An Open-Label, Multicenter, Phase Ib Study To Evaluate Safety And Therapeutic Activity Of Ro6874281, An Immunocytokine, Consisting Of Interleukin-2 Variant (Il-2v) Targeting Fibroblast Activation Protein-Α (Fap), In Combination With Pembrolizumab (Anti-Pd-1), In Participants With Previously Untreated Advanced And/Or Metastatic Melanoma

This is an open-label, multicenter, Phase Ib study to evaluate the safety and therapeutic
activity of RO6874281 in combination with pembrolizumab. The study will consist of 3 parts: a
safety run-in (Part I: Cohorts 1.1. and 1.2) and two expansion parts (Parts II and III). Part
II will start once all participants in Cohort 1.1 have completed the observation period. Part
III will start once all participants in Cohorts 1.1 and 1.2 have completed the observation
period.

Inclusion Criteria:

1. Histologically confirmed unresectable stage III or stage IV cutaneous or mucosal
melanoma (AJCC v8.0).

2. Participants need to have known BRAF status.

3. CPI naïve melanoma population: Participants with unresectable stage III or stage IV
cutaneous or mucosal melanoma who have not received prior treatment for advanced
disease. BRAF mutation-positive patients are eligible without prior treatment or after
failure of BRAF directed inhibitor therapy.

4. CPI experienced melanoma population: Participants with unresectable stage III or stage
IV cutaneous melanoma. Participants must have progressed during or after treatment
with anti PD-1 antibody therapy, either as monotherapy or in combination with other
agent(s).

5. Participants should have adequate cardiovascular, hematological, liver, and renal
function.

6. Participants with unilateral pleural effusion are eligible if they fulfill both of the
following: NYHA Class 1; Forced expiratory volume 1 (FEV1) >70% and forced vital
capacity (FVC) >70% of predicted value; participants with lung metastases should
present with DLCO >60% of predicted value.

Exclusion criteria:

Medical Conditions

1. Rapid disease progression or suspected hyperprogression (as determined by the
Investigator) or threat to vital organs or critical anatomical sites requiring urgent
alternative medical intervention.

2. Known active CNS metastases and/or carcinomatous meningitis/leptomeningeal disease:

Participants with previously treated brain metastases may participate.

3. History of treated asymptomatic CNS metastases.

4. An active second malignancy (exceptions are non-melanoma skin cancer, cervical
carcinoma in situ, or prostate carcinoma that is in remission under androgen
deprivation therapy for ≥ 2 years, or participants who have a history of malignancy
and have been treated with curative intent and the participant is expected to be cured
as per Investigator's assessment).

5. Evidence of significant, uncontrolled concomitant diseases that could affect
compliance with the protocol or interpretation of results, and known autoimmune
diseases or other disease with ongoing fibrosis (such as scleroderma, pulmonary
fibrosis. and emphysema).

6. Episode of significant cardiovascular/cerebrovascular acute disease within 6 months
before study treatment administration.

7. Active or uncontrolled infections, including latent tuberculosis.

8. Known HIV infection.

9. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

10. Severe infection within 4 weeks before study treatment administration, including, but
not limited to, hospitalization for complications of infection, bacteremia, or severe
pneumonia.

11. History of chronic liver disease or evidence of hepatic cirrhosis.

12. Dementia or altered mental status that would prohibit informed consent.

13. History of autoimmune disease.

14. Adverse events related to any previous radiotherapy, chemotherapy, targeted therapy,
CPI therapy or surgical procedure that have not resolved to Grade =< 1, except
alopecia (any grade) and Grade 2 peripheral neuropathy.

15. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan.

16. Bilateral pleural effusion.

17. Severe dyspnea at rest or requiring supplementary oxygen therapy.

18. Concurrent therapy with any other investigational drug (defined as a treatment for
which there is currently no regulatory authority approved indication).

19. Immunomodulating agents: Last dose with any of the following agents, for example,
etanercept, infliximab, tacrolimus, cyclosporine, mycophenolic acid, alefacept, or
efalizumab (or similar agents) < 28 days before study treatment administration.
Regular immunosuppressive therapy (i.e., for organ transplantation, chronic
rheumatologic disease)

20. Treatment with systemic immunosuppressive medications including, but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF
agents within 2 weeks prior to Cycle 1 Day 1.

21. Radiotherapy within the last 4 weeks before start of study treatment administration,
with the exception of limited field palliative radiotherapy.

22. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1.

23. Major surgery or significant traumatic injury < 28 days before study treatment
administration (excluding fine needle biopsies) or anticipation of the need for major
surgery during study treatment.

24. Known hypersensitivity to any of the components of the RO6874281 drug product or
pembrolizumab drug product, including but not limited to hypersensitivity to Chinese
Hamster Ovary cell products or other recombinant human or humanized antibodies.

25. No prior cytotoxic therapy for unresectable stage III or stage IV disease is
permitted.

26. Toxicity from prior anti-PD-1 antibody therapy (including adjuvant treatment).