24 weeks; New York Heart Association Class II-IV heart failure; or abnormal valve morphology documented by echocardiogram. For METRIC trial key exclusion criteria included:
    • Any prior use of BRAF/MEK inhibitors, or ipilimumab in the advanced or metastatic setting.
    • Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within the last 21 days. Chemotherapy given daily or weekly without the potential for delayed toxicity within the last 14 days.
    • History of other malignancy. Subjects who had been disease-free for 3 years or subjects who had a history of completely resected non-melanoma skin cancer were eligible.
    • Any serious and/or unstable pre-existing medical (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.
    • Brain metastases with the following exceptions that are ALL confirmed by the GSK Medical Monitor:
    • All known lesions must be previously treated with surgery or stereotactic radiosurgery (prior whole brain radiotherapy is not allowed), and
    • Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size), or if no longer present, must be confirmed as no evidence of disease, for 90 days prior to randomization (must be documented with two consecutive MRI or CT scans at least 60 days apart using contrast), and
    • Asymptomatic with no corticosteroids requirement for ≥ 30 days prior to randomization, and
    • No enzyme-inducing anticonvulsants for ≥ 30 days prior to randomization.
    • History or evidence of cardiovascular risk
    • History or current evidence / risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)

    Trial location(s)

    This study does not involve prospective enrollment of participants.

    Study documents

    No study documents available.

    Results overview

    No study documents available

    Recruitment status
    Study complete
    Actual primary completion date
    2015-20-03
    Actual study completion date
    2015-20-03

    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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