- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03352947
Continuous vs Intermittent Dabrafenib Plus Trametinib in BRAFV600 Mutant Stage 3 Unresectable or Metastatic Melanoma (INTERIM)
INTERIM: a Randomised Phase II Feasibility Study of INTERmittent Versus Continuous Dosing or Oral Targeted Combination Therapy in Patients With BRAFV600 Mutant Stage 3 Unresectable or Metastatic Melanoma
Study Overview
Detailed Description
Metastatic melanoma has a very poor prognosis: median overall survival is 8 months untreated and around 2 years even with optimal systemic therapies. A gene called BRAF is abnormal in about half of melanomas and biological agents targeting the BRAF pathway have been shown to extend life. They are now routinely available in NHS clinical practice.
Giving BRAF and MEK inhibitor drugs together offers the best anti-cancer treatment for these patients. However, treatment is limited by side-effects (often affecting the skin) and secondary resistance (which means the cancer regrows usually after about a year).
Laboratory experiments and case reports suggest intermittent dosing of these chronic orally administered drugs makes BRAF pathway inhibitors work for longer, extending life and reducing side effects. The INTERIM trial aims to test whether less treatment than usual is acceptable to patients and doctors and, potentially, more beneficial. The INTERIM trial also aims to develop better tools to monitor skin side-effects.
The target population will be male and female participants aged 18 and over with BRAFV600 mutant stage 3 unresectable or metastatic melanoma.Patients will be provided with information regarding the trial both through conversation with investigators and research nurses and in writing via a patient information sheet. Patients will be given time to ask questions and discuss with family/support structures before deciding to participate. If the patient agrees to take part, they will be asked to provide written consent.
Visit schedule for consenting patients:
Screening:
Consenting patients will enter the screening/baseline phase, which will be completed within 28 days prior to randomisation. This will include assessing the patient against inclusion & exclusion criteria.
Randomisation:
If eligible, patients will be randomly assigned to either treatment arms using a web-based central randomisation system. Patients will be randomised on a 1:1 basis to one of 2 arms:
Control arm: dabrafenib 150mg twice daily and trametinib 2mg once daily, taken by mouth continuously on a 4 week cycle Experimental arm: dabrafenib 150mg twice daily x 3 weeks and trametinib 2mg once daily x 2 weeks, on a 4 week cycle
On treatment:
During the first two cycles of treatment patients will attend the hospital every two weeks (on days 1 and 15 of the cycle) where they will have a clinical review.
From cycle 3 onwards patients will attend the hospital only on day 1 of the cycle.
If patients are on treatment for more than 52 weeks, clinic visits can be every other cycle with telephone follow-up between to ensure patient review is at least every 4 weeks until progression.
End of Treatment:
At the end of treatment an additional clinical visit will be performed to review the patient. If at the time of treatment cessation patients have not met the criteria for disease progression they will be followed up every 4 weeks. After 52 weeks since randomisation there will be the option of clinic visits every 8 weeks with telephone follow-up in between.
Disease progression:
Patients will have a clinical visit at the time of protocol-defined disease progression.
Follow-up after disease progression:
Patients will attend hospital every three months after disease progression for a minimum of 9 months from randomisation.
Trial procedures:
Clinical review & physical examinations:
Patients will be reviewed by the trial team during the screening period, at every treatment and follow-up visit. This will involve recording any medications they may be taking, and any symptoms and/or side-effects they may have. Patients will also have a physical examination, and assessment of blood pressure as part of this review, and the clinical team will assess the patient's clinical status using ECOG and Karnofsky performance status scales.
Baseline skin assessment & skin toxicity questionnaires:
At screening the patient and clinician will be asked to complete a questionnaire about the baseline condition of the patient's skin. If during treatment there are any skin-related adverse events both the patient and clinician will be asked to complete a skin toxicity questionnaire.
Compliance assessment:
During treatment at each clinical visit the patient will be asked to bring their medication along with their diary card.The clinical team will record how many tablets remain and how many tablets have been taken. The patient will be asked to record in the diary card the date and time when they take their medication. Both of these activities will be used to assess the patient's compliance to the treatment regimen.
