Metastatic MelanomaPhase 2SECOMBITNCT02631447
Sequential Combo Immuno and Target Therapy (SECOMBIT) Study
A Phase 2 study testing LGX818, MEK162 and Nivolumab in people with Metastatic Melanoma, run by Fondazione Melanoma Onlus at 30 sites in 10 countries.
Trial summary
To evaluate the best sequencing approach with the combination of target agents (LGX818 plus MEK162) and the combination of immunomodulatory antibodies (ipilimumab plus nivolumab) in patients with metastatic melanoma and BRAF V600 mutation. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Melanoma
- What is being tested?
- LGX818, MEK162 and Nivolumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 251 participants
- Where
- 30 sitesin 10 countries
- Study dates
- 14 Nov 2016to 31 May 2024
- 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
- Patients of either sex aged ≥ 18 years;
- Histologically confirmed stage III (unresectable) or stage IV melanoma with the BRAF V600 mutation. Patients with mucosal melanoma (but not those with ocular melanoma) are eligible for study participation;
- Treatment naïve for metastatic disease patients. Previous adjuvant treatment, included checkpoint inhibitors anti CTLA-4, anti PD-1/PDL-1 is allowed, except for stage IV (if completed at least 6 weeks prior to randomization, and all related adverse events have either returned to baseline or stabilized). BRAF inhibitor treatment in adjuvant setting is not permitted.
- Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria;
- Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrollment;
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1;
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- Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. An archive sample is mandatory at the screening visit; however, a new sample collection would be preferable;
- Female subjects of childbearing potential must have a negative pregnancy test result at baseline and must practice two highly effective methods of contraception for the total study duration plus 23 weeks (i.e. 30 days plus the time required for nivolumab to undergo five half lives) after the last dose of nivolumab and ipilimumab and 30 days after the last dose of binimetinib and encorafenib for female subjects. Additional pregnancy testing must be performed every 6 weeks during the treatment Combo-Immuno and every 4 weeks during the treatment Combo-Target, as well as at the end of the systemic exposure;
- Men who are sexually active with women of childbearing potential must practice a reliable method of contraception for the total study duration plus 31 weeks (i.e. 80 days plus the time required for nivolumab to undergo five half lives) after the last dose of nivolumab and ipilimumab and 90 days after the last dose of binimetinib and encorafenib;
- Adequate bone marrow haematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L AND platelet count ≥ 100 x 109/L AND haemoglobin ≥ 9 g/dL;
- Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) AND aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 X ULN (< 5 x ULN if liver metastases);
- Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥ 50 mL/min in females (calculated according to Cockroft-Gault formula);
- Serum calcium levels, international normalised ratio (INR) and partial thromboplastin time were within normal limits;
- Life expectancy of at least 3 months;
- Ability to understand study-related patient information and provision of written informed consent for participation in the study.
- Adequate electrolytes at Baseline, defined as serum potassium and magnesium levels within institutional normal limits (Note: replacement treatment to achieve adequate electrolytes will be allowed).
- Adequate cardiac function:
- left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated --acquisition (MUGA) scan or echocardiogram,
- QTc interval ≤ 480 ms (preferably the mean from triplicate ECGs)
Who cannot join
- Active brain metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration;
- Subjects with active, known or suspected autoimmune disease;
- Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment;
- Prior treatment for stage III (unresectable) or stage IV melanoma with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody;
- Female subjects who are pregnant (positive pregnancy test), breast-feeding, or who are of childbearing potential and not practicing a reliable method of birth control;
- Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study;
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- Patients with a history of uncontrolled cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy (patients with a history of cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy (past or present evidence of rethinophaty central serous retinopathy - CSR -, occlusion of retinal - RVOo retinal degenerative disease) or ophthalmopathy, which according to the ophthalmologic evaluation at baseline could be considered a risk factor for CSR / RVO ( eg. cupping of the optic disc, visual field defect, intraocular pressure - (eg: central IOP - > 21 mmHg);
- Previous or concurrent malignancy. Exceptions: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry
- History of Gilbert's syndrome;
- Inability to regularly access centre facilities for logistical or other reasons;
- History of poor co-operation, non-compliance with medical treatment, or unreliability;
- Participation in any interventional drug or medical device study within 30 days prior to treatment start.
