A Phase 1a/1b Study Exploring the Safety and Tolerability of INCB081776 in Participants With Advanced Malignancies

1. Participant must be >= 18 years of age at the time of signing the ICF.
2. Participant (or legally acceptable representative if applicable) provides
written informed consent for the study.
3. Must be willing and able to conform to and comply with all protocol
requirements,
including, all scheduled visits, protocol procedures, and the ability to
swallow oral capsules.
4. Part 1A, 1B, 2A, and 2B: Histologic or cytologic evidence of a solid
neoplasm for
which no standard therapy is available, or have progressed despite standard
therapy or are
intolerant to standard therapy, which may include chemotherapy, targeted
therapy,
biological therapy, and immunotherapy, inclusive of the cohort-specific
requirements
outlined below:
• Measurable lesions per RECIST v1.1 that are considered nonamenable to surgery
or other curative treatments or procedures, with at least 1 target lesion
available for evaluation. Tumor lesions located in a previously irradiated area
or in an area subjected to other loco-regional therapy are considered
measureable if progression has been demonstrated in the lesion.
• Part 1A and Part 2A only:
* Histologically confirmed advanced and/or metastatic solid tumors that are
considered unresectable and may include but are not limited to the following
tumor types: gastric or GEJ adenocarcinoma, HCC, melanoma, NSCLC, RCC,
soft-tissue sarcoma, SCCHN (recurrent or metastatic), TNBC, or urothelial
carcinoma. Additionally, MSI-H tumors are included in this part.
• Part 1B and 2B only:
* Cohort 1: advanced or metastatic melanoma
* Must have received available SOC, including but not limited to 1 prior
PD-1/L1 containing regimen (either as a single agent or in combination),
received at least 2 doses of the anti-PD-1/L1 agent, and experienced PD during
or after treatment.
* Known BRAF status (V600e and V600k).
* Ocular melanoma is excluded.
* Cohort 2: advanced or metastatic NSCLC
* Must have received available SOC, including but not limited to 1 prior
PD-1/L1 containing regimen (either as a single agent or in combination),
received at least 2 doses of the anti-PD-1/L1 agent, and experienced PD during
or after treatment.
* Participants with tumors harboring known driver mutations (EGFR, ALK, ROS1,
BRAF) who have previously been treated with appropriate targeted agents are
allowed to enroll.
* Known PD-L1 expression status and/or TPS
* Cohort 3: recurrent or metastatic SCCHN
* Must have received available SOC, including but not limited to 1 prior
PD-1/L1 containing regimen (either as a single agent or in combination),
received at least 2 doses of the anti-PD-1/L1 agent, and experienced PD during
or after treatment.
* Known PD-L1 expression status and/or TPS
* Carcinoma of the nasopharynx, thyroid, salivary gland, or nonsquamous
histologies are excluded.
* Cohort 4: advanced or metastatic soft-tissue sarcoma
* Must have received available SOC
* Eligible subtypes include leiomyosarcoma, poorly
differentiated/dedifferentiated liposarcoma, high-grade pleomorphic
undifferentiated sarcoma/MFH, myxofibrosarcoma, malignant peripheral nerve
sheath tumor, epithelioid sarcoma, clear cell sarcoma, synovial sarcoma,
rhabdomyosarcoma, fibrosarcoma, and angiosarcoma
* Must not have received prior anti-PD-1/L1 targeted treatment.
5. Part 1B and Part 2B: All participants enrolled into Part 1B or Part 2B must
be willing
to provide a fresh baseline tumor biopsy and an on-study biopsy between Cycle 2
Day 1
and Cycle 3 Day 1.
ECOG performance status score of 0 or 1.
6. Willingness to avoid pregnancy or fathering children

1. Participants receiving potent inhibitors or inducers of CYP3A4.
2. Participants with macular degeneration, proliferative diabetic retinopathy
or diabetic
retinopathy with macular edema, retinal vein occlusions, uveitis, central
serous retinopathy, leukemic retinopathy, inherited retinal degenerations,
known family history of inherited retinal degenerations, and participants at
risk for angle closure glaucoma from pupillary dilation are ineligible.
Participants with other clinically significant abnormalities identified during
ophthalmic screening examinations that may confound ocular monitoring are
ineligible.
3. Clinically significant cardiac disease, including LVEF<40%, unstable angina,
acute
myocardial infarction within 6 months of Cycle 1 Day 1, New York Heart
Association
Class III or IV congestive heart failure, and arrhythmia requiring therapy.
4. History or presence of an abnormal rhythm or pattern on ECG that, in the
investigator's
opinion would have a clinically meaningful impact on the study.
5. Untreated brain or CNS metastases or brain or CNS metastases that have
progressed.
6. Participants who have active or inactive autoimmune disease or syndrome
either
independent of prior therapy or induced by prior immune checkpoint inhibitor
therapy that has required systemic treatment in the past 2 years or who are
receiving systemic therapy for an autoimmune or inflammatory disease
7. Parts 1B, 2A, and 2B only: Participants with prior Grade 3 or higher
immune-related
AEs or any ocular toxicity on prior immunotherapy.
8. Laboratory values not within the Protocol-defined range.
9. Participants receiving any vitamin K antagonists,
10. Treatment with anticancer medications or investigational drugs within the
following
intervals before the first administration of study drug:
a. At least 14 days for chemotherapy, targeted small molecule therapy, or
radiation
therapy. Participant must not have had radiation pneumonitis as a result of
treatment.
b. At least 28 days for a prior monoclonal antibody used for anticancer
therapy.
11. Has not recovered to <= Grade 1 or baseline from toxic effects of prior
therapy (including
prior immunotherapy) and/or complications from prior surgical intervention.
12. Parts 1B, 2A, and 2B only: No use of systemic corticosteroids within 7 days
before the
first dose of study treatment.
13. Receipt of a live vaccine within 3 months of the first dose of study
treatment
14. Active infection requiring systemic therapy.
15. Evidence of HBV or HCV infection or risk of reactivation.
16. Known history of HIV (HIV 1/2 antibodies).
17. Known hypersensitivity or severe reaction to any component of study drugs or
formulation components.
18. Is pregnant or breastfeeding or expecting to conceive or father children
within the
projected duration of the study, starting with the screening visit through 190
days after
the last dose of study treatment.
19. Any condition that would, in the investigator's judgment, interfere with
full participation
in the study, including administration of study treatment and attending
required study
visits; pose a significant risk to the participant; or interfere with
interpretation of study
data.
20. Inability of the participant to comprehend the ICF or unwillingness to sign
the ICF.
21. Participants with known dysphagia, short-gut syndrome, gastroparesis, or
other
conditions that limit the ingestion or gastrointestinal absorption of drugs
administered
orally.
22. Evidence of interstitial lung disease, history of interstitial lung
disease, or active,
noninfectious pneumonitis.
23. History of organ transplant, including allogeneic stem cell transplantation
(except
Cohort 1C).
24. Diagnosis of oculocutaneous albinism.