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Stage IV MelanomaPhase 2TraMel-WTNCT04059224

TraMel-WT: A Trial of Trametinib in Patients With Advanced Pretreated BRAFV600 Wild-type Melanoma

A Phase 2 study testing Trametinib and Dabrafenib in people with Stage IV Melanoma and Stage III Melanoma, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This phase 2 trial will investigate the efficacy and safety of trametinib and dabrafenib in patients with advanced BRAF V600 (v-Raf murine sarcoma viral oncogene homolog B) wild-type melanoma (stratified according to BRAF V600 wild-type/NRAS (neuroblastoma Ras viral oncogene homolog) mutant and BRAF V600… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Stage IV Melanoma, Stage III Melanoma
What is being tested?
Trametinib and Dabrafenib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
45 participants
Where
1 siteBelgium
Study dates
28 Jan 2019to 30 Jun 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥ 18 years of age.
  • Signed written informed consent.
  • Histologically confirmed advanced melanoma that is either stage III (unresectable) or stage IV (metastatic).
  • Absence of a BRAF V600 mutation as determined by a validated test.
  • In case of mucosal or acral melanoma, absence of a cKIT (proto-oncogene c-Kit) mutation as determined by a validated test.
  • Presence of archival melanoma tissue of possibility of new biopsy for mutational testing.
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  • Subjects must have failed at least one prior systemic treatment with immune checkpoint inhibitors: CTLA-4 (cytotoxic T-lymphocyt antigen 4) blocking immune checkpoint inhibitors (ipilimumab or other experimental anti-CTLA-4 antibodies), PD-1 (programmed cell death 1) blocking immune checkpoint inhibitors (pembrolizumab, nivolumab or other experimental anti-PD-1 antibodies) and/or PD-L1 (programmed cell death ligand 1) blocking immune checkpoint inhibitors (avelumab, atezolizumab, durvalumab or other experimental anti-PD-L1 antibodies). Progression of disease per Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or per immune related response criteria (irRC) must have been documented during this treatment. Patients who are not able to undergo such treatment are also eligible.
  • The presence of at least one measurable lesion per RECIST, version 1.1
  • Interval between the date of the last administration of prior therapy for melanoma and the date of recruitment: a. ≥12 weeks following the date of the first administration and ≥4 weeks following the date of the last administration of CTLA-4, PD-1 or PD-L1 blocking immune checkpoint inhibitor; b. ≥4 weeks following the date of the last administration of chemotherapy (≥ 6 weeks in case of a nitrosurea or mitomycin C containing regimen); c. ≥4 weeks following major surgery or extensive radiotherapy.
  • All prior anti-cancer treatment-related toxicities (except alopecia) must be ≤ grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.03; National Cancer Institute [NCI] 2010) at the time of recruitment.
  • Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
  • Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to recruitment and agree to use effective contraception throughout the treatment period, and for 16 weeks after the last dose of study treatment.
  • Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from 14 days prior to administration of the first dose of study treatment, throughout the treatment period, and for 16 weeks after the last dose of study treatment.
  • An Eastern Cooperative Oncology Group (ECOG) performance status
  • Adequate baseline organ function as defined as follows: Absolute neutrophil count: ≥ 1.2 x 103/mm3; Hemoglobin: ≥ 9.0 g/dL; Platelet count: ≥ 75 x 103/mm3; prothrombin time/international normalized ratio and activated partial thromboplastin time: ≤ 1.5 x ULN (upper limit of normal); Albumin: ≥ 2.5 g/dL; Total bilirubin: ≤ 1.5 x ULN; aspartate aminotransferase and alanine aminotransferase: ≤ 2.5 x ULN; Calculated creatinine clearance: ≥ 50 mL/min (by use of the Cockroft-Gault formula); LVEF (left ventricular ejection fraction) ≥ LLN (lower limit of normal) by transthoracic echocardiogram

