Clinical Trials /

CAcTUS - Circulating Tumour DNA Guided Switch

NCT03808441

Description:

The stay aims to determine whether switching from targeted therapy to immunotherapy based on a decrease in levels of circulating tumour DNA in the blood, will improve the outcome in melanoma patients.

Related Conditions:
  • Cutaneous Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CAcTUS - Circulating Tumour DNA Guided Switch
  • Official Title: A Parallel Arm, Biomarker Driven, Phase II Trial to Determine the Role of Circulating Tumour DNA in Guiding a Switch Between Targeted Therapy and Immune Therapy in Patients With Advanced Cutaneous Melanoma

Clinical Trial IDs

  • ORG STUDY ID: CFTSp129
  • NCT ID: NCT03808441

Conditions

  • Melanoma

Purpose

The stay aims to determine whether switching from targeted therapy to immunotherapy based on a decrease in levels of circulating tumour DNA in the blood, will improve the outcome in melanoma patients.

Detailed Description

      The optimal scheduling of targeted and immune therapies in metastatic melanoma is unknown. At
      present, patients are treated with targeted therapy until acquired resistance develops, and
      then switched to immune therapy. Pre-clinical data has revealed that BRAF inhibition results
      in an environment that can enhance immune responses. Tumours responding to BRAF inhibitors
      but not resistant have been shown to have increased T cell infiltration, improved T cell
      recognition of melanoma associated antigens and reduced production of immunosuppressive
      cytokines. Furthermore, in response to targeted therapy LDH levels, which are associated with
      decreased response to immune therapy reduces, which may improve efficacy of immunotherapy.

      A precise definition of response is required in order to decide upon a switch to immune
      therapy. A radiological definition of response is currently the standard assessment. However
      a scan at a fixed time point of 2 or 3 months does not reflect the wide range of response
      dynamics or allow decision making on an individual patient basis. The investigators have
      developed techniques using circulating tumour DNA (ctDNA) in the metastatic setting, which
      are able to accurately monitor tumour burden over time.

      The aim of this pilot study is to provide a signal as to whether:

        1. In BRAF mutant melanoma the efficacy of immune therapy is enhanced by response to
           pre-treatment with MAPK pathway inhibition with dabrafenib + trametinib.

        2. Changes in ctDNA levels can be used to accurately inform when to switch from targeted to
           immune therapy.

      Data from this study will provide the basis for follow on studies with sufficient power to
      assess whether tumours responding to BRAF inhibition as defined by response in ctDNA can
      improve efficacy of immune therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Standard ArmNo InterventionDabrafenib + Trametinib Switch to N+I at first progression
    ctDNA Guided SwitchActive ComparatorDabrafenib + Trametinib Switch to N+I when ctDNA levels in the blood have dropped by ≥80%.

      Eligibility Criteria

              Inclusion Criteria:
      
                1. Patient capable of giving written informed consent
      
                2. Patients must be willing and able to comply with scheduled visits, treatment schedule,
                   laboratory tests and other requirements of the study.
      
                3. Histological confirmation of cutaneous melanoma
      
                4. ≥ 16 years
      
                5. Stage III un-resectable/ IV disease
      
                6. BRAF p.V600E/K/R mutation confirmed (exact point mutation must be provided to the
                   investigators)
      
                7. At least one target lesion measurable by CT or MRI as per RECIST 1.1
      
                8. Baseline ctDNA (as defined by the mutant BRAF VAF in plasma) ≥5%
      
                9. Adequate organ function
      
               10. ECOG performance status 0/1
      
               11. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to
                   the first dose of study drug
      
               12. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
                   test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to
                   the start of study drug.
      
               13. WOCBP must agree to follow instructions for method(s) of contraception for the
                   duration of treatment with study drugs plus 5 half-lives of the drugs they are taking
                   at treatment completion (5 times the half-life = 125 days [nivolumab]; 5 times the
                   half-life = 90 days [ipilimumab]; 5 times the half life = 40 hours [dabrafenib]; 5
                   times the half life = 50 days [trametinib]) plus 30 days (duration of ovulatory
                   cycle).
      
               14. Males who are sexually active with WOCBP must agree to follow instructions for
                   method(s) of contraception for the duration of treatment plus 5 half-lives of the
                   study drug as above plus 90 days (duration of sperm turnover).
      
               15. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
                   from contraceptive requirements
      
              Exclusion Criteria:
      
                1. Prior systemic anti-cancer treatment (immune therapy, targeted therapy, vaccine
                   therapy, or investigational treatment) for unresectable Stage III or Stage IV
                   melanoma.
      
                2. Prior adjuvant therapy with BRAF +/- MEK inhibitor or adjuvant therapy with
                   combination PD-1 inhibitor plus CTLA-4 inhibitor. Prior adjuvant therapy with PD-1
                   inhibitor is allowed so long as relapse occurred > 6 months from discontinuation of
                   treatment and treatment not stopped due to grade 3 or 4 toxicity.
      
