Clinical trial NCT02631447: Sequential Combo Immuno and Target Therapy (SECOMBIT) 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Melanoma
Keywords: Metastatic Melanoma
BRAF mutation
Lead sponsor: Fondazione Melanoma Onlus
Sponsor class: OTHER
Collaborators: name: Clinical Research Technology S.r.l.
First posted: 2015-12-16
Enrollment: 251
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

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, 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.
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 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;
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 and 90 days after the last dose of binimetinib and encorafenib;
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.
16. 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).
17. 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)

Exclusion Criteria:

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 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;
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 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);
8. 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
9. History of Gilbert's syndrome;
10. Inability to regularly access centre facilities for logistical or other reasons;
11. History of poor co-operation, non-compliance with medical treatment, or unreliability;
12. Participation in any interventional drug or medical device study within 30 days prior to treatment start.
13. 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;
14. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
15. Receipt of live vaccine within 30 days prior to study drug administration.
16. History of severe or life-threatening skin adverse events or reactions to drugs.

Primary outcomes:
measure: Overall Survival
timeFrame: 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:
measure: Total Progression free survival
timeFrame: Baseline (Day 1), every 6 weeks until second disease progression is documented (Approximately around 2 years)
measure: Percentage of patients alive at 2 and 3 years;
timeFrame: Time Frame: at 24^ and 36^ month
measure: Best overall response rate (BORR);
timeFrame: Time Frame: up to 24 months
measure: Duration of response (DoR);
timeFrame: Time Frame: up to 24 months
measure: Toxicity of the investigational medicinal products (IMPs).
timeFrame: Time Frame: up to 24 months
measure: Quality of life and general health
timeFrame: Time Frame: up to 24 months
measure: 3 years PFS rate
timeFrame: Time Frame: up to 36 months
Other outcomes:
Locations:
city: Salzburg
country: Austria
facility: Paracelsus Medical University
state: AT
city: St. Pölten
country: Austria
facility: Karl Landsteiner University of Health Sciencies - University Clinic
state: AT
city: Graz
country: Austria
facility: Medical University of Graz
state: AU
city: Wien
country: Austria
facility: Medical University of Vienna
city: Paris
country: France
facility: Hôpitaux Universitaires Saint-Louis
city: Tuebingen
country: Germany
facility: University of Tuebingen
city: Athens
country: Greece
facility: University of Athens
city: Meldola
country: Italy
facility: IRCCS - Istituto Scientifico Romagnolo per la Cura e lo Studio dei Tumori (I.R.S.T) S.r.l.
state: Forlì-Cesena
city: Bari
country: Italy
facility: National Institute of Cancer
city: Bari
country: Italy
facility: Università degli Studi di Bari Aldo Moro
city: Bergamo
country: Italy
facility: Azienda Ospedaliera Papa Giovanni XXIII
city: Genova
country: Italy
facility: IRCCS San Martino - IST
city: Milano
country: Italy
facility: Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori
city: Milano
country: Italy
facility: IEO - Istituto Europeo di Oncologia - IRCCS
city: Naples
country: Italy
facility: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"
city: Naples
country: Italy
facility: Azienda Ospedaliero Universitaria Federico II
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
city: Roma
country: Italy
facility: Istituto Nazionale Tumori Regina Elena
city: Roma
country: Italy
facility: Istituto Dermopatico dell'Immacolata - IDI - IRCCS
city: San Giovanni Rotondo
country: Italy
facility: IRCCS Casa Sollievo della Sofferenza
city: Torino
country: Italy
facility: Azienda Ospedaliera Universitaria - Città della Salute e della Scienza di Torino
city: Udine
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata di Udine
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Institute - Oncology Center
state: PL
city: Barcelona
country: Spain
facility: Hospital Universitario Quiròn Dexeus
state: SP
city: Barcelona
country: Spain
facility: Hospital Clínic Barcelona
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Zurich
country: Switzerland
facility: University Hospital Zurich
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Fondazione Melanoma Onlus
name: Paolo Ascierto, MD
role: STUDY_CHAIR
References:
citation: 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.