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Neoadjuvant Dabrafenib, Trametinib and/or Pembrolizumab in BRAF Mutant Resectable Stage III Melanoma (NeoTrio)

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ClinicalTrials.gov Identifier: NCT02858921
Recruitment Status : Recruiting
First Posted : August 8, 2016
Last Update Posted : November 9, 2017
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Novartis
Information provided by (Responsible Party):
Melanoma Institute Australia

Brief Summary:
This study aims to determine which of 3 drug combinations best reduces the size of tumour prior to surgery for advanced melanoma and prevents the recurrence of melanoma after surgery.

Condition or disease Intervention/treatment Phase
Melanoma Drug: Dabrafenib Drug: Trametinib Drug: Pembrolizumab Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Randomised, Open Label Study of Neoadjuvant Dabrafenib, Trametinib and / or Pembrolizumab in BRAF V600 Mutant Resectable Stage IIIB/C Melanoma
Actual Study Start Date : November 8, 2017
Estimated Primary Completion Date : November 2018
Estimated Study Completion Date : November 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Sequential D + T, THEN Pembrolizumab
Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day for 2 weeks, then followed by treatment with Pembrolizumab 2mg/kg delivered intravenously at weeks 2, 4, 6, and 9, then once every 3 weeks from week 12 for 50 weeks.
Drug: Dabrafenib
Dabrafenib, a 4-(3-aminosulfonylphenyl)-5-(pyrimidine-3-yl) thiazole, is a potent and selective inhibitor of B-RAF kinase activity with a mode of action consistent with adenosine triphosphate (ATP)-competitive inhibition, and is approved as monotherapy in BRAF V600E-mutant advanced/metastatic melanoma.
Other Name: Tafinlar

Drug: Trametinib
Trametinib, a pyrido - pyrimidine derivative, is a potent and highly selective allosteric non-competitive inhibitor of MEK1/MEK2 activation and kinase activity has been approved as monotherapy in BRAF (V600E)-mutant and BRAF (V600K)-mutant melanoma.
Other Name: Mekinist

Drug: Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Other Name: Keytruda

Experimental: Concurrent D + T AND Pembrolizumab
Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day + Pembrolizumab 200mg intravenously once every 3 weeks for 52 weeks
Drug: Dabrafenib
Dabrafenib, a 4-(3-aminosulfonylphenyl)-5-(pyrimidine-3-yl) thiazole, is a potent and selective inhibitor of B-RAF kinase activity with a mode of action consistent with adenosine triphosphate (ATP)-competitive inhibition, and is approved as monotherapy in BRAF V600E-mutant advanced/metastatic melanoma.
Other Name: Tafinlar

Drug: Trametinib
Trametinib, a pyrido - pyrimidine derivative, is a potent and highly selective allosteric non-competitive inhibitor of MEK1/MEK2 activation and kinase activity has been approved as monotherapy in BRAF (V600E)-mutant and BRAF (V600K)-mutant melanoma.
Other Name: Mekinist

Drug: Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Other Name: Keytruda

Experimental: Pembrolizumab ONLY
Pembrolizumab 200mg intravenously once every 3 weeks alone for 52 weeks.
Drug: Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Other Name: Keytruda




Primary Outcome Measures :
  1. Pathological response rate [ Time Frame: From baseline to 12 weeks ]
    Proportion of patients with complete absence of residual melanoma cells in the planned resected tumour site(s) at week 12 surgery.


Secondary Outcome Measures :
  1. Objective clinical (RECIST) response rate [ Time Frame: From baseline to 12 weeks ]
    Proportion of patients with complete and partial responses at 12 weeks compared to baseline per RECIST guidelines for each treatment arm.

