Study of Efficacy and Safety of Novel Spartalizumab Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: PDR001; LAG525; INC280; ACZ885; LEE011
Intervention description: 400 mg of PDR001 administered every 4 weeks intravenously; 600 mg of LAG525 administered every 4 weeks intravenously; 400 mg of INC280 administered twice daily orally; 200 mg of ACZ885 administered every 4 weeks subcutaneosuly; 600 mg of LEE011 orally taken once daily on Days 1-21 of a 28-day cycle
Intervention MeSH terms: Spartalizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Masking description: After approval of protocol amendment 5 (26Jun2020), a non-randomized single arm was added
Enrollment: 196.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Unresectable; melanoma; metastatic melanoma; advanced melanoma; spartalizumab; PDR001; LAG525; capmatinib; INC280; canakinumab; ACZ885; ribociclib; LEE011; immunotherapy; platform study; LAG-3

Summary:

      The primary purpose of this study is to evaluate the efficacy of novel spartalizumab (PDR001)
      combinations in previously treated unresectable or metastatic melanoma
    

Eligibility criteria:

        Key inclusion criteria for Arm 1, 2, 3, 4:

          -  Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma
             using AJCC edition 8.

          -  Previously treated for unresectable or metastatic melanoma:

               -  Subjects with V600BRAF wild-type disease had to have received prior systemic
                  therapy for unresectable or metastatic melanoma with anti-PD-1/PD-L1.
                  Additionally, subjects may have received anti-CTLA-4 as a single agent or in
                  combination with anti-PD-1/PD-L1, irrespective of the sequence. No additional
                  systemic treatment was allowed for advanced or metastatic melanoma.

        A maximum of two prior lines of systemic therapies for unresectable or metastatic melanoma
        were allowed.

        The last dose of prior therapy (anti-PD-1, anti-PD-L1, or anti-CTLA-4) had to have been
        received more than four weeks before randomization.

          -  Subjects with V600BRAF mutant disease had to have received prior systemic therapy for
             unresectable or metastatic melanoma with anti-PD-1/PD-L1 and V600BRAF inhibitor.
             Additionally, subjects may have received anti-CTLA-4 as a single agent or in
             combination with anti-PD-1/PD-L1, or MEK inhibitor (in combination with V600BRAF
             inhibitor or as a single agent), irrespective of the sequence. No additional systemic
             treatment was allowed for advanced or metastatic melanoma.

          -  A maximum of three prior lines of systemic therapies for unresectable or metastatic
             melanoma were allowed.

          -  The last dose of prior therapy had to have been received more than 4 weeks (for
             anti-PD-1, anti-PD-L1, or anti-CTLA-4) or more than 2 weeks (for V600BRAF or MEK
             inhibitor) prior to randomization.

          -  All subjects (with V600BRAF wild-type disease and with V600BRAF mutant disease) had to
             have documented disease progression as per RECIST v1.1 while on/after the last therapy
             received prior to study entry and while on/after treatment with anti-PD1/PD-L1. The
             last progression had to have occurred within 12 weeks prior to randomization in the
             study.

               -  ECOG performance status 0-2.

               -  At least one measurable lesion per RECIST v1.1.

               -  At least one lesion, suitable for sequential mandatory tumor biopsies (screening
                  and on-treatment) in accordance with the biopsy guidelines specified in the
                  protocol. The same lesion had to be biopsied sequentially.

               -  Screening tumor biopsy had to fulfill the tissue quality criteria outlined in the
                  protocol, as assessed by a local pathologist.

        Key inclusion criteria for Arm 1A:

          -  Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma
             according to AJCC Edition 8.

          -  Previously treated for unresectable or metastatic melanoma:

               -  All subjects had to have received anti-PD-1 checkpoint inhibitor therapy (i.e.,
                  pembrolizumab or nivolumab) either as monotherapy or in combination with
                  ipilimumab as the last systemic therapy prior to enrollment and had to have
                  confirmed disease progression as per RECIST v1.1 (confirmed on a subsequent scan,
                  which could be the scan performed during screening) while on or after this
                  therapy prior to enrollment.

               -  Subjects with V600BRAF wild-type disease had to have received no more than 2
                  prior systemic therapies, including prior anti-PD-1/PD-L1 (as monotherapy or in
                  combination with ipilimumab).

               -  Subjects with V600BRAF mutant disease had to have received no more than 3 prior
                  systemic therapies, including anti-PD-1/PD-L1 (as monotherapy or in combination
                  with ipilimumab) and V600BRAF inhibitor (as monotherapy or in combination with a
                  MEK inhibitor).

               -  The last dose of anti-PD-1-based therapy had to have been received more than four
                  weeks prior to the first dose of study treatment.

               -  The last documented disease progression had to have occurred within 12 weeks
                  prior to the first dose of study treatment.

               -  No additional systemic treatment was allowed for advanced or metastatic melanoma
                  (this included, for example, tumor-infiltrating lymphocyte therapy).

          -  ECOG performance status 0-1.

          -  At least one measurable lesion per RECIST v1.1.

          -  Subjects had to have a baseline tumor sample that was positive for LAG-3 per central
             assessment.

        Key exclusion criteria common to all combination arms:

          -  Subjects with uveal or mucosal melanoma.

          -  Presence of clinically active or unstable brain metastasis at the time of screening.

          -  Use of any live vaccines against infectious diseases within 3 months before
             randomization/enrollment.

          -  Active infection requiring systemic antibiotic therapy at the time of
             randomization/enrollment.

          -  Subjects with a condition requiring systemic treatment with either corticosteroids
             (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
             days of randomization/enrollment. Inhaled or topical steroids, and adrenal replacement
             steroid doses >10 mg daily prednisone equivalent, were permitted in the absence of
             active autoimmune disease.

          -  Active, known or suspected autoimmune disease or a documented history of autoimmune
             disease.

          -  Prior allogenic bone marrow or solid organ transplant.

          -  History of known hypersensitivity to any of the investigational drugs used in this
             study.

          -  Malignant disease, other than that being treated in this study.

          -  Prior systemic therapy for unresectable or metastatic melanoma with any
             investigational agent or with any other agent except anti-PD-1/PD-L1 and anti-CTLA-4
             (and V600BRAF and MEK inhibitors if the subject has V600BRAF mutant disease). Prior
             neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months before
             the start of the study treatment.

          -  Medical history or current diagnosis of myocarditis.

          -  Cardiac Troponin T (or Troponin I) level > 2 x ULN at screening.