- Positive test for human immunodeficiency virus (HIV), hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- Receipt of live vaccine within 30 days prior to study drug administration.
- History of severe or life-threatening skin adverse events or reactions to drugs.
Trial locations and contacts
30 sites in 10 countries.
30 sites in 10 countries
Italy15 sites
National Institute of Cancer
Bari, 70124
Università degli Studi di Bari Aldo Moro
Bari, 70124
Azienda Ospedaliera Papa Giovanni XXIII
Bergamo, 24127
IRCCS San Martino - IST
Genova, 16132
IRCCS - Istituto Scientifico Romagnolo per la Cura e lo Studio dei Tumori (I.R.S.T) S.r.l.
Meldola, Forlì-Cesena, 47014
Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori
Milan, 20133
IEO - Istituto Europeo di Oncologia - IRCCS
Milan
Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"
Naples, 80131
Azienda Ospedaliero Universitaria Federico II
Naples
Istituto Oncologico Veneto
Padova, 35128
Istituto Nazionale Tumori Regina Elena
Roma, 00144
Istituto Dermopatico dell'Immacolata - IDI - IRCCS
Roma, 00167
IRCCS Casa Sollievo della Sofferenza
San Giovanni Rotondo
Azienda Ospedaliera Universitaria - Città della Salute e della Scienza di Torino
Torino, 10126
Azienda Ospedaliera Universitaria Integrata di Udine
Udine
Austria4 sites
Medical University of Graz
Graz, AU, A-803
Paracelsus Medical University
Salzburg, AT, 5020
Karl Landsteiner University of Health Sciencies - University Clinic
Sankt Pölten, AT, 3100
Medical University of Vienna
Vienna, 1090
Spain3 sites
Hospital Universitario Quiròn Dexeus
Barcelona, SP, 08028
Hospital Clínic Barcelona
Barcelona, 08036
Clinica Universidad de Navarra
Pamplona, 28027
United Kingdom2 sites
The Royal Marsden NHS Foundation Trust
London, SW36J
The Christie NHS Foundation Trust
Manchester, M204B
Poland1 site
Maria Sklodowska-Curie Institute - Oncology Center
Warsaw, PL, 02781
About this study
Official title: A Three Arms Prospective, Randomized Phase II Study to Evaluate the Best Sequential Approach With Combo Immunotherapy (Ipilimumab/Nivolumab) and Combo Target Therapy (LGX818/MEK162) in Patients With Metastatic Melanoma and BRAF Mutation
To evaluate the best sequencing approach with the combination of target agents (LGX818 plus MEK162) and the combination of immunomodulatory antibodies (ipilimumab plus nivolumab) in patients with metastatic melanoma and BRAF V600 mutation.
Read the detailed description
The combination BRAF (B-raf murine sarcoma viral oncogene homolog B1) inhibitor plus mitogen-activated protein kinase (MEK) inhibitor seems to be more effective in the V600 BRAF mutated advanced melanoma patients compared to treatment with the BRAF inhibitors alone. In fact, a phase I-II study showed a better overall response rate (ORR) and progression-free survival (PFS) in the combination arm (dabrafenib plus trametinib) respect to the single agent treatment (dabrafenib): 76% and 9.4 months versus 54% and 5.8 months respectively. Another phase I study with a similar combination (vemurafenib plus cobimetinib) showed an ORR of 85% in vemurafenib-naïve patients.
Recently, the results of a phase I study about the combination ipilimumab plus nivolumab have been reported. In this study at the selected schedule (ipilimumab 3 mg/kg and nivolumab 1 mg/kg), 53% of patients had an objective response, all with tumor reduction of 80% or more. Reponses were durable, although longer follow-up is needed.
A recent phase I study has shown a high rate of liver toxicity with the combo ipilimumab plus vemurafenib . which makes difficult a combination with these two different drugs. Moreover, a better efficacy of the sequencing treatment BRAF inhibitors/ipilimumab vs. the single agent treatment was also observed; for this reason it was also suggested to start immunotherapy treatment in the BRAF V600 mutated melanoma population as first option, in order to increase the percentage of patients who can benefit from the sequencing, considering the possibility of a fast progression of the disease after the BRAF inhibitors treatment.
Taking into account these considerations, it seems impossible to think to combine all the four compounds (the target agents and immunomodulating monoclonal antibodies). The risk of a high rate of toxicity is realistic and would render this approach inapplicable.
