Study of mRNA-4359 Administered Alone and in Combination With Immune Checkpoint Blockade in Participants With Advanced Solid Tumors

Key Inclusion Criteria:

• Males or females ≥18 years of age who have provided written informed consent priorto completing any study-specific procedure. For Arm 2d, participants ≥12 years areeligible with informed consent/assent.

• Dose Escalation (Arm 1a): Participant has histologically confirmed locally advancedor metastatic cancer (cutaneous melanoma, NSCLC, non-muscle invasive bladder cancer,head and neck squamous cell carcinoma, microsatellite stable colorectal cancer [MSSCRC], basal cell carcinoma, or triple negative breast cancer) with measurabledisease as determined by RECIST v1.1. Arm 1a participants must have received, andthen progressed, relapsed, or been intolerant to, or ineligible for, at least 1standard treatment regimen in the advanced or metastatic setting. Participants witha known driver mutation must have also received or been offered a mutation-directedtherapy, where indicated. Participants must have a tumor lesion amenable to biopsyand must have another lesion that can be followed for response.

• Dose Confirmation (Arm 1b): Participant has histologically confirmed locallyadvanced or metastatic, and CPI refractory melanoma or locally advanced ormetastatic, and CPI refractory NSCLC with measurable disease as determined by RECISTv1.1 who has disease progression after, at least 1 line of standard therapy (nolimit to prior lines of therapy), and has been treated with or refused standard ofcare treatment. Participants in PD arm Group 2 must also have PD-L1 TPS ≥1%.Participants must have primary refractory or acquired secondary resistance to priorimmune checkpoint treatments. Primary refractory is defined as prior exposure toanti-programmed death-1 (PD-1)/PD-L1 antibody for at least 6 weeks but no more than 6 months with demonstration of progression on 2 separate scans at least 4 weeksapart but no more than 12 weeks apart and progression occurring within 6 monthsafter first dose of anti-PD-1 antibody. Acquired secondary resistance must haveconfirmed objective response or prolonged stable disease (SD) (>6 months), followedby disease progression in the setting of ongoing treatment and confirmed progressionon scans at least 4 weeks apart. Participants must have a tumor lesion amenable tobiopsy and must have another lesion that can be followed for response.

1. For NSCLC participants with known EGFR, ALK, proto-oncogene tyrosine-proteinkinase reactive oxygen species (ROS1), or other actionable mutations for whichthere are approved targeted therapies, participants must have received priorapproved targeted therapy or have been offered and declined approved targetedtherapy.

2. Expansion of the melanoma Arm 1b cohort (up to approximately 16 additionalevaluable participants) will require prospective central testing of Screeningtumor biopsies to confirm PD-L1 TPS ≥1% for eligibility.

• Dose Expansion Arms (Arm 2): Participant has histologically confirmed:

1. Arm 2a: Locally advanced or metastatic melanoma who have not yet received anyprior systemic therapy for their melanoma in this setting.

2. Arm 2b: Newly diagnosed locally advanced or metastatic NSCLC with a PD-L1 TPSof ≥50% with no known EGFR or ALK positive tumor mutations who have not yetreceived any prior systemic therapy for their NSCLC (that is, treatment-naive).

3. Arm 2c: Locally advanced or metastatic melanoma in participants who have notreceived prior systemic therapy for melanoma in the advanced/metastaticsetting.

4. Arm 2d: Advanced/metastatic melanoma that is CPI refractory and having acentrally confirmed PD-L1 TPS of ≥1% on their Screening tumor biopsy.

• All participants must have measurable disease as determined by RECIST v1.1.

• Participants must have a tumor lesion amenable to biopsy and must provide tumorbiopsy sample at baseline (archival formalin-fixed, paraffin-embedded [FFPE] tissuecollected within 90 days of informed consent is accepted as long as no interveningtherapy is received, during this time), and optionally at all on-treatmenttimepoints (including response or progression) if medically feasible. Participantsin Arm 2c: Sufficient tumor tissue (slides or FFPE block) for PD-L1 testing isrequired as per Laboratory Manual. Participants in Arm 2c may be replaced in thiscohort if not PD-L1 evaluable. Participants in Arm 1b melanoma expansion cohort andArm 2d: Central confirmation of PD-L1 TPS score is required prior to enrollment.

• If the participant is undergoing a new biopsy, they must have another lesion outsideof the lesion biopsied at baseline that can be followed as a RECIST v1.1 targetlesion for response.

• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.

• Participant has adequate hematological and biological function.

Key Exclusion Criteria:

• Participant has active central nervous system tumors or metastases.

• Participant has received treatment with prohibited medications (that is, concurrentanticancer therapy including other chemotherapy, radiation [local radiation forpalliative care is permitted with approval from the Sponsor], hormonal anticancertreatment, biologic therapy, or immunotherapy) or investigational agents within 5half-lives or 14 days prior to the first day of study treatment, whichever isshorter. Prior exposure to any investigational or approved agent designed tosimultaneously target both indoleamine 2,3-dioxygenase (IDO1) and PD-L1 is alsoexclusionary.

• Participant has required the use of additional immunosuppression (for example,infliximab) other than corticosteroids for the management of an AE, has experiencedrecurrence of an AE if rechallenged, and currently requires maintenance doses of >10milligrams (mg) prednisone or equivalent per day.

• Participant has any plan to receive a live attenuated vaccine during study treatmentor has received a live vaccine within 30 days before the first dose of studytreatment. Examples of live vaccines include, but are not limited to measles, mumps,rubella, varicella/zoster (chicken pox), yellow fever, rabies, BacillusCalmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines and non-livecoronavirus disease 2019 (COVID-19) for injection are generally allowed.

• Participant has reversible toxicities from prior cancer therapy that have notrecovered to Grade 1 or baseline. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) Grade ≥2 from previous anticancertherapy with the exception of alopecia, vitiligo, and prespecified laboratoryvalues.

• Participant who is pregnant, breastfeeding, or is of childbearing potential, definedas those who are capable of becoming pregnant who are not willing to employ a highlyeffective method of contraception during dosing and for 90 days after the last doseof mRNA-4359 or 4 months after the last dose of pembrolizumab or 5 months after thelast dose of ipilimumab/nivolumab administrations, whichever is longer.

• Sexually active participants who refuse to use a condom during intercourse orparticipants who will not refrain from sperm donation while taking study treatmentand for 90 days after the last dose of mRNA-4359 or 4 months after the last dose ofpembrolizumab or 5 months after the last dose ipilimumab/nivolumab, whichever islonger, or who will not refrain from sperm donation for the same time period.

• Participant has any unstable or clinically significant concurrent medical condition (for example, substance abuse, uncontrolled intercurrent illness including activeinfection, arterial thrombosis, and symptomatic pulmonary embolism) that would, inthe opinion of the Investigator, jeopardize the safety of a participant, impacttheir expected survival through the end of the study participation, and/or impacttheir ability to comply with the protocol. Also including but not limited to,ongoing or active infection, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, active gastrointestinalbleeding or hemoptysis or history of bleeding disorder, or psychiatricillness/social situations that would limit compliance with study requirement,substantially increase risk of incurring AEs, or compromise the ability of theparticipant to give written informed consent.

• Participant has concurrent enrollment in another clinical study (unless it is anobservational noninterventional clinical study).