Clinical Trials /

Continuous vs Intermittent Dabrafenib Plus Trametinib in BRAFV600 Mutant Stage 3 Unresectable or Metastatic Melanoma

NCT03352947

Description:

This feasibility study aims to determine if intermittent dosing is deliverable, based on patient and professional willingness to take part in a randomised trial evaluating less rather than the standard durations of treatment. The trial will evaluate treatment compliance, Progression Free Survival and Quality of Life, to inform whether a subsequent definitive trial is justified and how it should be designed.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Continuous vs Intermittent Dabrafenib Plus Trametinib in BRAFV600 Mutant Stage 3 Unresectable or Metastatic Melanoma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: INTERIM
  • SECONDARY ID: 2016-005228-27
  • SECONDARY ID: PB-PG-0815-20048
  • NCT ID: NCT03352947

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
DabrafenibTafinlarContinuous (Standard)
TrametinibMekinistContinuous (Standard)

Purpose

This feasibility study aims to determine if intermittent dosing is deliverable, based on patient and professional willingness to take part in a randomised trial evaluating less rather than the standard durations of treatment. The trial will evaluate treatment compliance, Progression Free Survival and Quality of Life, to inform whether a subsequent definitive trial is justified and how it should be designed.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Continuous (Standard)Active ComparatorDabrafenib 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
  • Dabrafenib
  • Trametinib
Intermittent (experimental)ExperimentalDabrafenib 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
  • Dabrafenib
  • Trametinib

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Average number of patients recruited per site per two months.

Secondary Outcome Measures

Measure:Incidence of treatment emergent adverse events (safety and tolerability)
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Assess using standard cancer National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4.03)
Measure:Objective response rate
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:assessed according to RECIST v1.1
Measure:Time to treatment failure
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Time from starting drug treatment (day 1, cycle 1) until day 1 of last cycle + 28 days
Measure:Overall survival
Time Frame:Assessed up to 5 years
Safety Issue:
Description:calculated as duration from date of randomisation to the date of death from any cause
Measure:Patient Reported Outcomes focusing on skin toxicity evaluation
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:assessed using skin-specific patient reported outcome measures
Measure:Patient Experience
Time Frame:Surveys at screening and after 9 months. Interviews by invitation at a later date
Safety Issue:
Description:Surveys of patients in both arms of the trial. Semi-structured interview in a subset of patients.
Measure:Quality of Life
Time Frame:At 6 months from baseline
Safety Issue:
Description:Using EORTC QLQ-C30 questionnaire
Measure:Health Economic Evaluation
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Using EQ-5D 5L questionnaire

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Cambridge University Hospitals NHS Foundation Trust

Last Updated

November 23, 2017