Sequencing with these different combinations seems to be more feasible. However, also in this case it would be important to start with the best combination in order to give to the patients the best chance to increase the overall survival.
The aim of this prospective randomized phase II study is to evaluate the sequencing of these two different combinations and evaluate which is the best of these approaches.
- Conditions
- Metastatic Melanoma
- Being tested
- LGX818, MEK162, Nivolumab, Ipilimumab
- Keywords
- Metastatic Melanoma, BRAF mutation
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LGX818Drug
Also called Combo target, IMP3
LGX818 450 mg p.o. od
MEK162Drug
Also called Combo target, IMP4
MEK162 45 mg p.o. bid
NivolumabDrug
Also called Combo Immuno, IMP1
Nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks
IpilimumabDrug
Also called Combo Immuno, IMP2
Nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks
| Study group | Role | What they receive |
|---|---|---|
| Arm A: Combo Target/Combo Immuno | Experimental | Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) until PD; then Combo Immuno (nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks) until PD Receives: Drug: LGX818; Drug: MEK162; Drug: Nivolumab; Drug: Ipilimumab |
| Arm B: Como immuno/Combo Target | Experimental | Combo Immuno (nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks) until PD; then Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) until PD Receives: Drug: LGX818; Drug: MEK162; Drug: Nivolumab; Drug: Ipilimumab |
| Arm C: Sandwich | Experimental | Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) for 8 weeks followed by Combo Immuno (nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks) until PD; then Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) until PD Receives: Drug: LGX818; Drug: MEK162; Drug: Nivolumab; Drug: Ipilimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival
OS is defined as the time between the date of randomization and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive. OS data will be collected continuously while subjects are on study medication and every 3 months via in-person or phone contact after discontinuation of study medication
Measured: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month
Secondary outcomes (7)
Total Progression free survival
PFS is defined as the time between the date of randomization and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first.
Tumor responses will be assessed by the Investigator according to RECIST Criteria (version 1.1)
Measured: Baseline (Day 1), every 6 weeks until second disease progression is documented (Approximately around 2 years)
Percentage of patients alive at 2 and 3 years;
Percentage of patients alive at 2 and 3 years will be reported using Wilson score intervals.
Measured: Time Frame: at 24^ and 36^ month
Best overall response rate (BORR);
It will be calculated as the percentage of ITT population patients who have a CR o o PR before any evidence of progression (as defined by RECIST).
Measured: Time Frame: up to 24 months
Duration of response (DoR);
It will be calculated as the percentage of ITT population patients who have a CR o o PR before any evidence of progression (as defined by RECIST).
Measured: Time Frame: up to 24 months
Toxicity of the investigational medicinal products (IMPs).
Safety and tolerability will be assessed in terms od AEs, laboratory data, ECG data, vitals signs and weight, which will be collected for all patients. AEs (both in terms od MedDRA preferred terms and CTCAE grade), laboratory data, ECG data, vital signs and weight will be listes individually by patient and summarized by treatment received. ECG changes will be summarized for each treatment group.
Measured: Time Frame: up to 24 months
Quality of life and general health
Changes from baseline in EQ-5D and QLQ-C30 total score will be summarized by means of descriptive statistical methods.
Measured: Time Frame: up to 24 months
3 years PFS rate
3 years PFS rate; calculated from the date of randomization;
Measured: Time Frame: up to 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Dec 2015 (estimated)
- Study start14 Nov 2016
- Primary completion31 May 2024
- Study completion31 May 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Metastatic MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 251 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fondazione Melanoma Onlus
- Sponsor type
- University, hospital or other
- Collaborators
- Clinical Research Technology S.r.l.
- Responsible party
- Sponsor
- Investigators
- Paolo Ascierto, MD, Study chair, Fondazione Melanoma Onlus
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02631447
- Sponsor's protocol ID
- SECOMBIT
- Other IDs
- 2014-004842-92, 2014
- Acronym
- SECOMBIT
- Status last verified
- Jun 2024
- First submitted
- 9 Dec 2015
- Last updated
- 7 Jun 2024
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Helgadottir H, Capone M, Ridolfi L, Zambelli A, Piccin L, Gogas H, Tucci M, Quaglino P, Del Vecchio M, Minisini AM, Spagnolo F, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Lebbe C, Bulgarelli J, Chiarion Sileni V, Paone M, Melero I, Trojaniello C, Bergqvist M, Dummer R, Giannarelli D, Palmieri G, Ascierto PA. Circulating thymidine kinase activity predicts survival and optimal treatment sequencing in BRAF-mutated metastatic melanoma in the SECOMBIT trial. Clin Cancer Res. 2026 Aug 4. doi: 10.1158/1078-0432.CCR-26-1402. Online ahead of print.
