Clinical Trials /

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

NCT03235245

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy With Ipilimumab and Nivolumab Preceded or Not by a Targeted Therapy With Encorafenib and Binimetinib
  • Official Title: Combination of Targeted Therapy (Encorafenib and Binimetinib) Followed by Combination of Immunotherapy (Ipilimumab and Nivolumab) vs Immediate Combination of Immunotherapy in Patients With Unresectable or Metastatic Melanoma With BRAF V600 Mutation : an EORTC Randomized Phase II Study (EBIN)

Clinical Trial IDs

  • ORG STUDY ID: EORTC-1612-MG
  • SECONDARY ID: 2017-002887-42
  • NCT ID: NCT03235245

Conditions

  • Unresectable Stage III Melanoma
  • Stage IV Melanoma

Interventions

DrugSynonymsArms
Nivolumab + IpilimumabARM A: Nivolumab + Ipilimumab
Encorafenib + BinimetinibARM B: Encorafenib + Binimetinib + Nivolumab + Ipilimumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
ARM A: Nivolumab + IpilimumabActive Comparatornivolumab 3 mg/kg q3w + ipilimumab 1 mg/kg q3w for 4 injections followed by nivolumab 480 mg IV q4w until completion of 2 years total treatment or progression. Then treatment will be left at the investigator choice and continued until the 2nd progression.
  • Nivolumab + Ipilimumab
ARM B: Encorafenib + Binimetinib + Nivolumab + IpilimumabExperimentalencorafenib 450 mg QD + binimetinib 45 mg BID orally for 12 weeks followed, after a week of pause, by nivolumab 3 mg/kg q3w + ipilimumab 1 mg/kg q3w for 4 injections, followed by nivolumab 480 mg IV q4w until completion of 2 years total treatment or progression. Then patients will be rechallenged with encorafenib 450 mg QD + binimetinib 45 mg BID orally continuously until the 2nd progression.
  • Nivolumab + Ipilimumab
  • Encorafenib + Binimetinib

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:4.1 years from first patient in
Safety Issue:
Description:PRS 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. Progression will be assessed according to the RECIST criteria (version 1.1)

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:6 years from first patient in
Safety Issue:
Description:OS is defined as the time from the date of randomization to the date of death, whatever the cause.
Measure:Complete Response (CR) rate
Time Frame:4.1 years from first patient in
Safety Issue:
Description:CR will be assessed according to the RECIST criteria (version 1.1)
Measure:Time to Complete Response (CR)
Time Frame:4.1 years from first patient in
Safety Issue:
Description:Time to CR is defined as the time from the date of randomization until the occurrence of first CR.
Measure:Duration of Complete Response (CR)
Time Frame:4.1 years from first patient in
Safety Issue:
Description:Duration of CR will be measured from the time measurement criteria for CR are first met until the first date that recurrence is objectively documented.
Measure:Best overall response rate
Time Frame:4.1 years from first patient in
Safety Issue:
Description:Best overall response will be assessed according to the RECIST criteria (version 1.1)
Measure:Time to best response
Time Frame:4.1 years from first patient in
Safety Issue:
Description:Time to best response is defined as the time from the date of randomization until the occurrence of the best response (CR or PR, whichever comes first). CR and PR will be assessed according to the RECIST criteria (version 1.1)
Measure:Duration of best response
Time Frame:4.1 years from first patient in
Safety Issue:
Description:Best response duration will be measured from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented. CR and PR will be assessed according to the RECIST criteria (version 1.1)
Measure:Occurrence of adverse events
Time Frame:4.1 years from first patient in
Safety Issue:
Description:This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting.
Measure:Progression-free survival 2 (PFS2)
Time Frame:4.1 years from first patient in
Safety Issue:
Description:PFS2 is defined as the time from randomization to second objective disease progression, or death from any cause, whichever first. The second objective disease progression will be assessed according to the RECIST criteria (version 1.1)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:European Organisation for Research and Treatment of Cancer - EORTC

Trial Keywords

  • cutaneous melanoma
  • mucosal melanoma
  • BRAF mutation

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