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A three arms prospective, randomized phase II study to evaluate the best sequential appro-ach with combo immunotherapy (ipilimumab-nivolumab) and combo target therapy (LGX818/ MEK162) in patients with metastatic melanoma and BRAF mutation - SECOMBIT (Sequential Combo Immuno and Target therapy study)

Studio Clinico

Patologia: Melanoma

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: 

Fase di studio: II

Richiesta mandatoria di tessuto: 

Linee di trattamento: Prima linea

Criteri di inclusione: 

1) Patients of either sex aged ≥ 18 years;
2) 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;
3) Treatment naïve for metastatic disease patients. Previous adjuvant treatment, included checkpoint inhibitors anti CTLA-4, anti PD-1/PDL-1 is allowed. (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.
4) Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria;
5) Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrollment;
6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1;
7) 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;
8) Female subjects of childbearing potential must have a negative pregnancy test result at baseline and must practice a reliable method 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;
9) 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;
10) 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;
11) 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);
12) 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);
13) Serum calcium levels, international normalised ratio (INR) and partial thromboplastin time were within normal limits;
14) Life expectancy of at least 3 months;
15) Ability to understand study-related patient information and provision of written informed consent for participation in the study.

Criteri di esclusione: 

1) 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;
2) Subjects with active, known or suspected autoimmune disease;
3) Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment;
4) Prior treatment 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;
5) 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;
6) 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;
7) Patients with a history of 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);
8) History of Gilbert's syndrome;
9) Inability to regularly access centre facilities for logistical or other reasons;
10) History of poor co-operation, non-compliance with medical treatment, or unreliability;
11) Participation in any interventional drug or medical device study within 30 days prior to treatment start.
12) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
13) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

Numero di pazienti previsti: 

230

Schema di trattamento: 

Arm A: Combo Target (LGX818 450 mg p.o. od + MEK162. 45 mg p.o bid) until PD; then Combo Immuno (nivolumab 1 mg/kg solution intravenously (i.v.) combined with ipilimumab 3 mg/kg solution i.v.every 3 weeks for 4 doses then nivolumab 3 mg/kg solution i.v.every 2 weeks) until progression of disease (PD).
Arm B: Combo Immuno (nivolumab 1 mg/kg solution i.v.combined with ipilimumab 3 mg/kg solution i.v.every 3 weeks for 4 doses then nivolumab 3 mg/kg solution i.v.every 2 weeks) until PD; then Combo Target (LGX818 450 mg p.o.od + MEK162 45 mg p.o. bid) until PD.
Arm C: 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 i.v.combined with ipilimumab 3 mg/kg solution i.v.every 3 weeks for 4 doses then nivolumab 3 mg/kg
solution i.v.every 2 weeks) until PD; then Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) until PD.

Trattamento sperimentale: 

LGX818, MEK162, nivolumab, ipilimumab

 

Trattamento di controllo: 

/

Obiettivi primari dello studio: 

To define the best sequencing combination treatment in primary efficacy variable overall survival (OS).

 

Obiettivi secondari dello studio: 

- Total PFS;
- 3 years PFS rate;
- Percentage of patients alive at 2 and 3 years;
- Best overall response rate (BORR);
- Duration of response (DoR);
- Toxicity of the investigational medicinal products (IMPs)
- Quality of life and general health status defined by:
    - Health-related quality of life (HRQoL), by means of the 30-item European Organisation for Research and Treatment of Care quality of life questionnaire (EORTC QLQ-C30);
    - General health status, by means of the European Quality of Life 5-Dimensions(EQ-5D) questionnaire;
    - Impairment of work productivity and activity, by means of the Work
       Productivity and Activity Impairment: General Health (WPAI:GH) questionnaire.

Biological markers (biomarkers ancillary study)
The objective of the biomarkers ancillary study is to focus on understanding mechanisms of action/resistance. In particular, the ancillary study:
- Will inform how to sequence targeted RAF/MEK agents with immunotherapy agents (i.e. ipilumumab and nivolumab) in melanoma;
- Will be hypothesis-generating only.

 

Centri partecipanti

Nord Italia

Ospedale Papa Giovanni XXIII Bergamo
Piazza OMS 1 - 24127 Bergamo - BG

Riferimento: Dr. Mario Mandalà

 

IRCCS - IRST
Via P. Maroncelli 40 - 47014 Meldola - FC

Riferimento: Dr. Massimo Guidoboni

 

IRCCS A.O.U. San Martino - IST
Largo Rosanna Benzi 10 - 16132 Genova - GE

Riferimento: Dr.ssa Paola Queirolo

 

IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI

Riferimento: Dr. Michele Del Vecchio
Email: michele.delvecchio@istitutotumori.mi.it

 

Istituto Europeo di Oncologia
Via Ripamonti 435 - 20141 Milano - MI

Riferimento: Dr. Pierfrancesco Ferrucci
Telefono: 0294371094
Email: pier.ferrucci@ieo.it

 

Istituto Clinico Humanitas Rozzano
Via Manzoni 56 - 20089 Rozzano - MI

 

Istituto Oncologico Veneto IRCCS
Via Gattamelata 64 - 35128 Padova - PD

Riferimento: Dr.ssa Vanna Chiarion Sileni
Telefono: 0498215938
Email: unita.melanomaesofago@iov.veneto.it

 

AOU Città della Salute e della Scienza di Torino
Corso Bramante 88 - 10126 Torino - TO

Riferimento: Prof.ssa Maria Teresa Fierro

 

Azienda Ospedaliera Santa Maria della Misericordia
Piazzale Santa Maria della Misericordia 15 - 33100 Udine - UD

Riferimento: Dr. Alessandro Marco Minisini
Email: minisini.alessandro@aoud.sanita.fvg.it

 

Centro Italia

Istituto Dermopatico dell'Immacolata
Via Monti di Creta 104 - 00167 Roma - RM

Riferimento: Dr. Paolo Marchetti

 

Istituto Nazionale Tumori “Regina Elena”
Via Elio Chianesi 53 - 00144 Roma - RM

Riferimento: Dr.ssa Virginia Ferraresi
Email: ferraresi@ifo.it

 

Sud Italia e isole

Istituto Tumori “Giovanni Paolo II” IRCCS
Viale Orazio Flacco 65 - 70124 Bari - BA

Riferimento: Dr. Michele Guida

 

IRCCS Ospedale Casa Sollievo della Sofferenza
Viale Cappuccini 1 - 71013 San Giovanni Rotondo - FG

Riferimento: Dr. Evaristo Maiello
Telefono: 0882410640
Email: e.maiello@operapadrepio.it

 

Azienda Ospedaliera Universitaria Federico II
Via Sergio Pansini 5 - 80131 Napoli - NA

Riferimento: Prof. Sabino De Placido

 

Istituto Nazionale Tumori IRCCS Fondazione Pascale
Via Mariano Semmola - 80131 Napoli - NA

Riferimento: Dr. Paolo Ascierto
Telefono: 0815903236
Email: p.ascierto@istitutotumori.na.it

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2014-004842-92

Data di inserimento: 05.10.2018

Promotore

CRO

/

Principal Investigator ITALIA

Istituto Nazionale dei Tumori IRCCS - Fondazione Pascale, Napoli

Riferimento: Dr. Paolo Ascierto

Telefono: 0815903236

Email: p.ascierto@istitutotumori.na.it

Localita: Napoli

 

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