Pregnancy test:
Women of child bearing potential will have a pregnancy test at screening to ensure they are not pregnant and are therefore able to receive the trial drugs.
Electrocardiogram (ECG):
An ECG test is required before starting the trial.
Echocardiogram (ECHO):
An ECHO is required prior to starting the trial in patients with a history of cardiac problems, in patients with no cardiac history and a normal ECG it must be performed within two weeks of starting trial drug. ECHOs will subsequently be performed as standard of care, the recommended frequency is during cycle 4 and every 12 weeks thereafter to ensure that patients are tolerating the trial drugs well.
Blood samples (routine and research):
Patients will be asked to have routine blood tests (FBC, renal, liver, bone profiles, LDH) to ensure that they are fit enough for the trial, and that they are tolerating the drug well. These blood samples will be taken at every clinical visit during treatment and at disease progression.
Patients will also be asked to give extra blood for research related to this trial. The samples will be used to measure circulating tumour DNA (ctDNA). An extra blood sample will be taken every 2 weeks for the first two cycles of treatment, every 4 weeks for the next two cycles, then every 8 weeks, and at disease progression.
Patients will be asked if they wish to participate in optional pharmacokinetic sampling. This will involve collection of 9 blood samples on both cycle 1 day 1, and cycle 2 day 15 at timepoints after they have taken their tablets. Additionally, 3 blood samples would be taken if their disease progresses.
Tumour assessments:
Patients will have an initial CT scan of body and head during the screening period. Scans will be repeated between days 8-15 of cycle 2 and then every 8 weeks until the end of treatment. If treatment continues beyond 52 weeks imaging can be reduced to every 12 weeks. If the initial screening head scan is clear, the head scan only requires repeating at every other assessment.
Quality of Life questionnaires:
Patients will be asked to fill in questionnaires about their quality of life at screening on day 1 of cycle 2, and then every12 weeks until the end of participation in the trial.
Tumour Tissue collection:
Upon starting treatment patients will be asked to donate previously archived tissue collected for research purposes. If patients undergo surgical resection or biopsy during the course of the trial for progressive disease, a tumour sample will be requested for this research.
Patient Experience survey:
Patient who do not consent to participate in the trial will be asked to complete a questionnaire to explore their reasons for declining. Additionally, patients who do participate in the trial will be asked to complete patient experience questionnaires after consent and after 9 months participation in the trial. These questionnaires will ask the patients about their experience of participating in the trial and any toxicity they experienced.
Patients may continue on allocated treatment as long as they benefit from the treatment and it is tolerable. Patients will be followed for a minimum of 9 months from randomisation to a maximum of 5 years.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
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England
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Cambridge, England, United Kingdom, CB2 2QQ
- Addenbrooke's Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Signed informed consent
- Age ≥18 years old
- Histologically or cytologically confirmed BRAFV600 mutant stage 3 unresectable or metastatic melanoma
- Measurable disease by RECIST
- ECOG performance status 0-2
- Minimum life expectancy 12 weeks
- Adequate bone marrow, renal and liver function
- Received no prior BRAF or MEK inhibitor therapy for metastatic disease
- Willing and able to comply with the scheduled visits, treatment plans, laboratory tests, completion of QoL questionnaires and other study procedures
- Archival tumour tissue sample available
- Women of child-bearing potential and all sexually active male patients must agree to use effective contraception methods throughout treatment
Exclusion Criteria:
- Concomitant immunotherapy being administered to treat advanced melanoma
- Other invasive malignancies diagnosed within the last year which are not in complete remission, or for which additional therapy is required
- Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the investigator would place the patient at undue risk or interfere with the trial
- Women who are pregnant, plan to become pregnant or are lactating during the trial period
- Other investigational anti-cancer drugs
- Use of strong inducers and inhibitors of CYP3A or CYP2C8
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: Continuous (Standard)
Dabrafenib 150mg twice daily 12 hours apart, on days 1-28 of a 28 day cycle plus Trametinib 2mg once daily, on days 1-28 of a 28 day cycle
|
150mg Dabrafenib twice daily day 1-21 of 28 day cycle in intermittent arm Day 1-28 of 28 day cycle in continuous arm
Other Names:
Trametinib 2mg once daily Day 1-14 of a 28 day cycle in intermittent arm Day 1-28 of a 28 day cycle in the continuous arm
Other Names:
|
EXPERIMENTAL: Intermittent (experimental)
Dabrafenib 150mg twice daily 12 hours apart, on days 1-21 of a 28 day cycle plus Trametinib 2mg once daily, on days 1-14 of a 28 day cycle
|
150mg Dabrafenib twice daily day 1-21 of 28 day cycle in intermittent arm Day 1-28 of 28 day cycle in continuous arm
Other Names:
Trametinib 2mg once daily Day 1-14 of a 28 day cycle in intermittent arm Day 1-28 of a 28 day cycle in the continuous arm
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Recruitment Rate
Time Frame: To be assessed once the trial has been recruiting for 15 months, or when 15 sites have been open for 6 months whichever is sooner
|
Average number of patients recruited per site per two months.