PubMed 42550831Ascierto PA, Mandala M, Ferrucci PF, Guidoboni M, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Gogas H, Richtig E, Quaglino P, Lebbe C, Helgadottir H, Queirolo P, Spagnolo F, Tucci M, Del Vecchio M, Gonzalez-Cao M, Minisini AM, De Placido S, Sanmamed MF, Casula M, Bulgarelli J, Pisano M, Piccinini C, Piccin L, Cossu A, Mallardo D, Paone M, Vitale MG, Melero I, Grimaldi AM, Giannarelli D, Palmieri G, Dummer R, Sileni VC. Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma. NEJM Evid. 2024 Oct;3(10):EVIDoa2400087. doi: 10.1056/EVIDoa2400087. Epub 2024 Sep 24.
PubMed 39315864Ascierto PA, Casula M, Bulgarelli J, Pisano M, Piccinini C, Piccin L, Cossu A, Mandala M, Ferrucci PF, Guidoboni M, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Gogas H, Richtig E, Fierro MT, Lebbe C, Helgadottir H, Queirolo P, Spagnolo F, Tucci M, Del Vecchio M, Cao MG, Minisini AM, De Placido S, Sanmamed MF, Mallardo D, Paone M, Vitale MG, Melero I, Grimaldi AM, Giannarelli D, Dummer R, Sileni VC, Palmieri G. Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial. Nat Commun. 2024 Jan 2;15(1):146. doi: 10.1038/s41467-023-44475-6.
PubMed 38167503Ascierto PA, Mandala M, Ferrucci PF, Guidoboni M, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Gogas H, Richtig E, Fierro MT, Lebbe C, Helgadottir H, Queirolo P, Spagnolo F, Tucci M, Del Vecchio M, Gonzales Cao M, Minisini AM, De Placido S, Sanmamed MF, Mallardo D, Curvietto M, Melero I, Palmieri G, Grimaldi AM, Giannarelli D, Dummer R, Chiarion Sileni V. Sequencing of Ipilimumab Plus Nivolumab and Encorafenib Plus Binimetinib for Untreated BRAF-Mutated Metastatic Melanoma (SECOMBIT): A Randomized, Three-Arm, Open-Label Phase II Trial. J Clin Oncol. 2023 Jan 10;41(2):212-221. doi: 10.1200/JCO.21.02961. Epub 2022 Sep 1.
PubMed 36049147
Study at a glance
From the registry record, last updated by the sponsor on 7 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Three Arms Prospective, Randomized Phase II Study to Evaluate the Best Sequential Approach With Combo Immunotherapy (Ipilimumab/Nivolumab) and Combo Target Therapy (LGX818/MEK162) in Patients With Metastatic Melanoma and BRAF Mutation
- ClinicalTrials.gov ID
- NCT02631447
- Acronym / sponsor ID
- SECOMBIT / SECOMBIT
- Conditions
- Metastatic Melanoma
- Keywords
- Metastatic Melanoma, BRAF mutation
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 251 participants (actual)
- Lead sponsor
- Fondazione Melanoma OnlusUniversity, hospital or other
- Collaborators
- Clinical Research Technology S.r.l.
- Study start
- 14 Nov 2016 (actual)
- Primary completion
- 31 May 2024 (actual)
- Study completion
- 31 May 2024 (actual)
- First posted
- 16 Dec 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To evaluate the best sequencing approach with the combination of target agents (LGX818 plus MEK162) and the combination of immunomodulatory antibodies (ipilimumab plus nivolumab) in patients with metastatic melanoma and BRAF V600 mutation.
