A Study Exploring the Safety and Tolerability of INCB081776 in Participants With Advanced Malignancies

Inclusion Criteria:

• Male and female participants at least 18 years of age with advanced malignancies who have received or been intolerant to standard therapy:

Parts 1A and 2A:

* Histologically confirmed advanced or metastatic gastric or GEJ adenocarcinoma, HCC, melanoma, NSCLC, RCC, soft-tissue sarcoma, SCCHN (recurrent or metastatic), TNBC, or urothelial carcinoma. Additional tumor histologies, including MSI-H tumors, may be allowed with approval from the medical monitor.
* Measurable disease per RECIST v1.1.

Parts 1B and 2B:

• Histologic confirmation of the cohort-specific tumor types specified below: Cohort 1 - Advanced or metastatic melanoma Cohort 2 - Advanced or metastatic NSCLC Cohort 3 - Recurrent or metastatic SCCHN Cohort 4 - Advanced or metastatic soft-tissue sarcoma

* Cohorts 1-3 must have received 1 prior PD-1/L1 treatment and have experienced PD during or after that treatment and have progressed on other SOC therapy(ies); Cohort 4 must be PD-1/L1 treatment naïve but have progressed on SOC therapy(ies).
* Measurable disease per RECIST v1.1.
* Must be willing to submit to a fresh baseline tumor biopsy and an on-treatment biopsy between Cycle 2 Day 1 and Cycle 3 Day 1.
* Care should be taken to biopsy the same lesion for the baseline and on-treatment samples. If a participant has a solitary target lesion, this should not be biopsied.

Part 1C:

* Participants with relapsed/refractory AML following standard therapy; acute promyelocytic leukemia (M3) and therapy-related AML are excluded.
* FLT3-ITD and IDH1/2 wild-type or mutated are eligible; appropriate targeted therapy for participants with actionable mutations must have been received.

Exclusion Criteria:

* Laboratory values not within the protocol-defined range.
* History of retinal disease as defined in the protocol.
* Clinically significant cardiac disease as per protocol-defined criteria.
* History or presence of an ECG that, in the investigator's opinion, is clinically meaningful as per protocol-defined criteria.
* Untreated brain or central nervous system (CNS) metastases or brain or CNS metastases that have progressed as per protocol-defined criteria.
* Active or inactive autoimmune disease or syndrome that has required systemic treatment in the past 2 years or receiving systemic therapy for an autoimmune or inflammatory disease.
* Prior Grade 3 or higher immune-related AEs or any ocular toxicity on prior immunotherapy as per protocol-defined criteria.
* Receipt of any vitamin K antagonists, systemic corticosteroids, live vaccines, or treatment with any anticancer medications or investigational drugs within the protocol-defined intervals.
* Has not recovered to ≤ Grade 1 or baseline from toxic effects of prior therapy and/or complications from prior surgical intervention before starting study treatment.
* Active infection requiring systemic therapy.
* Evidence of hepatitis B virus or hepatitis C virus infection or risk of reactivation.
* Known history of HIV (HIV 1/2 antibodies).