| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BRAF V600 mutation–positive unresectable or metastatic melanoma. |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025650 |
| E.1.2 | Term | Malignant melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
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| E.2.2 | Secondary objectives of the trial |
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
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Histologically or cytologically confirmed unresectable stage III/ IV cutaneous or mucosal melanoma
• Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment
• Tumor tissue 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 institutional upper limit of normal (< 5x ULN in case of liver metastases)
• Lipase < 2.0 x the ULN and no radiologic or clinical evidence of pancreatitis
• Serum phosphorus, calcium, magnesium and potassium within normal ranges as per local lab values
• Creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min for patient with creatinine levels > 1.5 x institutional laboratory value (according to Cockroft-Gault, Appendix D in protocol);
• 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 (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 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 (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 ENCO: there is a potential for ENCO to induce CYP3A4, which may reduce the effectiveness of hormonal contraception methods.
• 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
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| E.4 | Principal 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 1 year 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 (eg, 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 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 myasthenia
• 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.... |
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| E.5 End points |
| E.5.1 | 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 efficay endpoints will be:
• 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
• 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
SAFETY
Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4).
-> Statistical methods:
All the main analyses of the efficacy endpoints (PFS and OS) will be performed on the ITT population using the ITT principle: patients will be considered in the treatment group as indicated at randomization, regardless the “treatment” duration, cause of going off-protocol treatment, possible switch to another treatment before the 1st progression, etc.
The Kaplan-Meier technique will be used to obtain estimates of the survival-type distributions (PFS, time to CR, time to best response, PFS2 and OS from randomization, duration of CR and of response). In addition, based on the Kaplan-Meier curves, estimates at given time-points will be provided (e.g. 9-, 12- and 18-month PFS rates), along with their standard errors, computed using the Greenwood formula. Medians - if reached - will be presented with a 95% confidence interval (CI) based on the non-parametric method of Brookmeyer and Crowley.
The comparison of the PFS between the two treatment groups will be done using the log-rank test stratified by stage/LDH, at a 1-sided alpha level of 5% (2-sided alpha level of 10%).
The HR of arm B:arm A, and its 2-sided 90% confidence interval, will be estimated using a Cox proportional hazards (PH) model (using Efron’s tie-handling method), stratified by stage/LDH as indicated at randomization, with treatment as the single covariate.
For PFS analysis, in case a category of the stage/LDH variable contains less than 10% of the total number of events (e.g. 134 PFS events), patients in such a category will be poolled together with the one of an adjacent category, allowing to perform a meaningful stratified treatment comparison.
In each treatment arm, the rates of CR and of ORR (CR+PR) will be summarized with their corresponding 2-sided 95% CI. As one does not expect that the incidences of CR rate to be very high in both groups, and this phase II study the sample size is relatively low, no statistical inference will be done. Idem for the ORR rates and the irRECIST rates.
At the time of PFS final analysis, PFS2 and OS analyses will be performed, but they will be descriptive only; no formal comparisons will be done.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS is 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
Accrual: 40 pts/0-<6 months and 160 pts/year thereafter; Rate of lost to follow-up: 2.5%/year
134 PFS events expected to be reached after 4.1 years (49 months)
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| E.5.2 | 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 60
• Translational research projects to explore the biology of melanoma and in parallel assessing the prognostic and/or predictive value of potential biomarkers
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| E.5.2.1 | 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 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study occurs when all of the following criteria have been satisfied:
1. 5 months after all patients have stopped protocol treatment
2. The trial is mature for the 2 final analyses of the efficacy endpoints as defined in the protocol: one for PFS and one for OS
3. The database has been fully cleaned and frozen for these 2 final analyses |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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