BRAF V600 mutation–positive unresectable or metastatic melanoma. MedDRA version: 21.1 Level: PT Classification code 10025650 Term: Malignant melanoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Opdivo
Product Name: nivolumab
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: nivolumab
CAS Number: 946414-94-4
Current Sponsor code: NIVOLUMAB
Other descr
Sponsors
EORTC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Histologically or cytologically confirmed unresectable stage III/ IV cutaneous or mucosal melanoma (unknown primary also allowed) • Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment • Tumor tissue (FFPE) from an unresectable or metastatic site of disease must be provided for biomarker analyses. This can be an archived sample if obtained at maximum 3 months prior to randomization and if the patient did not receive treatment since then. • Measurable disease per RECIST 1.1 criteria by computed tomography (CT) or magnetic resonance imaging (MRI) of Chest/Abdomen/Pelvis and brain CT/MRI performed within 28 days prior to randomization • Patients = 18 years of age • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 • Patients must be able to swallow and retain oral tablets • Adequate organ function within 14 days prior to randomization: • Absolute neutrophil count (ANC) = 1.5 x 109/L (= 1500 per mm3) • Lymphocyte count = 1.0 x 109/L (= 1000 per mm3) • Platelet count = 100 x 109/L (= 100,000 per mm3) • Hemoglobin = 9.0 g/dL (= 5.59 mmol/l) • Total bilirubin = 1.5 x institutional upper limit of normal (ULN) or direct bilirubin = ULN for patients with total bilirubin levels > 1.5 x ULN. • AST (SGOT)/ALT (SGPT) = 2.5 x ULN ( 1.5 x ULN (according to Cockroft- Gault) • International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) = 1.5 x ULN Note: patients receiving anticoagulant therapy (have to be shifted to low molecular weight heparin (LMWH) before treatment start; as warfarin and related 4-hydroxycoumarin-containing molecules are not permitted) are eligible if their PT or INR or PTT is within the recommended range for the desired level of anticoagulation. • Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement can be included. • Adequate cardiac function: - left ventricular ejection fraction (LVEF) = 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram, - 12-lead ECG. Single ECG should be obtained after the patient has been in a supine position for 5 minutes and recorded while the patient remains in that position on which QTcF must be <470 ms. • Women of child bearing potential (WOCBP) must have a negative serum (preferred) or urine pregnancy test within 72 hours prior to registration. Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons. • Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and after the study treatment: - for at least 5 months for a woman and 7 months for a man
Exclusion criteria
Exclusion criteria: • Uveal melanoma • Any symptomatic brain or leptomeningeal disease. Subjects with brain metastases are eligible if these have been locally treated and there is no magnetic resonance imaging (MRI) evidence of progression 4 weeks after end of treatment. 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. • Any prior treatment for advanced disease including treatment with an anti-programmed death receptor-1 (PD-1), anti-programmed death-1 ligand-1 (PD-L1), anti-PD-L2, anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody, anti-LAG-3, anti-TIM-3, anti-IDO, etc or BRAF or MEK inhibitors. • History of hypersensitivity to study drugs or any excipient • Prior adjuvant melanoma therapy with IFN, anti-PD1, anti-PDL1 or anti-CTLA-4 or any other systemic treatment is permitted if completed at least 6 months prior to randomization and all related adverse events have returned to grade = 1. • Concomitant administration of strong inducers and inhibitors of P-gp, glucuronidation, CYP3A4 • Concomitant anticoagulation at therapeutic doses with oral anticoagulants • Live vaccines within 30 days prior to the first dose of study therapy. • Current participation or treatment with other investigational agent or use of an investigational device within 4 weeks of the first dose of study treatment • Child-Pugh B/C and patients with history of acute or chronic pancreatitis • Known history or current evidence of active Hepatitis B or C • History of Human Immunodeficiency Virus (HIV) • Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 2 weeks prior to the first dose of study treatment - Corticosteroid use as premedication for IV contrast allergies/reactions is allowed - Conditions requiring systemic treatment with <10 mg daily prednisone equivalents or equivalent doses of any other corticosteroid are allowed - History of interstitial lung disease (ILD) OR pneumonitis (other than chronic obstructive pulmonary disease (COPD) exacerbation) that has required oral or IV steroids are not allowed • Active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed • Autoimmune paraneoplastic syndrome requiring immunosuppressive or dedicated treatment. A specific attention should be given in order to detect any minor myasthenia signs at enrolment • History of any other hematologic or primary solid tumor malignancy, unless in remission for at least 5 years. A patient with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible • Previous allogeneic tissue/solid organ transplant • Active infection requiring therapy • Major surgery or trauma within 12 weeks prior to first dose of treatment or presence of any non-healing wound. • Minor surgery within 28 days before randomization with complete wound healing at least 10 days before randomization is permitted. • Any anticancer treatment within 4 weeks before randomization • Patients with clinically relevant ongoing complications from prior anticancer therapies. • 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 • His
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to prospectively assess whether a sequential approach with an induction period of 12 weeks with encorafenib + binimetinib followed by an immunotherapy combination with nivolumab + ipilimumab improves Progression Free Survival (PFS) compared to an immunotherapy combination nivolumab + ipilimumab alone as first line treatment in patients with BRAF V600 mutation–positive unresectable or metastatic melanoma. ;Secondary Objective: The secondary objectives are: •To prospectively assess whether a sequential approach with an induction period of 12 weeks with encorafenib + binimetinib followed by combination immunotherapy with nivolumab + ipilimumab improves Overall Survival (OS) as compared to combination immunotherapy nivolumab + ipilimumab alone. •To prospectively assess in both treatment groups: •Complete response (CR) rate, time to CR and duration of CR •Best overall response (CR+PR) rate (ORR), time to best response and duration of response •To prospectively assess adverse event (AE) profiles (AE, grade 3-4 AE rate and Serious Adverse Event) between patients receiving the sequential approach versus patients receiving combination immunotherapy alone. The exploratory objectives are: •To assess the iRECIST tumor response in both treatment groups. •To assess PFS2 in both treatment arms. •To assess response to second line by RECIST 1.1 •To compare Quality of Life between the two arms. •TR ;Primary end point(s): -> Criteria for evaluation: EFFICACY Main efficay endpoint will be: Progression-free survival (PFS): defined as the time from the date of randomization until the first date of progression, or until date of death (whatever the cause), whichever occurs first. For patients who remain alive and whose disease has not progressed, PFS will be censored on the date of last visit/contact when a disease assessment was performed. PFS will be based on the disease assessment or date of death provided by the local investigator Secondary | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficay endpoints will be: - Overall survival (OS) - CR rate, time to CR and duration of CR - Best overall objective response (CR+PR) rate (ORR), time to best objective reponse (OR) and duration of OR Exploratory endpoints: • iRECIST tumor response • PFS2 • Response to second line by RECIST 1.1 • Quality of life • Health-related quality of life (HRQoL), by means of the 30-item EORTC QLQ-C30 version 3 at baseline, week 12, 24, 36 and 52 • Translational research projects to explore the biology of melanoma and in parallel assessing the prognostic and/or predictive value of potential biomarkers ;Timepoint(s) of evaluation of this end point: Overall survival (OS) is defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of patients still alive will be censored at the moment of last visit/contact. All patients will have their BEST OVERALL IMMUNE RESPONSE (iBOR) from the start of study treatment until confirmed progression according to iRECIST or the start of further anticancer therapy or maximum 1y after treatment starts whatever comes first. Each patient will be followed until death or for approximately 5y following enrollment in order to document the long-term outcome (e.g. PFS and OS). Under the same assumptions of accrual period (Accrual: 40 pts/0-<6 months and 160 pts/year thereafter; Rate of lost to follow-up: 2.5%/year) OS endpoint reached after 7y | — |
Countries
Belgium, Denmark, Finland, Germany, Italy, Netherlands, Poland, Spain, United Kingdom
Contacts
Public ContactRegulatory Affairs Department
European Organisation for the Research and Treatment of Cancer
Outcome results
None listed