                3. Current use of a prohibited medication
      
                4. History of another malignancy. Exception: patients who have been disease-free for 3
                   years, (i.e. patients with second malignancies that are indolent or definitively
                   treated at least 3 years ago) or patients with a history of completely resected
                   non-melanoma skin cancer. No additional therapy should be required whilst the patient
                   is on study.
      
                5. Any serious or unstable pre-existing medical conditions (aside from malignancy
                   exceptions specified above), psychiatric disorders, or other conditions that could
                   interfere with the patients safety, obtaining informed consent, or compliance with
                   study procedures.
      
                6. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
                   Virus (HCV) infection (patients with laboratory evidence of cleared or chronic (not
                   active) HBV and HCV infection will be permitted).
      
                7. A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
      
                8. Patients with active, known or suspected autoimmune disease. Patients with type 1
                   diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
                   (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or
                   conditions not expected to recur in the absence of an external trigger will be
                   permitted to enrol.
      
                9. Patients with a condition requiring systemic treatment with either corticosteroids
                   (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
                   days of study drug administration. Inhaled or topical steroids and adrenal replacement
                   steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of
                   active autoimmune disease.
      
               10. Patients with interstitial lung disease that is symptomatic or may interfere with the
                   detection or management of suspected drug-related pulmonary toxicity.
      
               11. Brain metastases and leptomeningeal metastases are excluded unless:
      
                     -  Asymptomatic and untreated at presentation, OR
      
                     -  Symptomatic lesions have been definitively treated with surgery or stereotactic
                        surgery (whole-brain radiation may be given as adjuvant treatment), and do not
                        require steroids for control of symptoms
      
                     -  Symptomatic metastases, treated or untreated, or metastases requiring steroids to
                        control symptoms, are excluded
      
               12. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to randomisation
      
               13. Coronary syndromes (including myocardial infarction within 6 months or unstable
                   angina)
      
               14. A history or evidence of current ≥ Class II congestive heart failure as defined by the
                   New York Heart Association (NYHA) guidelines with an ejection fraction of <50%
      
               15. Treatment refractory hypertension defined as a blood pressure of systolic> 150 mmHg
                   and/or diastolic > 95 mm Hg on >3 occasions which cannot be controlled by
                   anti-hypertensive therapy;
      
               16. Known cardiac metastases;
      
               17. Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia,
                   hypocalcaemia), long QT syndrome or taking medicinal products known to prolong the QT
                   interval.
      
               18. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous
                   retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g.,
                   uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled
                   diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes)
      
               19. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
                   chemically related to the study treatments including monoclonal antibodies, their
                   excipients, and/or dimethyl sulfoxide (DMSO) and/or Polysorbate-80-containing
                   infusions.
      
               20. Females who are breast-feeding.
      
               21. Prisoners or patients who are involuntarily incarcerated.
      
               22. Patients who are compulsorily detained for treatment of either a psychiatric or
                   physical (e.g., infectious disease) illness.
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:16 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:CtDNA result critical (red) blood samples returned within 7 working days of samples being received in the laboratory
      Time Frame:12 months from last patient starting trial treatment
      Safety Issue:
      Description:Feasibility of returning samples to hospitals from the laboratory to inform clinical decisions

      Secondary Outcome Measures

      Measure:Screen failure due to ctDNA levels of mutant BRAF VAF <5% Efficacy
      Time Frame:Through study completion, an average of 1 year
      Safety Issue:
      Description:To assess whether BRAF VAF (within the ctDNA) of ≥5% is an appropriate target for study inclusion (by assessing the number and proportion of screen failures
      Measure:First progression free survival (PFS) at 12 months
      Time Frame:Through study completion, an average of 1 year
      Safety Issue:
      Description:To explore whether PFS at 12 months would improve in patients switching from targeted to immune therapy on response to treatment as guided by ctDNA levels of mutant BRAF VAF
      Measure:First progression free survival
      Time Frame:When all patients finished follow up, 4 years after last patient starting treatment
      Safety Issue:
      Description:Time to first progression in both arms
      Measure:Second progression free survival
      Time Frame:When all patients finished follow up, 4 years after last patient starting treatment
      Safety Issue:
      Description:Time to second progression in both arms
      Measure:Overall survival
      Time Frame:When all patients finished follow up, 4 years after last patient starting treatment
      Safety Issue:
      Description:Explore whether survival outcomes would improve in patients switching from targeted to immune therapy on response to treatment as guided by ctDNA levels of mutant BRAF VAF

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:The Christie NHS Foundation Trust

      Trial Keywords

      • Circulating tumour DNA
      • targeted therapy
      • immune therapy
      • dabrafenib
      • trametinib
      • ipilimumab
      • nivolumab

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