encorafenib for Unresectable or metastatic melanoma (BRAF V600 mutation–positive)

Inclusion criteria

• {"criterion_text":"- Histologically or cytologically confirmed unresectable stage III or IV cutaneous or mucosal melanoma (unknown primary also allowed)"}
• {"criterion_text":"- Adequate cardiac function: · left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram, · 12-lead ECG (in triplicate [2-5 minutes apart]). 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."}
• {"criterion_text":"- Women of childbearing 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 (i.e., females who have had evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). 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."}
• {"criterion_text":"- 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 after the last study treatment (nivolumab and ipilimumab or nivolumab alone). · for a period of at least 2 months after last dose of encorafenib and binimetinib. Note: A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Such methods include: · Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) · Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) · Intrauterine device (IUD) · Intrauterine hormone-releasing system (IUS) · Bilateral tubal occlusion · Vasectomized partner · Sexual abstinence. Note: for patient that will receive encorafenib: there is a potential for encorafenib to induce CYP3A4, which may reduce the effectiveness of hormonal contraception methods. Therefore, the use of at least 1 form of non-hormonal contraception is required during participation in this study."}
• {"criterion_text":"- Female patients must not be breast feeding during the trial treatment and for a period of at least 5 months after treatment discontinuation."}
• {"criterion_text":"- Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up."}
• {"criterion_text":"- Before patient registration/randomization and before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations"}
• {"criterion_text":"- Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Patients ≥ 18 years of age"}
• {"criterion_text":"- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1"}
• {"criterion_text":"- Patients must be able to swallow and retain oral tablets"}
• {"criterion_text":"- 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 (< 5x ULN in case of liver metastases) · Lipase < 2.0 x the ULN and no radiologic or clinical evidence of pancreatitis · Serum phosphorus, total calcium, total magnesium and potassium within normal ranges as per local lab values; in case of small variation (+/-10%) in phosphorus, calcium or magnesium, the patient may be considered eligible and the decision will be left to the investigator · Creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min for patient with creatinine levels > 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 ULNNote: 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."}
• {"criterion_text":"- Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement can be included."}

Exclusion criteria

• {"criterion_text":"- Uveal melanoma"}
• {"criterion_text":"- Child-Pugh B/C and patients with history of acute or chronic pancreatitis"}
• {"criterion_text":"- Known history or current evidence of active Hepatitis B (e.g., HBsAg reactive) or C (e.g., HCV RNA [qualitative] is detected)"}
• {"criterion_text":"- History of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies)"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed"}
• {"criterion_text":"- Autoimmune paraneoplastic syndrome requiring immunosuppressive or dedicated treatment. A specific attention should be given in order to detect any minor myasthenia signs at enrolment; acetylcholine receptor antibodies will be systematically tested when symptoms are suggestive of a myastheni"}
• {"criterion_text":"- 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, for example cervical cancer in situ or pT1a incidental prostate cancer"}
• {"criterion_text":"- Previous allogeneic tissue/solid organ transplant"}
• {"criterion_text":"- Active infection requiring therapy"}
• {"criterion_text":"- Major surgery or trauma within 12 weeks prior to first dose of treatment or presence of any non-healing wound. Complete wound healing from major surgery must have occurred one month before the first dose of study treatment."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Minor surgery (including uncomplicated tooth extractions) within 28 days before randomization with complete wound healing at least 10 days before randomization is permitted."}
• {"criterion_text":"- Any anticancer treatment within 4 weeks before randomization e.g., radiation, surgery, systemic therapy."}
• {"criterion_text":"- Patients with clinically relevant ongoing complications from prior anticancer therapies."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); an ophthalmological assessment is mandatory within 28 days from the first dose of study treatment."}
• {"criterion_text":"- History of retinal degenerative disease"}
• {"criterion_text":"- Impaired gastrointestinal function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)"}
• {"criterion_text":"- Patients with neuromuscular disorders that are associated with CK > ULN (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)"}
• {"criterion_text":"- Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. Note: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on binimetinib treatment"}
• {"criterion_text":"- Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: · History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) <6 months prior to screening · Symptomatic congestive heart failure (i.e., Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality <6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg, despite current therapy"}
• {"criterion_text":"- History of chronic inflammatory bowel disease or Crohn’s disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to starting study treatmen"}
• {"criterion_text":"- History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including stroke, transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis, pulmonary emboli, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis"}
• {"criterion_text":"- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial"}
• {"criterion_text":"- History of hypersensitivity to study drugs or any excipient (refer to Investigator's brochures for binimetinib and encorafenib and SmPCs for ipilimumab and nivolumab)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Concomitant administration of strong inducers and inhibitors of P-gp, glucuronidation, CYP3A4 (e.g., rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [hypericin])"}
• {"criterion_text":"- Concomitant anticoagulation at therapeutic doses with oral anticoagulants (e.g., warfarin)"}
• {"criterion_text":"- Live vaccines within 30 days prior to the first dose of study therapy. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, H1N1 flu, rabies, BCG, and typhoid vaccine."}
• {"criterion_text":"- Current participation or treatment with other investigational agent or use of an investigational device within 4 weeks of the first dose of study treatment"}

