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Neoadjuvant Dabrafenib + Trametinib for AJCC Stage IIIB-C BRAF V600 Mutation Positive Melanoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Melanoma Institute Australia
Sponsor:
Information provided by (Responsible Party):
Melanoma Institute Australia
ClinicalTrials.gov Identifier:
NCT01972347
First received: June 17, 2013
Last updated: September 16, 2014
Last verified: September 2014
  Purpose

This is an open label, single centre, phase II study of neoadjuvant drug treatment with dabrafenib + trametinib in patients with resectable American Joint Committee on Cancer (AJCC) Stage IIIB-C BRAF V600 mutation positive melanoma.

The main aim of this study is to find out if giving of a new combined drug treatment to patients with melanoma that has spread to the lymph nodes BEFORE they have surgery, will result in improved clinical and pathological response of the melanoma tissue after 12 weeks treatment.


Condition Intervention Phase
Melanoma
Drug: Dabrafenib
Drug: Trametinib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label, Single Centre, Phase II Pilot Study of Neoadjuvant Dabrafenib + Trametinib in Patients With Resectable American Joint Committee on Cancer (AJCC) Stage IIIB-C BRAF V600 Mutation Positive Melanoma

Resource links provided by NLM:


Further study details as provided by Melanoma Institute Australia:

Primary Outcome Measures:
  • The proportion of viable melanoma tissue, compared to baseline, at complete lymph node dissection after 12 weeks of neoadjuvant treatment. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    The proportion of viable melanoma tissue, compared to baseline, at complete lymph node dissection after 12 weeks of neoadjuvant treatment.


Secondary Outcome Measures:
  • Correlation of a range of tumour biomarkers at baseline, early treatment and 12 week intervals with pathological and clinical response. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Tumour morphological assessment by hematoxylin and eosin, (% necrosis, % melanoma cells, % tumour infiltrating T lymphocytes).

  • Effects of neoadjuvant study treatment on surgical outcomes after complete lymph node dissection. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Number of episodes (and patient number) of infection at wound site requiring intravenous antibiotics and wound drainage, duration of time from surgery to removal of drain because of ceased or minimal drainage, number of episodes (and patient number) of seroma formation at wound site requiring any intervention and volume of seroma drainage, number of episodes (and patient number) of bleeding .from wound requiring return to theatre or transfusion(s), bioimpedance measures of limb distal to site of CLND (axilla and groin only) at baseline, and weeks 8, 24 and 40 after CLND (20, 40 and 52 weeks after starting study treatment) and correlation of surgical outcomes with response to study treatment.

  • Effects of study treatment on host immune response in tumour tissue and peripheral blood. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Immune tumour tissue will be assessed as outlined in 3b and 3c. Peripheral blood will be examined for levels of cytokines and chemokines (Millipore multiplex) and changes in host immune response in tumour and peripheral blood will be correlated with pathological and clinical response.

  • Correlation of pyrexia episodes and signs with baseline melanoma disease burden (number and size of lymph nodes), RECIST response, pathological response, immune related changes in tumour tissue and peripheral blood. [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    Correlation of pyrexia episodes and signs with baseline melanoma disease burden (number and size of lymph nodes), RECIST response, pathological response, immune related changes in tumour tissue and peripheral blood.

  • Description of specific blood and serum changes that occur with pyrexia. [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    Measurement of the following, at regular intervals in all patients, with or without pyrexia, and at every febrile episode: serum chemokines and cytokines, including IL-1, IL6, IL-8, IL-10, IL-18, PD1, gamma interferon and TNF-alpha; plasma and serum parent and metabolite concentrations, white blood cell subsets, liver function tests; AST, ALT, Bilirubin, full blood count, other changes such as cortisol, adrenocorticotropic hormone.

  • Relapse free survival [ Time Frame: 52 weeks plus the time when 70% of patients have died ] [ Designated as safety issue: No ]
    Relapse free survival defined as the interval from commencement of study treatment to local or distant recurrence with censoring of patients dying from causes other than melanoma or treatment related toxicity at date of death. Patients alive without recurrence or with second primary cancers will be censored at date of last assessment. A second primary melanoma will not be considered relapse.

  • Overall survival [ Time Frame: 52 weeks plus until the time that 70% of patients have died ] [ Designated as safety issue: No ]
    Overall survival defined as the interval from commencement of study treatment to the date of death. Patients still alive will be censored at the date of last follow up (until 70% of patients have died)

  • Description of adverse events and how these correlate with clinical outcomes [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    Description of adverse events and how these correlate with clinical outcomes

  • The clinical response to 12 weeks neoadjuvant treatment [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    The clinical response will be measured according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1

  • Correlation of a range of tumour biomarkers at baseline, early treatment and 12 week intervals with pathological and clinical response. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Immunohistochemistry; including, but not restricted to CD3, CD4, CD8, FOXP3, PD-L1, PD-1, Tunel assay (apoptosis), macrophages (CD68, CD163), Ki67, cyclin D1, pERK, p27, p21, p16, SROUTY, DUSP 4and6, pAKT, MITF, beta-catenin, PDGFR, EGFR, IGFR, MCL-1, BCL-2, p53, Gramzyme B, CD20, CD1a.