Detailed description
The combination BRAF (B-raf murine sarcoma viral oncogene homolog B1) inhibitor plus mitogen-activated protein kinase (MEK) inhibitor seems to be more effective in the V600 BRAF mutated advanced melanoma patients compared to treatment with the BRAF inhibitors alone. In fact, a phase I-II study showed a better overall response rate (ORR) and progression-free survival (PFS) in the combination arm (dabrafenib plus trametinib) respect to the single agent treatment (dabrafenib): 76% and 9.4 months versus 54% and 5.8 months respectively. Another phase I study with a similar combination (vemurafenib plus cobimetinib) showed an ORR of 85% in vemurafenib-naïve patients.
Recently, the results of a phase I study about the combination ipilimumab plus nivolumab have been reported. In this study at the selected schedule (ipilimumab 3 mg/kg and nivolumab 1 mg/kg), 53% of patients had an objective response, all with tumor reduction of 80% or more. Reponses were durable, although longer follow-up is needed.
A recent phase I study has shown a high rate of liver toxicity with the combo ipilimumab plus vemurafenib . which makes difficult a combination with these two different drugs. Moreover, a better efficacy of the sequencing treatment BRAF inhibitors/ipilimumab vs. the single agent treatment was also observed; for this reason it was also suggested to start immunotherapy treatment in the BRAF V600 mutated melanoma population as first option, in order to increase the percentage of patients who can benefit from the sequencing, considering the possibility of a fast progression of the disease after the BRAF inhibitors treatment.
Taking into account these considerations, it seems impossible to think to combine all the four compounds (the target agents and immunomodulating monoclonal antibodies). The risk of a high rate of toxicity is realistic and would render this approach inapplicable.
Sequencing with these different combinations seems to be more feasible. However, also in this case it would be important to start with the best combination in order to give to the patients the best chance to increase the overall survival.
The aim of this prospective randomized phase II study is to evaluate the sequencing of these two different combinations and evaluate which is the best of these approaches.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arm A: Combo Target/Combo Immuno | Experimental | Drug: LGX818, Drug: MEK162, Drug: Nivolumab, Drug: IpilimumabCombo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) until PD; then Combo Immuno (nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks) until PD |
| Arm B: Como immuno/Combo Target | Experimental | Drug: LGX818, Drug: MEK162, Drug: Nivolumab, Drug: IpilimumabCombo Immuno (nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks) until PD; then Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) until PD |
| Arm C: Sandwich | Experimental | Drug: LGX818, Drug: MEK162, Drug: Nivolumab, Drug: IpilimumabCombo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) for 8 weeks followed by Combo Immuno (nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks) until PD; then Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) until PD |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- Patients of either sex aged ≥ 18 years;
- Histologically confirmed stage III (unresectable) or stage IV melanoma with the BRAF V600 mutation. Patients with mucosal melanoma (but not those with ocular melanoma) are eligible for study participation;
- Treatment naïve for metastatic disease patients. Previous adjuvant treatment, included checkpoint inhibitors anti CTLA-4, anti PD-1/PDL-1 is allowed, except for stage IV (if completed at least 6 weeks prior to randomization, and all related adverse events have either returned to baseline or stabilized). BRAF inhibitor treatment in adjuvant setting is not permitted.
- Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria;
- Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrollment;
Key exclusion criteria (16 listed)
- Active brain metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration;
- Subjects with active, known or suspected autoimmune disease;
- Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment;
- Prior treatment for stage III (unresectable) or stage IV melanoma with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody;
- Female subjects who are pregnant (positive pregnancy test), breast-feeding, or who are of childbearing potential and not practicing a reliable method of birth control;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LGX818Also: Combo target, IMP3LGX818 450 mg p.o. od | Drug | Arm A: Combo Target/Combo Immuno, Arm B: Como immuno/Combo Target, Arm C: Sandwich |
| MEK162Also: Combo target, IMP4MEK162 45 mg p.o. bid | Drug | Arm A: Combo Target/Combo Immuno, Arm B: Como immuno/Combo Target, Arm C: Sandwich |
| NivolumabAlso: Combo Immuno, IMP1Nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks | Drug | Arm A: Combo Target/Combo Immuno, Arm B: Como immuno/Combo Target, Arm C: Sandwich |
| IpilimumabAlso: Combo Immuno, IMP2Nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks | Drug | Arm A: Combo Target/Combo Immuno, Arm B: Como immuno/Combo Target, Arm C: Sandwich |
Primary outcome
Overall Survival
Time frame: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month
OS is defined as the time between the date of randomization and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive. OS data will be collected continuously while subjects are on study medication and every 3 months via in-person or phone contact after discontinuation of study medication
7 secondary outcomes
Total Progression free survival
Time frame: Baseline (Day 1), every 6 weeks until second disease progression is documented (Approximately around 2 years)
Percentage of patients alive at 2 and 3 years;
Time frame: Time Frame: at 24^ and 36^ month
Best overall response rate (BORR);
Time frame: Time Frame: up to 24 months
Duration of response (DoR);
Time frame: Time Frame: up to 24 months
Toxicity of the investigational medicinal products (IMPs).