  2. Relapse free survival [ Time Frame: 5 years ]
    The amount of time that patients are disease free from the time of surgery at 12 weeks from study entry

  3. Overall survival [ Time Frame: 5 years ]
    The proportion of patients who are alive from the time of study entry

  4. Incidence of post operative infection [ Time Frame: 12 weeks ]
    The number of patients (and the number of episodes) who develop a post operative infection of the surgical wound requiring intravenous antibiotics and/or wound drainage

  5. Incidence of post operative seroma formation [ Time Frame: 12 weeks ]
    The number of patients (and the number of episodes) who develop a seroma at the surgical site that requires any intervention and the volume of seroma drainage

  6. Duration of post operative wound drainage time [ Time Frame: 12 weeks ]
    The number of days that a wound drain remains in situ from the time of surgery

  7. Incidence of post operative bleeding requiring return to theatre or transfusion [ Time Frame: 12 weeks ]
    The number of patients (and the number of episodes) who have a bleed from the post operative surgical wound that requires a blood transfusion or return to theatre to stop the bleeding

  8. Comparison of surgeon's opinion of operability evaluated at baseline to time of surgery [ Time Frame: Baseline and 12 weeks ]
    The change, if any, in the surgeon's assessment of 'operability' from baseline opinion (based on clinical and imaging examination) to time of operation

  9. Incidence of any treatment-emergent adverse events [ Time Frame: 52 weeks ]
    The number of study treatment related adverse events of all Common Terminology Criteria for Adverse Events (CTCAE) grades from the time of starting study treatment to the time of permanent discontinuation of study treatment

  10. Characterisation of the immunophenotype of tumour infiltrating cells in melanoma tissue [ Time Frame: Baseline, Week 1, Week 4, week 12 ]
    The effects of study treatment on the body's immune cells within the tumour tissue prior to surgery

  11. Description of the morphological assessment of melanoma tissue [ Time Frame: Baseline, Week 1, Week 4, week 12 ]
    The effects of study treatment on the degree of necrosis and genetic markers in tumour tissue prior to surgery

  12. Description of the RNA expression profile of melanoma tumour [ Time Frame: Baseline, Week 1, Week 4, week 12 ]
    The effects of study treatment on the baseline function of RNA expression in tumour tissue prior to surgery

  13. Measurement of leucocyte subpopulations in peripheral blood [ Time Frame: Baseline, Week 1, Week 4, week 12 ]
    The effects of study treatment on the number and type of white cells in the blood

  14. Measurement of circulating tumour DNA [ Time Frame: Baseline, Week 1, Week 4, week 12 ]
    The levels of melanoma DNA that is circulating in the blood stream and the changes during study treatment


Other Outcome Measures:
  1. Concordance of metabolic response measured by pathological response [ Time Frame: 12 weeks ]
    The activity of melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the findings from the pathological examination of completely excised tumour tissue

  2. Concordance of metabolic response measured by RECIST response [ Time Frame: 52 weeks ]
    The activity of melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans

  3. Concordance of pathological response measured by RECIST response [ Time Frame: 12 weeks ]
    he findings from the pathological examination of completely excised tumour tissue and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans

  4. Concordance of metabolic response with RECIST response at relapse [ Time Frame: 52 weeks ]
    The activity of recurrent melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans

  5. Concordance of immune related response criteria (irRC) with RECIST response [ Time Frame: Weeks 6, 12 and 52 ]
    The application of two different criterion to establish the tumour burden as assessed with computed tomorgraphy and magnetic resonanse imaging



