Clinical Trials /

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

NCT02858921

Description:

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.

Related Conditions:
  • Cutaneous Melanoma
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Dabrafenib, Trametinib and/or Pembrolizumab in BRAF Mutant Resectable Stage III Melanoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: MIA2015/179
  • NCT ID: NCT02858921

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
DabrafenibTafinlarSequential D + T, THEN Pembrolizumab
TrametinibMekinistSequential D + T, THEN Pembrolizumab
PembrolizumabKeytrudaSequential D + T, THEN Pembrolizumab

Purpose

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.

Detailed Description

      The new drug options for advanced melanoma include oncogene-targeted therapy (such as
      dabrafenib, trametinib and vemurafenib) and immune checkpoint blockade (such as
      pembrolizumab, nivolumab and ipilimumab). These drugs have shown remarkable efficacy and have
      regulatory approval for metastatic disease. However, most patients with advanced disease
      eventually progress. It is unknown if earlier treatment with systemic therapy after surgery
      improves long term survival or what is the optimal sequencing or combination of therapy. An
      efficient method of assessing drugs and combinations in humans is critical, particularly as
      combinations of molecularly targeted and/or immune therapies may have similar signals for
      efficacy in pre-clinical models, and recapitulation of the human immune system in animal
      models is limited.

      Neoadjuvant clinical trials in patients with resectable but bulky stage III/IV melanoma
      allows for the rapid evaluation of drug activity in humans utilising multiple clinical
      endpoints (metabolic response with Positron Emission Tomography [PET], clinical response with
      Computed Tomography [CT] imaging, pathological response, relapse-free survival and overall
      survival) and translational endpoints (morphological, genetic and immunophenotyping of tumour
      and blood).

      Surgery remains the standard of care for resectable Stage III or IV melanoma, despite the
      recent drug therapy advances described above. The Food and Drug Administration (FDA) has
      recently expanded the approved use of ipilimumab to include a new use as adjuvant therapy for
      patients with resectable stage III / IV melanoma, to lower the risk of relapse following
      surgery. Neoadjuvant therapy in this group of patients may also result in improved survival
      rates and in the duration of local and distant disease control, with reduced surgical
      morbidity and the potential for early elimination of microscopic metastatic disease.

      There is an emerging and rapidly growing evidence base of the value of combining targeted and
      immunotherapies in a number of histological subtypes of cancers. The support for a potential
      synergy between the two treatment modalities has been established, as has the increased
      toxicity profile. Both single agent BRAF inhibitors and combined BRAF and MEK inhibitors
      induce a marked clonal T cell infiltrate in responding melanoma metastases early during
      treatment (day 7-15), which is transient, and is not present at progression. Concurrently,
      melanoma tumour antigen and the programmed death-ligand 1 (PDL1) expression increase early
      during treatment.

      It is unknown whether there is potential for converting a subset of patients who fail either
      immunotherapy or targeted therapy alone into long-term responders by treating with programmed
      cell death protein 1 (PD-1) inhibitors in conjunction with mitogen-activated protein kinases
      (MAPK) targeted therapies. Furthermore, it is unclear whether the PD-1 inhibitor would be
      best combined sequentially or concurrently with MAPK inhibitors. Mouse models have provided a
      clear rational for combining these treatments upfront, however there is no human tissue
      evidence to guide best combination strategies.

      The question of how best to maximize clinical outcome via concurrent versus sequential
      targeted and immune therapy may be explored efficiently in the human neoadjuvant setting,
      with detailed interrogation of multiple biopsies early during treatment. Immunological,
      proteomic and genetic features in tissue and blood provide an in vivo assessment of tumour
      responsiveness to therapy. This may enable more selective application of therapeutic agents
      to patients who are more likely to benefit. Such findings would improve the therapeutic index
      and cost effectiveness of these agents. Earlier systemic therapy prior to surgery also means
      earlier targeting of distant micrometastases that could become the source of future disease
      relapse.

