Immunotherapy With Ipilimumab and Nivolumab Preceded or Not by a Targeted Therapy With Encorafenib and Binimetinib (EBIN)

  • STATUS
    Recruiting
  • End date
    Feb 1, 2024
  • participants needed
    270
  • sponsor
    European Organisation for Research and Treatment of Cancer - EORTC
Updated on 16 February 2022
ct scan
metastatic melanoma
measurable disease
BRAF
ipilimumab

Summary

This is a multicenter, 2-arm open-label, randomized comparative phase II study. The objective of this trial is to prospectively evaluate whether a sequential approach with an induction period of 12 weeks with encorafenib + binimetinib followed by combination immunotherapy with nivolumab + ipilimumab improves progression free survival compared to combination immunotherapy nivolumab + ipilimumab alone in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

Details
Condition Unresectable Stage III Melanoma, Stage IV Melanoma
Treatment Nivolumab + Ipilimumab, Encorafenib + Binimetinib
Clinical Study IdentifierNCT03235245
SponsorEuropean Organisation for Research and Treatment of Cancer - EORTC
Last Modified on16 February 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Histologically or cytologically confirmed unresectable stage III or 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 CT 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
Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement can be included
Adequate cardiac function

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 for at least 4 weeks after treatment and treatment is completed 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
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 either returned to 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) or Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies)
Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 15 days prior to the first dose of study treatment
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 is 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. 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
Uncontrolled hypertension defined as persistent elevation of systolic blood pressure 150 mmHg or diastolic blood pressure 100mmHg, 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 treatment
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
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