Who cannot join

  • Subjects with uveal melanoma.
  • Prior treatment with MAPK-pathway inhibitors
  • Subjects with clinically active brain metastases (lesions should be stable and have been definitely treated with stereotactic radiation therapy, surgery or gamma knife therapy with no evidence of disease progression prior to enrollment.
  • Any contra-indication for evaluation by whole body 18FDG-PET/CT (18-fluorodeoxyglucose positron emission tomography/computed tomography) and MRI (magnetic resonance imaging) of the brain.
  • History of another malignancy. Exception: subjects who have been disease-free for 3 years, (i.e. subjects with second malignancies that are indolent or definitively treated at least 3 years ago) or subjects with a history of completely resected non-melanoma skin cancer.
  • Current use of any prohibited medication.
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  • Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to recruitment.
  • Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures.
  • Known Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted).
  • No enzyme inducing anticonvulsants for ≥4 weeks prior to recruitment
  • A history or evidence of cardiovascular risk including any of the following:
  • Current LVEF < LLN; b. A QT interval corrected (QTc) for heart rate using the Bazett's formula (QTcB) ≥ 480 milliseconds; c. A history or evidence of current clinically significant uncontrolled arrhythmias. Exception: subjects with atrial fibrillation controlled for > 30 days prior to recruitment are eligible. d. A history (within 6 months prior to recruitment) of acute coronary syndromes (including myocardial infarction or unstable angina), or coronary angioplasty; e. A history or evidence of current ≥ Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; f. Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by antihypertensive therapy; g. Patients with intra-cardiac defibrillators or permanent pacemakers; h. Known cardiac metastases; i. Abnormal cardiac valve morphology (≥ grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.
  • Uncorrectable electrolyte abnormalities (e.g. hypokalemia, hypomagnesemia, hypocalcemia), long QT syndrome or taking medicinal products known to prolong the QT interval.
  • A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including: a. 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); or b. Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as: i. Evidence of new optic disc cupping; ii. Evidence of new visual field defects on automated perimetry; iii. Intraocular pressure >21 mmHg as measured by tonography.
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
  • Females who are nursing.

Trial locations and contacts

1 site in 1 country.

Belgium1 site

  • Universitair Ziekenhuis Brussel

    Jette, Brussels Capital, 1090

Other trials in Belgium

About this study

Official title: TraMel-WT: A Stratified Dual-stratum Open-label Two-stage Phase 2 Trial of Trametinib in Patients With Advanced Pretreated BRAFV600 Wild-type Melanoma

This phase 2 trial will investigate the efficacy and safety of trametinib and dabrafenib in patients with advanced BRAF V600 (v-Raf murine sarcoma viral oncogene homolog B) wild-type melanoma (stratified according to BRAF V600 wild-type/NRAS (neuroblastoma Ras viral oncogene homolog) mutant and BRAF V600 wild-type/NRAS wild-type melanoma patients) that have been pretreated and progressed following treatment with PD-1- (programmed cell death-1) and CTLA-4-blocking (cytotoxic T-lymphocyte-associated antigen 4) immune checkpoint inhibitors. The investigators hypothesize that treatment with trametinib will result in objective antitumor activity. In order to improve the tolerability and optimize the dose intensity of trametinib, a minimal dose of dabrafenib will be added to prevent and manage trametinib-related skin toxicity.

Read the detailed description

This will be a non-randomized stratified dual-arm open-label two-stage single-centre phase 2 trial.

Patients are eligible if they are diagnosed with BRAF V600 (v-Raf murine sarcoma viral oncogene homolog B) wild-type unresectable AJCC (American Joint Committee on Cancer) stage III or IV melanoma and are documented with progression of disease following treatment with a PD-1- (programmed cell death-1) and CTLA-4-blocking (cytotoxic T-lymphocyte-associated antigen 4) immune checkpoint inhibitor or who have a contraindication for treatment with immune checkpoint inhibitors.

Patients will be considered for study participation not earlier than 4 weeks after the last dosing of the prior therapy.

Patients will be stratified according to their NRAS (neuroblastoma RAS viral oncogene homolog) mutation status: arm A involves patients with advanced pretreated BRAF V600 wild-type/NRAS mutant melanoma; arm B involves patients with advanced pretreated BRAF V600 wild-type/NRAS wild-type melanoma.

All patients will be treated with trametinib 2 mg once a day and dabrafenib 50 mg twice a day. Throughout their study participation, patients will be continuously monitored for safety and evaluated for tumor response every 8 weeks or sooner if there is clinical suspicion of progressive disease. Patients will be treated until progression of disease, unacceptable toxicity or withdrawal of consent.

The primary endpoint of the study is the objective response rate. Secondary endpoints are progression-free survival, overall survival and safety.

Being tested
Trametinib, Dabrafenib
Keywords
NRAS mutant, NRAS wild-type, BRAF V600 wild-type, Unresectable stage III melanoma, Stage IV melanoma, low-dose dabrafenib, dabrafenib, trametinib, Mekinist, Tafinlar
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TrametinibDrug

    Also called TRA, Mekinist

    Trametinib 2 mg once a day by mouth.

