Phase II Study of Sequential Encorafenib and Binimetinib Followed by Nivolumab and Ipilimumab Versus Immediate Nivolumab and Ipilimumab in BRAF V600 Mutant Melanoma
- Trial ID
- 2023-505376-30-00
- Protocol
- EORTC 1612-MG
Trial statistics
Objectives
The primary objective of this study is to prospectively assess whether a **sequential approach** with an induction period of 12 weeks using encorafenib and binimetinib, followed by an immunotherapy combination with nivolumab and ipilimumab, improves **Progression Free Survival (PFS)** compared to an immunotherapy combination of nivolumab and ipilimumab alone as first-line treatment in patients with **BRAF V600 mutation–positive unresectable or metastatic melanoma**. This is clinically relevant as it may offer a more effective treatment strategy for improving patient outcomes in this specific melanoma subtype.
Secondary objectives include:
- To prospectively assess whether the sequential approach improves **Overall Survival (OS)** compared to combination immunotherapy alone.
- To evaluate in both treatment groups the **Complete Response (CR) rate**, time to CR, and duration of CR, as well as the **Best Overall Response (ORR)** rate, time to best response, and duration of response.
- To assess the **adverse event (AE) profiles**, including grade 3-4 AE rate and serious adverse events, between patients receiving the sequential approach versus those receiving combination immunotherapy alone.
Participants
The clinical trial involves a total of **6 participants** diagnosed with **BRAF V600 mutation–positive unresectable or metastatic melanoma**. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on specific inclusion criteria, such as confirmed unresectable stage III or IV cutaneous or mucosal melanoma, adequate cardiac and organ function, and the ability to swallow and retain oral tablets. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study population includes individuals who are considered vulnerable, and all participants have provided written informed consent in accordance with ICH/GCP and national/local regulations. Key inclusion criteria include the presence of a BRAF V600E or V600K mutation in tumor tissue and measurable disease per RECIST 1.1 criteria. The sponsor has not provided additional information regarding the general health status or lifestyle habits of the participants.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a sequential treatment approach in patients with **BRAF V600 mutation–positive unresectable or metastatic melanoma**. This is a randomized, phase II study comparing a combination of targeted therapy followed by immunotherapy against immediate immunotherapy. The trial employs a double-blind, controlled methodology to ensure unbiased results. The estimated duration of the trial is from November 2018 to January 2027, with participant involvement expected to last up to 60 months, depending on the treatment arm and individual response.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed melanoma, adequate cardiac function, and the presence of the BRAF V600 mutation. Following randomization, participants will receive either a 12-week induction period of **encorafenib** and **binimetinib** followed by **nivolumab** and **ipilimumab**, or immediate treatment with nivolumab and ipilimumab. The primary endpoint is progression-free survival, with secondary endpoints including overall survival and objective response rates.
Study visits will include regular assessments to monitor disease progression and treatment response, with follow-up visits scheduled at intervals determined by the protocol. The end-of-study visit will occur upon completion of the treatment period or earlier if disease progression or unacceptable toxicity is observed. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. Participants are required to comply with scheduled visits and examinations, including biomarker analyses and imaging studies, to ensure comprehensive data collection throughout the trial.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Nivolumab**, marketed as OPDIVO, is provided as a 10 mg/mL concentrate for solution for infusion. It is administered via **intravenous injection**. The maximum daily dose is 480 mg, with a total maximum dose of 12,960 mg over a treatment period of up to 24 weeks. This medication is produced by Bristol-Myers Squibb Pharma EEIG and is classified under the ATC code L01FF01.
**Ipilimumab**, marketed as YERVOY, is available as a 5 mg/mL concentrate for solution for infusion. It is also administered through intravenous injection. The maximum daily dose is 1.0 mg/kg, with a total maximum dose of 4.0 mg/kg over a 12-week treatment period. This product is also manufactured by Bristol-Myers Squibb Pharma EEIG and falls under the ATC code L01FX04.
**Encorafenib**, marketed as Braftovi, is provided in the form of 75 mg hard capsules. It is administered orally, with a maximum daily dose of 450 mg and a total maximum dose of 821,250 mg over a 60-week treatment period. This medication is produced by Pierre Fabre Medicament and is classified under the ATC code L01EC03.
**Binimetinib**, marketed as Mektovi, is available as 15 mg film-coated tablets. It is administered orally, with a maximum daily dose of 90 mg and a total maximum dose of 164,250 mg over a 60-week treatment period. This product is also manufactured by Pierre Fabre Medicament and is classified under the ATC code L01EE03.
The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the treatment protocol. The trial aims to evaluate the efficacy of these medications in patients with unresectable or metastatic melanoma with BRAF V600 mutation.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**. PFS is defined as the time from the date of randomization until the first date of disease progression or death from any cause, whichever occurs first. For patients who remain alive and whose disease has not progressed, PFS will be censored on the date of the last visit or contact when a disease assessment was performed. This assessment will be based on the disease evaluation or date of death as provided by the local investigator.
Secondary efficacy endpoints include **Overall Survival (OS)**, which is defined as the time from the date of randomization to the date of death from any cause. The follow-up for patients who are still alive will be censored at the time of the last visit or contact. Additional secondary endpoints include the Complete Response (CR) rate, time to CR, and duration of CR, as well as the Best Overall Objective Response (CR+PR) rate (ORR), time to best objective response (OR), and duration of OR.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically or cytologically confirmed unresectable stage III or 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 (< 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.
- 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 (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.
- 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.
- 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.
- Female patients must not be breast feeding during the trial treatment and for a period of at least 5 months after treatment discontinuation.
- 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.
- Before patient registration/randomization and before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations
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 (refer to Investigator's brochures for binimetinib and encorafenib and SmPCs for ipilimumab and nivolumab).
- 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 (e.g., rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [hypericin])
- Concomitant anticoagulation at therapeutic doses with oral anticoagulants (e.g., warfarin)
- 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.
- 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 (e.g., HBsAg reactive) or C (e.g., HCV RNA [qualitative] is detected)
- History of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies)
- 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 (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
- 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
- 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
- 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. Complete wound healing from major surgery must have occurred one month before the first dose of study treatment.
- Minor surgery (including uncomplicated tooth extractions) 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 e.g., radiation, surgery, systemic therapy.
- 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
- 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.
- History of retinal degenerative disease
- 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)
- Patients with neuromuscular disorders that are associated with CK > ULN (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
- 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
- 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
- Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg, despite current therapy
- 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
- 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
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 12 Nov 2018 | 196 |
 Germany | Not Recruiting | 12 Nov 2018 | 8 |
 Italy | Not Recruiting | 12 Nov 2018 | 36 |
 The Netherlands | Not Recruiting | 12 Nov 2018 | — |
 Poland | Not Recruiting | 12 Nov 2018 | 4 |
 Spain | Not Recruiting | 12 Nov 2018 | 17 |
| Netherlands | — | — | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
YERVOY 5 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INJECTION | 1.0 | 12 | PRD363755 |
Mektovi 15 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 90 | 60 | PRD6728141 |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INJECTION | 480 | 24 | PRD2941375 |
YERVOY 5 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INJECTION | 1.0 | 12 | PRD363872 |
Braftovi 75 mg hard capsules | Test | HARD CAPSULES | ORAL | 450 | 60 | PRD6728382 |