      The rationale for this study design is therefore based on the hypothesis that two weeks of
      targeted therapy may be sufficient to induce an enhanced tumoral immunity to result in a
      higher pathological and clinical response using the 'Response Evaluation Criteria In Solid
      Tumors' (RECIST) guidelines when followed sequentially with pembrolizumab, than either
      pembrolizumab alone or the combination of targeted therapy and pembrolizumab upfront.

      The potential for toxicities that could affect adherence to the combined study treatments are
      recognised, as additive, overlapping or unforeseen adverse events may occur with the triple
      combination. The adverse event profiles and safety-related interruption to treatment will
      therefore be assessed in conjunction with the objective responses.

      The clinical and translational findings from this study have the potential to inform rational
      decisions regarding combinations of treatment both in the metastatic and the adjuvant
      settings. This is a critical study to inform future practice and future phase 3 clinical
      trials. The translational research performed on tissue biopsies and blood will provide
      mechanistic information to guide the selection of optimal combinations of therapies for phase
      3 studies in the advanced and the adjuvant setting.

      This is a phase II, randomised, open label, three arm, parallel group, clinical trial of
      neoadjuvant combined targeted and immune therapy for patients with BRAF V600 mutant
      resectable stage III (bulky regional stage IIIB-C) or resectable stage IV (M1a) melanoma.

      This translational study explores pathological and RECIST response rates for a 12-week
      duration of neoadjuvant therapy across 3 treatment arms. The key secondary outcomes to be
      measured include a detailed analysis of immunologic, proteomic and genetic biomarkers in
      tumour tissue and peripheral blood at weeks 1, 4 and 12 compared to baseline and correlated
      with clinical, metabolic and pathological response to neoadjuvant treatment, and relapse and
      overall survival to adjuvant treatment. In patients who relapse within 40 weeks of adjuvant
      treatment, further analysis of tumour tissue (if possible) will be undertaken. Relapse free
      and overall survival, surgical outcomes and adverse event profile will also be determined.

      Sixty patients will be randomised to one of three treatment groups in a 1:1:1 ratio, with 20
      patients in each treatment arm:

        -  "Sequential immunotherapy": 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.

        -  "Concurrent immunotherapy": Dabrafenib 150mg orally twice a day + Trametinib 2mg orally
           once a day + Pembrolizumab 200mg intravenously once every 3 weeks for 52 weeks.

        -  "Immunotherapy alone": Pembrolizumab 200mg intravenously once every 3 weeks alone for 52
           weeks.

      Allocation of treatment will be concealed prior to randomisation which will be performed via
      a web based system in permuted blocks and stratified by BRAF V600E mutation versus non BRAF
      V600E mutation (i.e. V600D, V600K, V600R, V600M).

      Neoadjuvant treatment for all three arms will be administered for 12 weeks, followed by
      complete resection of tumour to no evidence of disease. Surgery is followed by 40 weeks of
      adjuvant therapy or until disease relapse, death, intolerable adverse drug reactions or by
      withdrawal of patient consent. After 52 weeks of the study treatment phase, patients will be
      followed 3 monthly for relapse (and progression, following relapse) and survival for 5 years.

      The biomarker component of this study will require blood samples and core biopsies of tumour
      tissue at the following time points:

        -  Baseline (PRE)

        -  Week 1 (EDT 1)

        -  Week 4 (EDT 4)

        -  Week 12 - complete lymph node/metastasectomy dissection specimen (POST)

        -  At Relapse (RELAPSE) if applicable and available

      Surveillance of disease during the 12 week neoadjuvant period will be undertaken with 4
      weekly surgical assessments and with ultrasounds of the affected lymph node basin and / or
      metastatic region. CT of chest, abdomen and pelvis, and areas of known or suspected disease
      (e.g. extremities, neck) will be performed at week six, as will an PET of the whole body. All
      examinations will be compared to baseline investigations.
    