  • DabrafenibDrug

    Also called DAB, Tafinlar

    Dabrafenib 50 mg twice a day by mouth. Dabrafenib can be uptitrated to 150 mg twice a day in case of dose-limiting trametinib-associated skin toxicity.

Study groups in NCT04059224
Study groupRoleWhat they receive
Arm A: advanced BRAF V600 wild-type/NRAS-mutant melanomaExperimentalPatients will be treated with trametinib 2 mg once a day and dabrafenib 50 mg twice a day until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment.
Receives: Drug: Trametinib; Drug: Dabrafenib
Arm B: advanced BRAF V600 wild-type/NRAS wild-type melanomaExperimentalPatients will be treated with trametinib 2 mg once a day and dabrafenib 50 mg twice a day until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment.
Receives: Drug: Trametinib; Drug: Dabrafenib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Arm A: objective response rate on trametinib and dabrafenib

    Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1 [Eisenhauer 2009]).

    Measured: 2 years

  2. Arm B: objective response rate on trametinib and dabrafenib

    Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1 [Eisenhauer 2009]).

    Measured: 2 years

Secondary outcomes (5)

  1. Arm A: progression-free survival on trametinib and dabrafenib

    Progression-free survival (PFS; defined as the time from treatment initiation until the earliest date of disease progression or death due to any cause)

    Measured: 2 years

  2. Arm A: overall survival on trametinib and dabrafenib

    Overall survival (OS; defined as the time from treatment initiation until the date of death due to any cause).

    Measured: 2 years

  3. Arm B: progression-free survival on trametinib and dabrafenib

    Progression-free survival (PFS; defined as the time from treatment initiation until the earliest date of disease progression or death due to any cause)

    Measured: 2 years

  4. Arm B: overall survival on trametinib and dabrafenib

    Overall survival (OS; defined as the time from treatment initiation until the date of death due to any cause).

    Measured: 2 years

  5. Arms A and B: incidence of adverse events on trametinib and dabrafenib

    Adverse events graded by the Common Terminology Criteria of Adverse Events version 4 (CTCAE v4)

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Aug 2019
  2. Study start28 Jan 2019
  3. Primary completion30 Jun 2023
  4. Study completion30 Jun 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
Stratified dual-stratum open-label two-stage single-center phase 2 trial
Masking
None (open label)
Enrolment
45 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04059224
Sponsor's protocol ID
2018-BN-001
Acronym
TraMel-WT
Status last verified
Sep 2023
First submitted
13 Aug 2019
Last updated
26 Sep 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, Rutkowski P, Del Vecchio M, Gutzmer R, Mandala M, Thomas L, Demidov L, Garbe C, Hogg D, Liszkay G, Queirolo P, Wasserman E, Ford J, Weill M, Sirulnik LA, Jehl V, Bozon V, Long GV, Flaherty K. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):435-445. doi: 10.1016/S1470-2045(17)30180-8. Epub 2017 Mar 9.

    PubMed 28284557

  • Ranzani M, Alifrangis C, Perna D, Dutton-Regester K, Pritchard A, Wong K, Rashid M, Robles-Espinoza CD, Hayward NK, McDermott U, Garnett M, Adams DJ. BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib. Pigment Cell Melanoma Res. 2015 Jan;28(1):117-9. doi: 10.1111/pcmr.12316. Epub 2014 Oct 13. No abstract available.

    PubMed 25243813

  • Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51. doi: 10.1016/S0140-6736(15)60898-4. Epub 2015 May 31.

    PubMed 26037941

  • Awada G, Dirven I, Schwarze JK, Tijtgat J, Fasolino G, Kockx M, Neyns B. Phase II Clinical Trial of Trametinib and Low-Dose Dabrafenib in Advanced, Previously Treated BRAFV600/NRASQ61 Wild-Type Melanoma (TraMel-WT). JCO Precis Oncol. 2024 Oct;8:e2300493. doi: 10.1200/PO.23.00493. Epub 2024 Feb 14.

    PubMed 39374099

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Trametinib and Dabrafenib in people with Stage IV Melanoma and Stage III Melanoma, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Arm A: objective response rate on trametinib and dabrafenib (time frame: 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04059224, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Sep 2023.

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