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ≥18 years of age
  • Written informed consent.
  • Histologically confirmed, resectable American Joint Committee on Cancer (AJCC) stage IIIB, IIIC or IV (Tx, T0, T1-4, N1b, N2b, N2c, N3, M0) cutaneous melanoma or unknown primary melanoma with sufficient cutaneous, nodal or in-transit disease to enable multiple excisional or core biopsies (at baseline, week 1 and week 4). 'Resectable' tumours are defined as having no significant vascular, central nervous system or bony involvement. Only cases where a complete surgical resection with tumour-free margins can safely be achieved are defined as resectable. Patients who may not have sufficient disease to enable multiple biopsies at weeks 1 and 4 will not be excluded, however the intention of the study is that at least one biopsy at these time points is required.
  • Measurable disease according to RECIST version 1.1 criteria (≥ 10mm longest diameter for non-nodal lesions and / or ≥ 15mm in shortest diameter for lymph nodes) within 4 weeks of randomisation. 'Measurable' disease may be ascertained by CT or for cutaneous and superficial lesions, by caliper measurement with digital photography. CT preferred for all lesions where possible. PET imaging will be performed, but not used for the primary purpose of measuring response.
  • BRAF V600 mutation positive on immunohistochemistry or a local molecular test (e.g. Oncofocus): a. A positive V600E immunohistochemistry stain at study entry should be formally quantified with a local molecular test following study entry (e.g. Oncofocus); b. Molecular BRAF mutation status should preferentially be confirmed using tissue taken from the presenting stage III / IV disease. Alternatively, archival primary tissue is also acceptable to confirm BRAF mutation status.
  • Able to swallow and retain oral medication
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Demonstrated adequate organ function as defined:

    1. Absolute neutrophil count (ANC) ≥1.5 109/L
    2. Platelets ≥100 109/L
    3. Haemoglobin ≥90g/L
    4. Serum creatinine OR measured or calculated creatinine clearance (CrCl) (Glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for patient with creatinine levels > 1.5 X institutional ULN.
    5. Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN.
    6. Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for patients with liver metastases.
    7. Albumin >25 g/L
    8. International Normalized Ratio (INR) or Prothrombin Time (PT)
    9. Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Anticipated life expectancy of > 12 months.
  • Women of childbearing potential: a negative serum pregnancy test within 72 hours of first dose of study treatment and effective contraception from 14 days prior to study treatment until 4 months after the last dose.
  • Men with a female partner of childbearing potential to use effective contraception from 14 days prior to study treatment until 4 months after the last dose.

Exclusion Criteria:

  • Uveal or mucosal melanoma.
  • Prior anti-cancer treatment for melanoma, except for the following:

    1. surgery for a primary melanoma or previous stage III melanoma,
    2. adjuvant radiotherapy to the primary melanoma resected site or to lymph nodes for previous Stage III disease,
    3. previous adjuvant interferon or ipilimumab for resected stage II or III melanoma, Previous adjuvant treatment with PD-1 inhibitors or BRAF/MEK inhibitors is not permitted.
  • Received any investigational drug within 28 days or 5 half-lives of the planned first dose of this study treatment.
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients and / or dimethyl sulfoxide (DMSO).
  • Active infection requiring systemic therapy.
  • Current use of any prohibited medication as described in protocol.
  • Active autoimmune disease or a documented history of autoimmune disease or a syndrome requiring systemic steroids or immunosuppressive agents. Patients with the following are permitted to enrol:

    1. vitiligo,
    2. type I diabetes mellitus,
    3. residual hypothyroidism due to an autoimmune condition only requiring, and stable on hormone replacement,
    4. psoriasis not requiring systemic treatment,
    5. resolved childhood asthma or atopy,
    6. or conditions not expected to recur in the absence of an external trigger.
  • A requirement for chronic systemic steroid therapy (> 10mg/kg per day of prednisone or equivalent) within two weeks before the planned first dose of study treatment or any on any other form of immunosuppressive treatment. Patients who require inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if the patient is on a stable dose. Non-absorbed intra-articular steroid injections will also be permitted.
  • A known history of another malignancy or concurrent malignancy unless the patient is disease-free for a minimum of 1 year, is completely treated and at low-risk of recurrence. The time requirement does not apply for patients with successful definitive resection or curative treatment of:

    1. Non-melanoma skin cancer (e.g. basal cell or squamous cell carcinoma of the skin),
    2. superficial bladder cancer,
    3. in situ carcinoma of the cervix,
    4. in situ breast cancer,
    5. atypical melanocytic hyperplasia or melanoma in situ
    6. other in situ carcinomas,
    7. multiple primary melanomas, or other treated low risk tumours.
  • Known HIV, hepatitis B or C virus positive status or history of active tuberculosis (testing prior to randomisation is not required).
  • Administration of a live vaccine with 30 days of planned first dose of study treatment. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed, however intranasal influenza vaccines (e.g., Fluad®) are live attenuated vaccines, and are not allowed. Any vaccine is cautionary within 30 days.
  • Patients with a history or evidence of cardiovascular risk including any of the following:

    1. QT interval corrected for heart rate using the Bazett formula ≥480 msec, a diagnosis of long QT syndrome (Roman-Ward or Jervell Lange-Nielsen syndromes)
    2. Taking medications known to prolong the QT interval.
    3. Uncorrectable electrolyte abnormal abnormality (e.g. hypo- or hyperkalaemia, hypomagnesaemia, hypocalcaemia)
    4. Uncontrolled arrhythmias, with the exception of atrial fibrillation which is controlled for > 30 days prior to randomisation.
    5. Patients with implanted cardioverter/defibrillators.
    6. Acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty or stenting within 6 months prior to randomisation.
    7. A history or current evidence of New York Heart Association (NYHA) ≥Grade 2 congestive heart failure
    8. A current left ventricular ejection fraction (LVEF) below than the lower limit of normal (LLN).
    9. Any abnormal cardiac valve morphology documented by echocardiogram which in the opinion of the investigator could interfere with the patient's safety.
    10. Treatment-refractory hypertension defined as a systolic blood pressure of >140 mm Hg and/or a diastolic pressure of >90 mm Hg, which cannot be controlled by anti-hypertensive treatment.
  • Evidence or a risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR), including:

    1. 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).
    2. Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR, such as evidence of new optic disc cupping.
    3. Intraocular pressure > 21 mm Hg as measured by tonography.
    4. Evidence of new visual field defects on automated perimetry.
  • History or evidence of interstitial lung disease or active non-infectious pneumonitis.
  • Serious or unstable pre-existing medical conditions or other conditions that could interfere with the patient's safety, consent, or compliance.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent directed to another co-inhibitory T-cell receptor (i.e. OX-40, CTLA-4).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02858921


Contacts
Contact: Monica Osorio +612 9911 7296 Monica.Osorio@melanoma.org.au
Contact: Maria Gonzalez +612 9911 7200 maria.gonzalez@melamona.org.au

Locations
Australia, New South Wales
Westmead Hospital Recruiting
Sydney, New South Wales, Australia, 2145
Contact: Monica Osorio    +612 9911 7200    Monica.Osorio@melanoma.org.au   
Principal Investigator: Matthew Carlino         
Melanoma Institute Australia Not yet recruiting
Wollstonecraft, New South Wales, Australia, 2065
Contact: Maria Gonzalez    +612 9911 7200    maria.gonzalez@melanoma.org.au   
Principal Investigator: Alexander Menzies         
Sponsors and Collaborators
Melanoma Institute Australia
Merck Sharp & Dohme Corp.
Novartis
Investigators
Study Director: Georgina V Long Melanoma Institute Australia

Additional Information:
Responsible Party: Melanoma Institute Australia
ClinicalTrials.gov Identifier: NCT02858921     History of Changes
Other Study ID Numbers: MIA2015/179
First Posted: August 8, 2016    Key Record Dates
Last Update Posted: November 9, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Melanoma Institute Australia:
Neoadjuvant Therapy
Pembrolizumab
Dabrafenib
Trametinib
Pathological response
RECIST
Immune response
BRAF
Randomised
Stage IIIB/C
Biomarkers, Tumour
Biomarkers, Drug response
Metabolic Response

Additional relevant MeSH terms:
Melanoma
Nevi and Melanomas
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Pembrolizumab
Trametinib
Dabrafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action