Clinical Trials /

Sequential Combo Immuno and Target Therapy (SECOMBIT) Study

NCT02631447

Description:

To evaluate the best sequencing approach with the combination of target agents (LGX818 plus MEK162) and the combination of immunomodulatory antibodies (ipilimumab plus nivolumab) in patients with metastatic melanoma and BRAF V600 mutation.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Sequential Combo Immuno and Target Therapy (SECOMBIT) Study

Title

  • Brief Title: Sequential Combo Immuno and Target Therapy (SECOMBIT) Study
  • Official Title: A Three Arms Prospective, Randomized Phase II Study to Evaluate the Best Sequential Approach With Combo Immunotherapy (Ipilimumab/Nivolumab) and Combo Target Therapy (LGX818/MEK162) in Patients With Metastatic Melanoma and BRAF Mutation
  • Clinical Trial IDs

    NCT ID: NCT02631447

    ORG ID: SECOMBIT

    Trial Conditions

    Metastatic Melanoma

    Trial Interventions

    Drug Synonyms Arms
    LGX818 Combo target, IMP3 Arm A: Combo Target/Combo Immuno, Arm B: Como immuno/Combo Target, Arm C: Sandwich
    MEK162 Combo target, IMP4 Arm A: Combo Target/Combo Immuno, Arm B: Como immuno/Combo Target, Arm C: Sandwich
    Nivolumab Combo Immuno, IMP1 Arm A: Combo Target/Combo Immuno, Arm B: Como immuno/Combo Target, Arm C: Sandwich
    Ipilimumab Combo Immuno, IMP2 Arm A: Combo Target/Combo Immuno, Arm B: Como immuno/Combo Target, Arm C: Sandwich

    Trial Purpose

    To evaluate the best sequencing approach with the combination of target agents (LGX818 plus
    MEK162) and the combination of immunomodulatory antibodies (ipilimumab plus nivolumab) in
    patients with metastatic melanoma and BRAF V600 mutation.

    Detailed Description

    The combination BRAF (B-raf murine sarcoma viral oncogene homolog B1) inhibitor plus
    mitogen-activated protein kinase (MEK) inhibitor seems to be more effective in the V600 BRAF
    mutated advanced melanoma patients compared to treatment with the BRAF inhibitors alone. In
    fact, a phase I-II study showed a better overall response rate (ORR) and progression-free
    survival (PFS) in the combination arm (dabrafenib plus trametinib) respect to the single
    agent treatment (dabrafenib): 76% and 9.4 months versus 54% and 5.8 months respectively.
    Another phase I study with a similar combination (vemurafenib plus cobimetinib) showed an
    ORR of 85% in vemurafenib-nave patients.

    Recently, the results of a phase I study about the combination ipilimumab plus nivolumab
    have been reported. In this study at the selected schedule (ipilimumab 3 mg/kg and nivolumab
    1 mg/kg), 53% of patients had an objective response, all with tumor reduction of 80% or
    more. Reponses were durable, although longer follow-up is needed.

    A recent phase I study has shown a high rate of liver toxicity with the combo ipilimumab
    plus vemurafenib . which makes difficult a combination with these two different drugs.
    Moreover, a better efficacy of the sequencing treatment BRAF inhibitors/ipilimumab vs. the
    single agent treatment was also observed; for this reason it was also suggested to start
    immunotherapy treatment in the BRAF V600 mutated melanoma population as first option, in
    order to increase the percentage of patients who can benefit from the sequencing,
    considering the possibility of a fast progression of the disease after the BRAF inhibitors
    treatment.

    Taking into account these considerations, it seems impossible to think to combine all the
    four compounds (the target agents and immunomodulating monoclonal antibodies). The risk of a
    high rate of toxicity is realistic and would render this approach inapplicable.

    Sequencing with these different combinations seems to be more feasible. However, also in
    this case it would be important to start with the best combination in order to give to the
    patients the best chance to increase the overall survival.

    The aim of this prospective randomized phase II study is to evaluate the sequencing of these
    two different combinations and evaluate which is the best of these approaches.