Trial Arms

NameTypeDescriptionInterventions
Sequential D + T, THEN PembrolizumabExperimentalDabrafenib 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.
  • Dabrafenib
  • Trametinib
  • Pembrolizumab
Concurrent D + T AND PembrolizumabExperimentalDabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day + Pembrolizumab 200mg intravenously once every 3 weeks for 52 weeks
  • Dabrafenib
  • Trametinib
  • Pembrolizumab
Pembrolizumab ONLYExperimentalPembrolizumab 200mg intravenously once every 3 weeks alone for 52 weeks.
  • Pembrolizumab

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

Primary Outcome Measures

Measure:Pathological response rate
Time Frame:From baseline to 12 weeks
Safety Issue:
Description:Proportion of patients with complete absence of residual melanoma cells in the planned resected tumour site(s) at week 12 surgery.

Secondary Outcome Measures

Measure:Objective clinical (RECIST) response rate
Time Frame:From baseline to 12 weeks
Safety Issue:
Description:Proportion of patients with complete and partial responses at 12 weeks compared to baseline per RECIST guidelines for each treatment arm.
Measure:Relapse free survival
Time Frame:5 years
Safety Issue:
Description:The amount of time that patients are disease free from the time of surgery at 12 weeks from study entry
Measure:Overall survival
Time Frame:5 years
Safety Issue:
Description:The proportion of patients who are alive from the time of study entry
Measure:Incidence of post operative infection
Time Frame:12 weeks
Safety Issue:
Description: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
Measure:Incidence of post operative seroma formation
Time Frame:12 weeks
Safety Issue:
Description: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
Measure:Duration of post operative wound drainage time
Time Frame:12 weeks
Safety Issue:
Description:The number of days that a wound drain remains in situ from the time of surgery
Measure:Incidence of post operative bleeding requiring return to theatre or transfusion
Time Frame:12 weeks
Safety Issue:
Description: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
Measure:Comparison of surgeon's opinion of operability evaluated at baseline to time of surgery
Time Frame:Baseline and 12 weeks
Safety Issue:
Description:The change, if any, in the surgeon's assessment of 'operability' from baseline opinion (based on clinical and imaging examination) to time of operation
Measure:Incidence of any treatment-emergent adverse events
Time Frame:52 weeks
Safety Issue:
Description: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
Measure:Characterisation of the immunophenotype of tumour infiltrating cells in melanoma tissue
Time Frame:Baseline, Week 1, Week 4, week 12
Safety Issue:
Description:The effects of study treatment on the body's immune cells within the tumour tissue prior to surgery
Measure:Description of the morphological assessment of melanoma tissue
Time Frame:Baseline, Week 1, Week 4, week 12
Safety Issue:
Description:The effects of study treatment on the degree of necrosis and genetic markers in tumour tissue prior to surgery
Measure:Description of the RNA expression profile of melanoma tumour
Time Frame:Baseline, Week 1, Week 4, week 12
Safety Issue:
Description:The effects of study treatment on the baseline function of RNA expression in tumour tissue prior to surgery
Measure:Measurement of leucocyte subpopulations in peripheral blood
Time Frame:Baseline, Week 1, Week 4, week 12
Safety Issue:
Description:The effects of study treatment on the number and type of white cells in the blood
Measure:Measurement of circulating tumour DNA
Time Frame:Baseline, Week 1, Week 4, week 12
Safety Issue:
Description:The levels of melanoma DNA that is circulating in the blood stream and the changes during study treatment

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Melanoma Institute Australia

Trial Keywords

  • Neoadjuvant Therapy
  • Pembrolizumab
  • Dabrafenib
  • Trametinib
  • Pathological response
  • RECIST
  • Immune response
  • BRAF
  • Randomised
  • Stage IIIB/C
  • Biomarkers, Tumour
  • Biomarkers, Drug response
  • Metabolic Response

Last Updated

November 8, 2017