Time frame: Time Frame: up to 24 months
Quality of life and general health
Time frame: Time Frame: up to 24 months
3 years PFS rate
Time frame: Time Frame: up to 36 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jun 2024.
- Derived from this study: PubMed 42550831Helgadottir H, Capone M, Ridolfi L, Zambelli A, Piccin L, Gogas H, Tucci M, Quaglino P, Del Vecchio M, Minisini AM, Spagnolo F, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Lebbe C, Bulgarelli J, Chiarion Sileni V, Paone M, Melero I, Trojaniello C, Bergqvist M, Dummer R, Giannarelli D, Palmieri G, Ascierto PA. Circulating thymidine kinase activity predicts survival and optimal treatment sequencing in BRAF-mutated metastatic melanoma in the SECOMBIT trial. Clin Cancer Res. 2026 Aug 4. doi: 10.1158/1078-0432.CCR-26-1402. Online ahead of print.
- Derived from this study: PubMed 39315864Ascierto PA, Mandala M, Ferrucci PF, Guidoboni M, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Gogas H, Richtig E, Quaglino P, Lebbe C, Helgadottir H, Queirolo P, Spagnolo F, Tucci M, Del Vecchio M, Gonzalez-Cao M, Minisini AM, De Placido S, Sanmamed MF, Casula M, Bulgarelli J, Pisano M, Piccinini C, Piccin L, Cossu A, Mallardo D, Paone M, Vitale MG, Melero I, Grimaldi AM, Giannarelli D, Palmieri G, Dummer R, Sileni VC. Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma. NEJM Evid. 2024 Oct;3(10):EVIDoa2400087. doi: 10.1056/EVIDoa2400087. Epub 2024 Sep 24.
- Derived from this study: PubMed 38167503Ascierto PA, Casula M, Bulgarelli J, Pisano M, Piccinini C, Piccin L, Cossu A, Mandala M, Ferrucci PF, Guidoboni M, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Gogas H, Richtig E, Fierro MT, Lebbe C, Helgadottir H, Queirolo P, Spagnolo F, Tucci M, Del Vecchio M, Cao MG, Minisini AM, De Placido S, Sanmamed MF, Mallardo D, Paone M, Vitale MG, Melero I, Grimaldi AM, Giannarelli D, Dummer R, Sileni VC, Palmieri G. Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial. Nat Commun. 2024 Jan 2;15(1):146. doi: 10.1038/s41467-023-44475-6.
- Derived from this study: PubMed 36049147Ascierto PA, Mandala M, Ferrucci PF, Guidoboni M, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Gogas H, Richtig E, Fierro MT, Lebbe C, Helgadottir H, Queirolo P, Spagnolo F, Tucci M, Del Vecchio M, Gonzales Cao M, Minisini AM, De Placido S, Sanmamed MF, Mallardo D, Curvietto M, Melero I, Palmieri G, Grimaldi AM, Giannarelli D, Dummer R, Chiarion Sileni V. Sequencing of Ipilimumab Plus Nivolumab and Encorafenib Plus Binimetinib for Untreated BRAF-Mutated Metastatic Melanoma (SECOMBIT): A Randomized, Three-Arm, Open-Label Phase II Trial. J Clin Oncol. 2023 Jan 10;41(2):212-221. doi: 10.1200/JCO.21.02961. Epub 2022 Sep 1.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paolo Ascierto, MD study chair
Fondazione Melanoma Onlus
30 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing LGX818, MEK162 and Nivolumab in people with Metastatic Melanoma, run by Fondazione Melanoma Onlus at 30 sites in 10 countries.
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 19 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 7 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 30 sites in Italy, Austria, Spain, United Kingdom, France and 5 more countries. 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?
Overall Survival (time frame: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month). 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 NCT02631447, 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 7 Jun 2024.