Primary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"PFS defined as time from randomization to first progression or death; censored at date of last disease assessment/contact. PFS based on local investigator disease assessments."}

Secondary endpoints

• {"endpoint_text":"- Overall survival (OS): 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","definition_or_measurement_approach":"OS defined as time from randomization to death from any cause; follow-up censored at last visit/contact."}
• {"endpoint_text":"- CR rate, time to CR and duration of CR","definition_or_measurement_approach":"Complete response (CR) rate, time to CR and duration of CR to be assessed; measurable disease was specified per RECIST 1.1, so response assessments use RECIST 1.1 criteria."}
• {"endpoint_text":"- Best overall objective response (CR+PR) rate (ORR), time to best objective reponse (OR) and duration of OR","definition_or_measurement_approach":"Best overall objective response (CR+PR), time to best response and duration of response assessed; measurable disease per RECIST 1.1."}

Poland

Earliest CTIS Part Ii Submission Date

03-06-2024

Latest Decision Or Authorization Date

05-07-2024

Processing Time Days

32

Number Of Sites

1

Number Of Participants

4

Italy

Earliest CTIS Part Ii Submission Date

03-06-2024

Latest Decision Or Authorization Date

01-07-2024

Processing Time Days

28

Number Of Sites

7

Number Of Participants

36

France

Earliest CTIS Part Ii Submission Date

03-06-2024

Latest Decision Or Authorization Date

28-06-2024

Processing Time Days

25

Number Of Sites

17

Number Of Participants

196

Germany

Earliest CTIS Part Ii Submission Date

03-06-2024

Latest Decision Or Authorization Date

25-06-2024

Processing Time Days

22

Number Of Sites

3

Number Of Participants

8

Netherlands

Earliest CTIS Part Ii Submission Date

03-06-2024

Latest Decision Or Authorization Date

28-06-2024

Processing Time Days

25

Number Of Sites

1

Number Of Participants

3

Spain

Earliest CTIS Part Ii Submission Date

03-06-2024

Latest Decision Or Authorization Date

28-06-2024

Processing Time Days

25

Number Of Sites

3

Number Of Participants

17

Primary sponsor

Full Name

European Organisation For Research And Treatment Of Cancer

Organisation Type

Patient organisation/association

Country Of Registered Address

Belgium

Third parties

• {"country":"Luxembourg","full_name":"Luxembourg Institute Of Health","duties_or_roles":"sampling kits (+ shippment of samples kits+pick-up of biological samples),biobanking, QC of samples","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Belgium","full_name":"Clinigen Clinical Supplies Management","duties_or_roles":"Labeling for this trial, QP release and distribution to sites of all IMPs: IPI, NIVO, ENCO, BINI","organisation_type":"Pharmaceutical company"}