Study of Efficacy and Safety of Novel Spartalizumab Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma

Key inclusion criteria:

- 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 must have received prior therapy with
checkpoint inhibitor therapy (i.e. anti-PD-1/PD-L1 single-agent, or in combination
with anti-CTLA-4) and must have had objective evidence of disease progression (i.e.
RECIST v1.1) while on or after this therapy.

- Disease progression on or after prior therapy must have occurred within 12 weeks
prior to randomization in the study.

- The last dose of prior therapy (anti-PD-1, anti-PD-L1 or anti-CTLA-4) must have
been received more than 4 weeks prior to randomization.

- Subjects with V600BRAF mutant disease must have received prior therapy with checkpoint
inhibitor therapy (i.e. anti-PD-1/PD-L1 single-agent, or in combination with
anti-CTLA-4) and must have had objective evidence of disease progression (i.e. RECIST
v1.1) while on or after this therapy. Subjects must also have received prior therapy
with a V600BRAF inhibitor, either as a single-agent or in combination with a MEK
inhibitor.

- Disease progression on or after prior therapy must have occurred within 12 weeks
prior to randomization in the study.

- The last dose of prior therapy must 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.

- 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 protocol. The same
lesion must be biopsied sequentially.

- Screening tumor biopsy must fulfill the tissue quality criteria outlined in the
protocol, as assessed by a local pathologist

Key exclusion criteria common to all combination arms:

- Subjects with uveal or mucosal melanoma

- Presence of clinically active or unstable brain metastasis. Note: Subjects with
unstable brain lesions who have been definitively treated with stereotactic radiation
therapy, surgery or gamma knife therapy are eligible.

- Subjects with brain lesions who are untreated (i.e. newly discovered brain
lesions during screening) or received whole brain radiation must have documented
stable disease as assessed by two consecutive assessments ≥ 4 weeks apart and
have not required steroids for at least ≥ 4 weeks prior to randomization.

- Use of any live vaccines against infectious diseases within 3 months before
randomization.

- Active infection requiring systemic antibiotic therapy at time of randomization.

- Systemic chronic steroid therapy (˃ 10mg/day prednisone or equivalent) or any other
immunosuppressive therapy administered within 7 days prior to randomization. Note:
Local steroids such as topical, inhaled, nasal and ophthalmic steroids are allowed.

- Active, known or suspected autoimmune disease or a documented history of autoimmune
disease. Note: Subjects with vitiligo, controlled type I diabetes mellitus on stable
insulin dose, residual autoimmune-related hypothyroidism only requiring hormone
replacement or psoriasis not requiring systemic treatment are permitted.

- Prior allogenic bone marrow or solid organ transplant

- History of known hypersensitivity to any of the investigational drugs used in this
study

- Prior systemic therapy for unresectable or metastatic melanoma except anti-PD-1/PD-L1
single-agent or in combination with anti-CTLA-4, or V600BRAF and MEK inhibitors.

- Medical history or current diagnosis of myocarditis

- Cardiac Troponin T (TnT) level > 2 x ULN at screening