  • Correlation of a range of tumour biomarkers at baseline, early treatment and 12 week intervals with pathological and clinical response [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    RNA expression profile baseline (PRE), early treatment (EDT) and at 12 weeks POST), DNA mutation analysis, DNA copy number analysis, DNA methylation pattern, PRE and/or POST, DNA methylation pattern and proteomic profiling in PRE and POST samples.


Estimated Enrollment: 35
Study Start Date: August 2014
Estimated Study Completion Date: April 2017
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dabrafenib and Trametinib
Dabrafenib 150mg bid orally and Trametinib 2mg od orally for 52 weeks
Drug: Dabrafenib
Patients will receive neoadjuvant treatment with dabrafenib 150mg twice a day and trametinib 2mg once a day for 12 weeks. Patients will then have complete lymph node dissection and will continue on maintenance treatment with dabrafenib 150mg twice a day and trametinib 2mg once a day for 40 weeks.
Other Name: GSK2118436
Drug: Trametinib
Patients will receive neoadjuvant treatment with dabrafenib 150mg twice a day and trametinib 2mg once a day for 12 weeks. Patients will then have complete lymph node dissection and will continue on maintainance treatment with dabrafenib 150mg twice a day and trametinib 2mg once a day for 40 weeks.
Other Name: GSK1120212

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥18 years
  • Histologically confirmed AJCC Stage IIIB or IIIC (Tx, T1-4, N1b, N2b, N2c, N3, Mo) cutaneous melanoma or unknown primary determined to be BRAF V600 mutation positive, with sufficient nodal disease to enable biopsies prior to surgery.Patients must have disease that is measurable per RECIST version 1.1
  • Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
  • Adequate baseline organ function
  • Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception from 14 days prior to commencing study treatment, throughout the treatment period and for 4 months after the last dose of study treatment
  • Men with any female partner of childbearing potential must agree to use effective contraception from 14 days prior to commencing study treatment, throughout the treatment period and for 4 months after the last dose of study treatment

Exclusion Criteria:

  • Known mucosal or ocular melanoma or any in-transit metastases
  • Evidence of distant metastatic disease on screening evaluation
  • Prior anti-cancer treatment for melanoma (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, investigational treatment or radiotherapy). Prior surgery for melanoma is allowed.
  • Taken an investigational drug within 28 days or 5 half-lives, whichever is longer, prior to commencing study treatment.
  • Current or expected use of a prohibited medication(s)
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
  • Known HIV
  • A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • History of another malignancy or a concurrent malignancy except:

    1. Patients who have been disease-free for 3 years and have a life expectancy of > 5 years;
    2. Patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary melanomas.
  • A history or evidence of cardiovascular risk including any of the following: a. QT interval corrected for heart rate using the Bazett's formula ≥480 msec or ≥ 450 msec for patients with bundle branch block; b. History or evidence of current clinically significant uncontrolled arrhythmias; c. History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to commencement of study treatment; d. History or evidence of current ≥ Class II congestive heart failure; e. Abnormal cardiac valve morphology (≥ Grade 2) documented by echocardiogram (patients with Grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Patients with moderate valvular thickening should not be entered on study; f. Treatment refractory hypertension defined as a blood pressure of systolic > 140 mm Hg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy.
  • A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
  • Any serious or unstable pre-existing medical conditions (aside from the malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the treating clinician, could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures.
  • Breastfeeding females
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01972347

Contacts
Contact: Libby Emmett +612 9911 7372 libby.emmett@melanoma.org.au
Contact: Nicola Ware +612 9911 7363 nicola.ware@melanoma.org.au

Locations
Australia, New South Wales
Melanoma Institute Australia Recruiting
North Sydney, New South Wales, Australia, 2060
Contact: Libby Emmett    +612 9911 7372    libby.emmett@melanoma.org.au   
Contact: Nicola Ware    +612 9911 7363    nicola.ware@melanoma.org.au   
Principal Investigator: Georgina Long         
Sponsors and Collaborators
Melanoma Institute Australia
Investigators
Principal Investigator: Georgina Long Melanoma Institute Australia
  More Information

No publications provided

Responsible Party: Melanoma Institute Australia
ClinicalTrials.gov Identifier: NCT01972347     History of Changes
Other Study ID Numbers: 200332
Study First Received: June 17, 2013
Last Updated: September 16, 2014
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Melanoma Institute Australia:
Melanoma
Cutaneous melanoma
Malignant melanoma
Stage III B / C melanoma
Neoadjuvant treatment
Pyrexia
Biomarkers
Dabrafenib
Trametinib

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

ClinicalTrials.gov processed this record on November 20, 2014