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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02858921




Registration number
NCT02858921
Ethics application status
Date submitted
16/07/2016
Date registered
8/08/2016

Titles & IDs
Public title
Neoadjuvant Dabrafenib, Trametinib and/or Pembrolizumab in BRAF Mutant Resectable Stage III Melanoma
Scientific title
A Phase II, Randomised, Open Label Study of Neoadjuvant Dabrafenib, Trametinib and / or Pembrolizumab in BRAF V600 Mutant Resectable Stage IIIB/C Melanoma
Secondary ID [1] 0 0
MIA2015/179
Universal Trial Number (UTN)
Trial acronym
Neo Trio
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Dabrafenib
Treatment: Drugs - Trametinib
Treatment: Drugs - Pembrolizumab

Experimental: Sequential D + T, THEN Pembrolizumab - Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day for 1 week, then followed by treatment with Pembrolizumab 2mg/kg delivered intravenously at weeks 1, 3, and 6, then once every 3 weeks from week 6 for 46 weeks.

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 6 weeks, the Pembrolizumab alone for 46 weeks

Experimental: Pembrolizumab ONLY - Pembrolizumab 200mg intravenously once every 3 weeks alone for 52 weeks.


Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Pathological response rate
Timepoint [1] 0 0
From baseline to 6 weeks
Secondary outcome [1] 0 0
Objective clinical (RECIST) response rate
Timepoint [1] 0 0
From baseline to 6 weeks
Secondary outcome [2] 0 0
Relapse free survival
Timepoint [2] 0 0
5 years
Secondary outcome [3] 0 0
Overall survival
Timepoint [3] 0 0
5 years
Secondary outcome [4] 0 0
Incidence of post operative infection
Timepoint [4] 0 0
6 weeks
Secondary outcome [5] 0 0
Incidence of post operative seroma formation
Timepoint [5] 0 0
6 weeks
Secondary outcome [6] 0 0
Duration of post operative wound drainage time
Timepoint [6] 0 0
6 weeks
Secondary outcome [7] 0 0
Incidence of post operative bleeding requiring return to theatre or transfusion
Timepoint [7] 0 0
6 weeks
Secondary outcome [8] 0 0
Comparison of surgeon's opinion of operability evaluated at baseline to time of surgery
Timepoint [8] 0 0
Baseline and 6 weeks
Secondary outcome [9] 0 0
Incidence of any treatment-emergent adverse events
Timepoint [9] 0 0
52 weeks
Secondary outcome [10] 0 0
Characterisation of the immunophenotype of tumour infiltrating cells in melanoma tissue
Timepoint [10] 0 0
Baseline, Week 1, Week 2, Week 6
Secondary outcome [11] 0 0
Description of the morphological assessment of melanoma tissue
Timepoint [11] 0 0
Baseline, Week 1, Week 2, Week 6
Secondary outcome [12] 0 0
Description of the RNA expression profile of melanoma tumour
Timepoint [12] 0 0
Baseline, Week 1, Week 2, Week 6
Secondary outcome [13] 0 0
Measurement of leucocyte subpopulations in peripheral blood
Timepoint [13] 0 0
Baseline, Week 1, Week 2, Week 6
Secondary outcome [14] 0 0
Measurement of circulating tumour DNA
Timepoint [14] 0 0
Baseline, Week 1, Week 2, Week 6

Eligibility
Key inclusion criteria
* =18 years of age
* Written informed consent.
* Histologically confirmed, resectable American Joint Committee on Cancer (AJCC, 8th edition) stage IIIB, IIIC (Tx, T0, T1-4, N1b, N2b, N3b, M0) cutaneous melanoma or unknown primary melanoma with sufficient cutaneous and/or nodal disease to enable multiple excisional or core biopsies (at baseline, week 1 and week 2). '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 2 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* In transit disease
* 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).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
8/11/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/11/2024
Actual
Sample size
Target
Accrual to date
Final
60
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Westmead Hospital - Sydney
Recruitment hospital [2] 0 0
Melanoma Institute Australia - Wollstonecraft
Recruitment hospital [3] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 0 0
2145 - Sydney
Recruitment postcode(s) [2] 0 0
2065 - Wollstonecraft
Recruitment postcode(s) [3] 0 0
3000 - Melbourne

Funding & Sponsors
Primary sponsor type
Other
Name
Melanoma Institute Australia
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Merck Sharp & Dohme LLC
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/industry
Name [2] 0 0
Novartis
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Georgina V Long
Address 0 0
Melanoma Institute Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT02858921