To characterize the safety and tolerability.1. To describe the available RFS data by treatment arm.2. To describe the available DMFS data by treatment arm.3. To describe-reported health-related quality of life (HRQoL) bytreatment arm.
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
•Severity of adverse events and SAEs on-study graded according to NCI CTCAE
Version 5.0
•Changes from baseline and worst value on-study for clinical safety laboratory
assessments, physical examinations, vital signs, ECGs, ECHO,
dermatological examinations, ophthalmic examinations and ECOG performance status
•Incidence of dose interruptions, dose modifications and discontinuation due to
AEs and incidence of AEs requiring additional therapy
Secondary outcome
1. Recurrence-free survival (RFS) RFS is defined as the time between the date
of randomization and the date of
1) first recurrence (local, regional, or a distant metastasis),
2) new melanoma that is known to be either ulcerated, thick (Breslow
thickness>1 mm) or requiring a treatment other than surgery or 3) death
(whatever the cause), whichever occurs first (i.e., the date of the earliest of
recurrence, ulcerated or thick or requiring a treatment other than surgery new
melanoma, and death minus the date of randomization plus one day). For
participants who remain alive and whose disease has not recurred, RFS will be
censored on the date of last adequate disease assessment. RFS will be based on
the disease assessment and date of
death provided by the local investigator. A distant metastasis of cutaneous
melanoma will always be treated as an event in the RFS analysis, irrespective
of the presence of a new melanoma.
2. Distant metastasis-free survival (DMFS) DMFS is defined as the time between
the date of randomization and the date of first distant metastasis or date of
death (whatever the cause), whichever occurs first (i.e., the date of distant
metastasis for participants with a distant metastasis or the date of death for
without a distant metastasis minus the date of randomization plus one day). For
participants who remain alive and distant metastasis-free, DMFS will be
censored on the date of last adequate disease assessment. DMFS will be based on
the disease assessment and date of death provided by the local investigator. A
distant metastasis of cutaneous melanoma will always be treated as an event in
the DMFS analysis, irrespective of the presence of a new melanoma.
3.
• The change in the HRQoL from baseline over time and to the average of the
scores during the treatment
• The change in the HRQoL from baseline for post treatment visits
Background summary
•Severity of adverse events and SAEs on-study graded according to NCI CTCAE
Version 5.0
•Changes from baseline and worst value on-study for clinical safety laboratory
assessments, physical examinations, vital signs, ECGs, ECHO,
dermatological examinations, ophthalmic examinations and ECOG performance status
•Incidence of dose interruptions, dose modifications and discontinuation due to
AEs and incidence of AEs requiring additional therapy
Study objective
To characterize the safety and tolerability.
1. To describe the available RFS data by treatment arm.
2. To describe the available DMFS data by treatment arm.
3. To describe-reported health-related quality of life (HRQoL) by
treatment arm.
Study design
This is a randomized triple-blind placebo-controlled international multicenter
phase III superiority clinical trial of encorafenib and binimetinib combination
versus placebo in resected pT3b-4bN0 BRAF V600E/K melanoma participants.
Intervention
Subjects will be randomized 1:1 to receive either treatment with encorafenib
and binimetinib or placebo. The treatment will consist of a combination of
encorafenib 450 mg (6 capsules of 75 mg) once daily taken by mouth and
binimetinib 45 mg (3 tablets of 15 mg) twice daily taken by mouth for 12 months
or equivalent placebos for 12 months.
Study burden and risks
Participation into this phase III triple-blind clinical trial will give a
burden to participants above the routine standard of care approach that is
nowadays offered to these participants worldwide, which is currently simple
sequential follow-up surveillance. The frequency of this surveillance in terms
of amount of visits / intervals and if there is or not any imaging offered (and
if so, the frequency of this surveillance imaging) differs greatly across
countries and guidelines. Thus, participation into this trial might increase
the burden for participants in terms of the amount of visits and imaging
compared to the local / national guidelines for stage II melanoma. Moreover,
participants will also need to have more blood drawn than in an active
surveillance protocol. Of course, the largest burden and risk for participants
is the chance to develop adverse events due to the encorafenib & binimetinib
treatment in this trial. However, it is known from BRAF/MEK inhibition therapy
in advanced / metastatic melanoma and also from adjuvant therapy trials with
BRAF or BRAF/MEK inhibition that, although the frequency of adverse events
(including grade 3/4 adverse events) is relatively high, they usually resolve
quickly if the treatment is withheld for a short period of time. The rate of
treatment discontinuation that were suspected to be related to adverse events
on the combination treatment was only 6%. Although one cannot simply
extrapolate this rate to the adjuvant situation, where there is less incentive
to persist through adverse events and continue treatment, we expect less
treatment discontinuation on this specific BRAF/MEK inhibitor combination due
to a better safety profile compared to others such as dabrafenib & trametinib
(in the COMBI-AD trial, 26% of the participants discontinued the treatment due
to AEs). Potential benefit for participants is the chance that, for those
participants receiving encorafenib and binimetinib, the adjuvant therapy might
improve relapse-free survival (RFS), but also the distant-metastasis-free
survival (DMFS) and overall survival (OS). Considering the lack of other
treatment options and the high risk of relapse for these participants with a
pT3b-pT4bN0M0 melanoma, we believe the additional burden requested from
participants who participate in this trial, in terms of extra assessments
(blood, scans, visits) and potential adverse events is justified by the
potential benefits of their participation as described above.
