Sequential Combo Immuno and Target Therapy (SECOMBIT) Study

NCT02631447 | Completed Phase 2 DMC

• 2 other identifiers: SECOMBIT2014-004842-92
• Study Type: interventional
• Target: 251
• Locations: 10 countries
• Sites: 30

Brief 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.

Conditions

Metastatic Melanoma

Keywords

Metastatic Melanoma; BRAF mutation

Outcome Measures

Primary Outcomes (1)

• 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

  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

  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: at 24^ and 36^ month

• Best overall response rate (BORR);

  Time Frame: up to 24 months

• Duration of response (DoR);

  Time Frame: up to 24 months

• Toxicity of the investigational medicinal products (IMPs).

  Time Frame: up to 24 months

Study Arms (3)

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

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

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

Drug: LGX818; Drug: MEK162; Drug: Nivolumab; Drug: Ipilimumab

Interventions

LGX818 DRUG

LGX818 450 mg p.o. od

Also known as: Combo target, IMP3

Arm A: Combo Target/Combo Immuno; Arm B: Como immuno/Combo Target; Arm C: Sandwich

MEK162 DRUG

MEK162 45 mg p.o. bid

Also known as: Combo target, IMP4

Arm A: Combo Target/Combo Immuno; Arm B: Como immuno/Combo Target; Arm C: Sandwich

Nivolumab DRUG

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

Also known as: Combo Immuno, IMP1

Arm A: Combo Target/Combo Immuno; Arm B: Como immuno/Combo Target; Arm C: Sandwich

Ipilimumab DRUG

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

Also known as: Combo Immuno, IMP2

Arm A: Combo Target/Combo Immuno; Arm B: Como immuno/Combo Target; Arm C: Sandwich

Eligibility Criteria

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

You may qualify if:

• 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;
• 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.

You may not qualify if:

• 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;
• 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.

Sponsors & Collaborators

• Fondazione Melanoma Onlus: lead
• Clinical Research Technology S.r.l.: collaborator

Study Sites (30)

Paracelsus Medical University

Salzburg, AT, 5020, Austria

Location

Karl Landsteiner University of Health Sciencies - University Clinic

Sankt Pölten, AT, 3100, Austria

Location

Medical University of Graz

Graz, AU, A-803, Austria

Location

Medical University of Vienna

Vienna, 1090, Austria

Location

Hôpitaux Universitaires Saint-Louis

Paris, 75010, France

Location

University of Tuebingen

Tübingen, 72074, Germany

Location

University of Athens

Athens, 11527, Greece

Location

IRCCS - Istituto Scientifico Romagnolo per la Cura e lo Studio dei Tumori (I.R.S.T) S.r.l.

Meldola, Forlì-Cesena, 47014, Italy

Location

National Institute of Cancer

Bari, 70124, Italy

Location

Università degli Studi di Bari Aldo Moro

Bari, 70124, Italy

Location

Azienda Ospedaliera Papa Giovanni XXIII

Bergamo, 24127, Italy

Location

IRCCS San Martino - IST

Genova, 16132, Italy

Location

Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori

Milan, 20133, Italy

Location

IEO - Istituto Europeo di Oncologia - IRCCS

Milan, Italy

Location

Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"

Naples, 80131, Italy

Location

Azienda Ospedaliero Universitaria Federico II

Naples, Italy

Location

Istituto Oncologico Veneto

Padua, 35128, Italy

Location

Istituto Nazionale Tumori Regina Elena

Roma, 00144, Italy

Location

Istituto Dermopatico dell'Immacolata - IDI - IRCCS

Roma, 00167, Italy

Location

IRCCS Casa Sollievo della Sofferenza

San Giovanni Rotondo, Italy

Location

Azienda Ospedaliera Universitaria - Città della Salute e della Scienza di Torino

Torino, 10126, Italy

Location

Azienda Ospedaliera Universitaria Integrata di Udine

Udine, Italy

Location

Maria Sklodowska-Curie Institute - Oncology Center

Warsaw, PL, 02781, Poland

Location

Hospital Universitario Quiròn Dexeus

Barcelona, SP, 08028, Spain

Location

Hospital Clínic Barcelona

Barcelona, 08036, Spain

Location

Clinica Universidad de Navarra

Pamplona, 28027, Spain

Location

Karolinska University Hospital

Stockholm, S-171, Sweden

Location

University Hospital Zurich

Zurich, CH809, Switzerland

Location

The Royal Marsden NHS Foundation Trust

London, SW36J, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M204B, United Kingdom

Location

Related Publications (3)

• Ascierto 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.

  PMID: 39315864 DERIVED

• Ascierto 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.

  PMID: 38167503 DERIVED

• Ascierto 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.

  PMID: 36049147 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

encorafenib; binimetinib; Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Paolo Ascierto, MD

  Fondazione Melanoma Onlus

  STUDY CHAIR

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: December 9, 2015
• First Posted: December 16, 2015
• Study Start: November 14, 2016
• Primary Completion: May 31, 2024
• Study Completion: May 31, 2024
• Last Updated: June 7, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1); ES (3); GR (1); SE (1); IT (15); FR (1); PL (1); GB (2); CH (1); AU (4)