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

NCT02858921 | Unknown Phase 2 DMC

• 1 other identifier: MIA2015/179
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 3

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.

Conditions

Melanoma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Pathological response rate

  Proportion of patients with complete absence of residual melanoma cells in the planned resected tumour site(s) at week 6 surgery.

  From baseline to 6 weeks

Secondary Outcomes (14)

• Objective clinical (RECIST) response rate

  From baseline to 6 weeks

• Relapse free survival

  5 years

• Overall survival

  5 years

• Incidence of post operative infection

  6 weeks

• Incidence of post operative seroma formation

  6 weeks

Other Outcomes (7)

• Concordance of metabolic response measured by pathological response

  6 weeks

• Concordance of metabolic response measured by RECIST response

  52 weeks

• Concordance of pathological response measured by RECIST response

  6 weeks

Study Arms (3)

Sequential D + T, THEN Pembrolizumab

EXPERIMENTAL

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.

Drug: Dabrafenib; Drug: Trametinib; Drug: Pembrolizumab

Concurrent D + T AND Pembrolizumab

EXPERIMENTAL

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

Drug: Dabrafenib; Drug: Trametinib; Drug: Pembrolizumab

Pembrolizumab ONLY

EXPERIMENTAL

Pembrolizumab 200mg intravenously once every 3 weeks alone for 52 weeks.

Drug: Pembrolizumab

Interventions

Dabrafenib DRUG

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.

Also known as: Tafinlar

Concurrent D + T AND Pembrolizumab; Sequential D + T, THEN Pembrolizumab

Trametinib DRUG

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.

Also known as: Mekinist

Concurrent D + T AND Pembrolizumab; Sequential D + T, THEN Pembrolizumab

Pembrolizumab DRUG

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.

Also known as: Keytruda

Concurrent D + T AND Pembrolizumab; Pembrolizumab ONLY; Sequential D + T, THEN Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥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:
• Absolute neutrophil count (ANC) ≥1.5 109/L
• Platelets ≥100 109/L
• Haemoglobin ≥90g/L
• 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.
• Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 ULN.
• Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for patients with liver metastases.
• Albumin \>25 g/L

You may not qualify if:

• In transit disease
• Uveal or mucosal melanoma.
• Prior anti-cancer treatment for melanoma, except for the following:
• surgery for a primary melanoma or previous stage III melanoma,
• adjuvant radiotherapy to the primary melanoma resected site or to lymph nodes for previous Stage III disease,
• 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:
• vitiligo,
• type I diabetes mellitus,
• residual hypothyroidism due to an autoimmune condition only requiring, and stable on hormone replacement,
• psoriasis not requiring systemic treatment,

Sponsors & Collaborators

• Melanoma Institute Australia: lead
• Merck Sharp & Dohme LLC: collaborator
• Novartis: collaborator

Study Sites (3)

Westmead Hospital

Sydney, New South Wales, 2145, Australia

Location

Melanoma Institute Australia

Wollstonecraft, New South Wales, 2065, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

Related Publications (2)

• Long GV, Carlino MS, Au-Yeung G, Spillane AJ, Shannon KF, Gyorki DE, Hsiao E, Kapoor R, Thompson JR, Batula I, Howle J, Ch'ng S, Gonzalez M, Saw RPM, Pennington TE, Lo SN, Scolyer RA, Menzies AM. Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAFV600-mutant resectable melanoma: the randomized phase 2 NeoTrio trial. Nat Med. 2024 Sep;30(9):2540-2548. doi: 10.1038/s41591-024-03077-5. Epub 2024 Jun 21.

  PMID: 38907159 DERIVED

• Gorry C, McCullagh L, O'Donnell H, Barrett S, Schmitz S, Barry M, Curtin K, Beausang E, Barry R, Coyne I. Neoadjuvant treatment for stage III and IV cutaneous melanoma. Cochrane Database Syst Rev. 2023 Jan 17;1(1):CD012974. doi: 10.1002/14651858.CD012974.pub2.

  PMID: 36648215 DERIVED

Related Links

• Link to Registry Information on study of Neoadjuvant Dabrafenib + Trametinib for AJCC Stage IIIB-C BRAF V600 Mutation Positive Melanoma

MeSH Terms

Conditions

Melanoma; Neoplasms

Interventions

dabrafenib; trametinib; pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Georgina V Long

  Melanoma Institute Australia

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2016
• First Posted: August 8, 2016
• Study Start: November 8, 2017
• Primary Completion: January 2, 2022
• Study Completion: November 1, 2024
• Last Updated: August 30, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3)