|
To be assessed once the trial has been recruiting for 15 months, or when 15 sites have been open for 6 months whichever is sooner
|
Treatment compliance
Time Frame: 6 months from randomisation
|
percentage of patients completing the allocated treatment
|
6 months from randomisation
|
Overall Quality of Life
Time Frame: 6 months from randomisation
|
global health status score derived from (EORTC) QLQ-C30 questionnaire
|
6 months from randomisation
|
Progression Free survival
Time Frame: calculated as the duration from the date of randomisation to the date of first progression or death from any cause, whichever occurs first, assessed up to 5 years
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Assessed according to standard Response Criteria in Solid Tumours (RECIST v1.1)
|
calculated as the duration from the date of randomisation to the date of first progression or death from any cause, whichever occurs first, assessed up to 5 years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of treatment emergent adverse events (safety and tolerability)
Time Frame: Through study completion, an average of 1 year
|
Assess using standard cancer National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4.03)
|
Through study completion, an average of 1 year
|
Objective response rate
Time Frame: Through study completion, an average of 1 year
|
assessed according to RECIST v1.1
|
Through study completion, an average of 1 year
|
Time to treatment failure
Time Frame: Through study completion, an average of 1 year
|
Time from starting drug treatment (day 1, cycle 1) until day 1 of last cycle + 28 days
|
Through study completion, an average of 1 year
|
Overall survival
Time Frame: Assessed up to 5 years
|
calculated as duration from date of randomisation to the date of death from any cause
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Assessed up to 5 years
|
Patient Reported Outcomes focusing on skin toxicity evaluation
Time Frame: Through study completion, an average of 1 year
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assessed using skin-specific patient reported outcome measures
|
Through study completion, an average of 1 year
|
Patient Experience
Time Frame: Surveys at screening and after 9 months. Interviews by invitation at a later date
|
Surveys of patients in both arms of the trial.
Semi-structured interview in a subset of patients.
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Surveys at screening and after 9 months. Interviews by invitation at a later date
|
Impact on Quality of Life
Time Frame: At 6 months from baseline
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Using EORTC QLQ-C30 questionnaire
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At 6 months from baseline
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Health Economic Evaluation
Time Frame: Through study completion, an average of 1 year
|
Using EQ-5D 5L questionnaire
|
Through study completion, an average of 1 year
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Kinetics of BRAF mutation load in each arm of the trial
Time Frame: Through study completion, an average of 1 year
|
using blood and tumour tissue taken from recruited patients
|
Through study completion, an average of 1 year
|
Emerging genetic changes associated with acquired resistance
Time Frame: Through study completion, an average of 1 year
|
using blood and tumour tissue taken from recruited patients
|
Through study completion, an average of 1 year
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Pippa Corrie, FRCP, Addenbrookes
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ACTUAL)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neuroendocrine Tumors
- Nevi and Melanomas
- Melanoma
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Trametinib
- Dabrafenib
Other Study ID Numbers
- INTERIM
- 2016-005228-27 (EUDRACT_NUMBER)
- PB-PG-0815-20048 (OTHER_GRANT: NIHR)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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