    Trial Arms

    Name Type Description Interventions
    Arm A: Combo Target/Combo Immuno Experimental Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) until PD; then Combo Immuno (nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks) until PD LGX818, MEK162, Nivolumab, Ipilimumab
    Arm B: Como immuno/Combo Target Experimental Combo Immuno (nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks) until PD; then Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) until PD LGX818, MEK162, Nivolumab, Ipilimumab
    Arm C: Sandwich Experimental Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) for 8 weeks followed by Combo Immuno (nivolumab 1 mg/kg solution IV combined with ipilimumab 3 mg/kg solution IV every 3 weeks for 4 doses then nivolumab 3 mg/kg solution IV every 2 weeks) until PD; then Combo Target (LGX818 450 mg p.o. od + MEK162 45 mg p.o. bid) until PD LGX818, MEK162, Nivolumab, Ipilimumab

    Eligibility Criteria

    Inclusion Criteria:

    1. Patients of either sex aged 18 years;

    2. Histologically confirmed stage III (unresectable) or stage IV melanoma with the BRAF
    V600 mutation. Patients with mucosal melanoma (but not those with ocular melanoma)
    are eligible for study participation;

    3. Treatment nave patients. Interferon as prior adjuvant melanoma therapy is permitted
    (note that prior adjuvant melanoma therapy is permitted if completed at least 6 weeks
    prior to randomization, and all related adverse events have either returned to
    baseline or stabilized).

    4. Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI)
    per RECIST 1.1 criteria;

    5. Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment;

    6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1(appendix 7);

    7. Tumor tissue from an unresectable or metastatic site of disease must be provided for
    biomarker analyses. An archive sample is mandatory at the screening visit; however, a
    fresh sample would be preferable;

    8. Female subjects of childbearing potential must have a negative serum pregnancy test
    result at Baseline and must practice a reliable method of contraception for the total
    study duration plus 23 weeks (i.e. 30 days plus the time required for nivolumab to
    undergo five half lives) after the last dose of nivolumab and ipilimumab;

    9. Men who are sexually active with women of childbearing potential must practice a
    reliable method of contraception for the total study duration plus 31 weeks (i.e. 80
    days plus the time required for nivolumab to undergo five half lives) after the last
    dose of nivolumab and ipilimumab;

    10. Adequate bone marrow haematological function: absolute neutrophil count (ANC) 1.5 x
    109/L AND platelet count 100 x 109/L AND haemoglobin 9 g/dL;

    11. Adequate liver function: total bilirubin 1.5 x upper limit of normal (ULN) AND
    aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 2.5 X ULN (< 5 x
    ULN if liver metastases);

    12. Adequate renal function: serum creatinine 1.5 mg/dL OR creatinine clearance 60
    mL/min in males and 50 mL/min in females (calculated according to Cockroft-Gault
    formula);

    13. Serum calcium levels, international normalised ratio (INR) and partial thromboplastin
    time were within normal limits;

    14. Life expectancy of at least 3 months;

    15. Ability to understand study-related patient information and provision of written
    informed consent for participation in the study.

    Exclusion Criteria:

    1. Active brain metastases. Subjects with brain metastases are eligible if these have
    been treated and there is no magnetic resonance imaging (MRI) evidence of progression
    for at least 8 weeks after treatment is complete and 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;

    2. Subjects with active, known or suspected autoimmune disease;

    3. Subjects with a condition requiring systemic treatment with either corticosteroids
    (>10 mg daily prednisone equivalents) or other immunosuppressive medications within
    14 days of treatment;

    4. Prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed
    Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated
    antigen-4 (anti-CTLA-4) antibody;

    5. Female subjects who are pregnant (positive pregnancy test), breast-feeding, or who
    are of childbearing potential and not practicing a reliable method of birth control;

    6. Evidence of 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, or would interfere
    with the results of the study;

    7. Patients with a history of cardiovascular or interstitial lung disease and evidence
    or risk of retinal vein occlusion or central serous retinopathy;

    8. History of Gilbert's syndrome;

    9. Inability to regularly access centre facilities for logistical or other reasons;

    10. History of poor co-operation, non-compliance with medical treatment, or
    unreliability;

    11. Participation in any interventional drug or medical device study within 30 days prior
    to treatment start.

    12. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
    ribonucleic acid (HCV antibody) indicating acute or chronic infection;

    13. Known history of testing positive for human immunodeficiency virus (HIV) or known
    acquired immunodeficiency syndrome (AIDS);

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Overall Survival

    Secondary Outcome Measures

    Total Progression free survival

    Percentage of patients alive at 2 and 3 years;

    Best overall response rate (BORR);

    Duration of response (DoR);

    Toxicity of the investigational medicinal products (IMPs).

    Quality of life and general health

    Trial Keywords

    Metastatic Melanoma

    BRAF mutation