Les Cauquillous 00 00
Lavaur 81500
FR
Les Cauquillous 00 00
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FR
Listed location countries
Age
Inclusion criteria
Molecular Pre-screening
1.Before any related study activity, written informed consent must be
given according to ICH/GCP, and national/local regulations;
2.Male or female >= 18 years of age;
3.Surgically resected, with tumor free margins, and
histologically/pathologically confirmed new diagnosis of stage II (pT3bpT4bN0)
cutaneous melanoma per AJCC 8th edition;
4.Sentinel node (SN) staged node negative (pN0);
5.Sentinel node (SN) biopsy within 14 weeks from initial diagnosis of
melanoma;
6.Available tumor sample for central determination of the BRAFV600E/K
mutation. FFPE tumor tissue block or a minimum of 10 slides, optimally
up to 20 slides.
Screening
1.Before any related study activity, written informed consent must be
given according to ICH/GCP, and national/local regulations;
2.Presence of BRAF V600E/K mutation in tumor tissue as determined by
a local assay any time prior to screening (if done routinely in clinical
practice) and/or the central laboratory
i.If the participant is screened based on local assay result, the BRAF
V600E/K mutation status must be confirmed by the central laboratory
prior to randomization.
3.Participant still free of disease as evidenced by the required baseline
imaging and physical/dermatological assessments performed
respectively within 6 weeks and 2 weeks before the randomization (Day 1);
4.Randomization within 12 weeks from full surgical resection including
sentinel lymph node biopsy (SLNB);
5.Recovered from definitive surgery (e.g. complete wound healing, no
uncontrolled wound infections or indwelling drains);
6.ECOG performance status of 0 or 1;
7.Adequate haematological function:
i.Absolute neutrophil count (ANC) >= 1.5 x 1000000000/L
ii.Platelets >= 100 x 1000000000/L
iii.Hemoglobin >= 9.0 g/dL
8.Adequate renal function:
Serum creatinine <= 1.5 × ULN; or calculated creatinine clearance >= 50
mL/min by Cockcroft Gault formula;
9.Adequate electrolytes, defined as serum potassium and magnesium
levels within institutional normal limits;
10.Adequate hepatic function:
i.Serum total bilirubin <= 1.5 x ULN and < 2 mg/dL
ii.Alanine aminotransferase (ALT) and/or aspartate aminotransferase
(AST) <= 2.5 x ULN
11.Adequate cardiac function:
i.Left ventricular ejection fraction (LVEF) >= 50% as determined by a
multigated acquisition (MUGA) scan or echocardiogram
ii.Mean triplicate QT interval corrected for heart rate according to
Fridericia's formula (QTcF) value <= 480 msec and no history of QT
syndrome
12.Adequate coagulation function, defined as INR <=1.5× ULN unless the
patient is receiving anticoagulant therapy as long as PT or aPTT is within
the therapeutic range;
13.Negative serum β-HCG test (female patient of childbearing potential
only) performed within 3 days prior to Day 1;
14.Participants of childbearing / reproductive potential should use
adequate birth control measures (see Appendix 4, section 10.4.2):
Female participants are either postmenopausal for at least 1 year,
surgically sterile for at least 6 weeks or must agree to take appropriate
precautions to avoid pregnancy.
Male participants must agree to take appropriate precautions to avoid
fathering a child.
Exclusion criteria
Molecular pre-screening
1.Unknown ulceration status;
2.Uveal and mucosal melanoma;
3.Clinically apparent metastases (N+/M1);
4.Microsatellites, satellites and/or in-transit metastases;
5.Local (scar) recurrences.
Screening
1.Breast feeding women;
2.Pregnancy;
3.History or current evidence of retinal vein occlusion (RVO) or current
risk factors for RVO.
4.History of thromboembolic or cerebrovascular events <= 12 weeks prior to
randomization;
i.Note 1: Thromboembolic or cerebrovascular events include stroke,
transient ischemic attacks, cerebrovascular accidents, hemodynamically
significant deep vein thrombosis, pulmonary emboli, aortic aneurysm
requiring surgical repair or recent peripheral arterial thrombosis;
ii.Note 2: Participants with thromboembolic events related to indwelling
catheters or other procedures may be enrolled;
5.Previous or concurrent malignancy for the past 3 years. Except for
non-melanoma skin cancer and any in situ cancer;
6.Any condition with a life expectancy of less than 5 years;
7.Participants with a prior cancer associated with RAS mutation;
8.Previous treatment for melanoma beyond complete surgical resection
(any prior systemic anticancer therapy; prior radiotherapy);
9.Hypersensitivity to the study drugs or to any of the excipients;
10.Participants with severe lactose intolerance;
11.Impaired cardiovascular function or clinically significant
cardiovascular diseases, including any of the following:
i.History of acute myocardial infarction, acute coronary syndromes
(including unstable angina, coronary artery bypass graft, coronary
angioplasty or stenting) <= 6 months prior to randomization;
ii.Congestive heart failure requiring treatment (New York Heart
Association Grade >= 2);
iii.Uncontrolled hypertension defined as persistent systolic blood
pressure >= 150 mmHg or diastolic blood pressure >= 100 mmHg despite
optimal therapy;
iv.Presence of clinically significant cardiac arrhythmias including
uncontrolled atrial fibrillation or uncontrolled paroxysmal
supraventricular tachycardia (stable controlled atrial fibrillation or
paroxysmal supraventricular tachycardia is accepted);
12.Neuromuscular disorders that are associated with CK > ULN;
13.Non-infectious pneumonitis and Interstitial Lung Disease;
14.Positive SARs-CoV-2 or variants of SARs-CoV2 RT-PCR test at
screening or suspected to be infected with SARs-CoV2 or variants of
SARsCoV2 with confirmation pending;
15.Participants with active bacterial, fungal, or viral infection, including,
but not limited to: HBV, HCV, and known HIV or AIDS-related illness, or
an infection requiring systemic therapeutic treatment within 2 weeks
prior to randomization.
Note: Participants receiving prophylactic antibiotics are exceptions and
may participate.
Note: Participants with a positive HBsAg (i.e., either acute or chronic
active hepatitis) are excluded. Those with positive anti-HBcAb but
negative HBsAg and anti-HBsAb profile may be eligible upon review and
approval by the sponsor or designee.
Note: Participants with positive HCV antibody but undetectable HCV viral
load may be eligible upon review and approval by the sponsor or
designee.
Note: Participants with confirmed stable HIV disease may be eligible if
they have viral load < 50 copies/mL and CD4 count > 200 cells/mm3,
and on stable antiretroviral therapy for at least 6 months, provided that
they meet all other study eligibility criteria. Testing for HIV is not
mandated for study entry; however, testing must be performed at sites
where mandated locally following local clinical practice.;
16.Unable to ingest or digest tablets and capsules. This can be caused by
any impaired gastrointestinal function or disease, such as for example:
ulcerative diseases, malabsorption syndrome, small bowel resection,
ileus, etc. Or any condition causing uncontrolled nausea, vomiting or
diarrhea;
17.Presence of any psychological, familial, sociological or geographical
conditions potentially hampering compliance with the study protocol and
follow-up schedule according to Investigators's judgement; those conditions
should be assessed with the patient before randomization in
the trial;
18.Participant is a family member of the investigator or any associate,
colleague and employee assisting in the study conduct (secretary, nurse,
technician) or is otherwise in a position likely to represent a conflict of
interest, the participant is only eligible if the informed consent has been
sought by an appropriately qualified individual who is completely
independent of this relationship;
19.Participation in a clinical study with administration of an
investigational product within 4 weeks or five times the half-life of the
investigational product, whichever is longer, before the first dose of
study treatment;
20.Participants who has forfeited his / her freedom by administrative or
legal award or is under guardianship.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-004310-19-NL |
| ClinicalTrials.gov | NCT05270044 |
| CCMO | NL77403.031.21 |