A Phase 1, Open-Label, multicenter Study of INCA00186 as monotherapy or in combination with immunotherapy in participants with advanced solid tumors

Participants are eligible to be included in the study only if all of the
following criteria apply:
1. Ability to comprehend and willingness to sign a written ICF for the study.
2. Male or female participant aged 18 years or older inclusive at the time of
signing the ICF.
3. Must be willing and able to conform to and comply with all Protocol
requirements, including all scheduled visits and Protocol procedures.
4. Willingness to undergo pre- and on-treatment tumor biopsy (core or
excisional).
5. Have CD8 T-cell-positive tumors based on evaluation of CD8+ T-lymphocyte
presence by IHC performed on pretreatment tumor biopsy tissue.
6. ECOG performance status 0 or 1.
7. Measurable disease according to RECIST v1.1.
8. Phase 1a early dose level cohorts in each of the treatment groups only:
Participants with advanced or metastatic solid tumors experiencing disease
progression after treatment with available therapies, including anti-PD-(L)1
therapy (if applicable), that are known to confer clinical
benefit, or who are intolerant to, or ineligible for standard treatment.
Prior anti-PD-(L)1 therapy should not have been discontinued because of
intolerance.
9. Participants with SCCHN:
a. Participants with histologically or cytologically confirmed squamous cell
carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx not amenable
to local therapy with curative intent (surgery or radiation with or without
chemotherapy).
b. Participants should have disease progression after treatment with available
therapies, including anti-PD-(L)1 therapy (alone or as part of a combination),
that are known to confer clinical benefit or who are intolerant to or
ineligible for standard treatment. Prior anti-PD-(L)1 therapy should not have
been discontinued because of intolerance.
10. Participants with specified GI malignancies: Histologically or
cytologically confirmed advanced or metastatic CRC, gastric/GEJ cancer, HCC,
PDAC, or SCAC.
a. Participants should have disease progression after treatment with available
therapies, including anti-PD-(L)1 therapy (if applicable), that are known to
confer clinical benefit or who are intolerant to or ineligible for standard
treatment. Prior anti-PD-(L)1 therapy should not have been discontinued because
of intolerance.
11. For participants to be enrolled in cohorts including INCB106385: The
ability to swallow oral medication.
12. Willingness to avoid pregnancy or fathering children based on the criteria
below:
a. Male participants with reproductive potential must agree to take appropriate
precautions to avoid fathering children (with at least 99% certainty) and
refrain from donating sperm from screening through 190 days after the last dose
of study treatment. Permitted methods that are at least 99% effective in
preventing pregnancy should be communicated to the participants and
their understanding confirmed.
b. Female participants who are WOCBP must have a negative pregnancy test at
screening (serum test) and before the first dose of Day 1 (urine test) and must
agree to take appropriate precautions to avoid pregnancy (with at least 99%
certainty) and refrain from donating oocytes from screening through 190 days
after the last dose of study treatment. Permitted methods that are at least 99%
effective in preventing pregnancy should be communicated to the participants
and their
understanding confirmed.
c. Female participants not considered to be of childbearing potential as
defined are eligible.

Participants are excluded from the study if any of the following criteria
apply:
1. Clinically significant cardiac disease, unstable angina, acute myocardial
infarction within 6 months of Cycle 1 Day 1, and New York Heart Association
Class III or IV congestive heart failure.
2. History or presence of an ECG abnormality that, in the investigator's
opinion, is clinically meaningful. For participants to be enrolled in cohorts
including INCB106385, screening QTcF interval > 450 milliseconds (ms) is
excluded; in the event that a single QTc is > 450 ms, the participant may
enroll if the average QTc for the 3 ECGs is < 450 ms.
3. Known active CNS metastases and/or carcinomatous meningitis.
4. Participants who have active or inactive autoimmune disease or syndrome (eg,
rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis,
inflammatory bowel disease) that has required systemic treatment in the past 2
years or who are receiving systemic therapy for an autoimmune or inflammatory
disease (ie, with use of disease modifying agents, corticosteroids, or
immunosuppressive drugs).
5. Diagnosis of immunodeficiency or is receiving chronic systemic steroid
therapy (doses > 10 mg daily of prednisone or equivalent) or any other form of
immunosuppressive therapy within 7 days before the first dose of study
treatment. Use of short courses of steroids for procedure
prophylaxis, inhaled or topical steroids, or systemic corticosteroids <= 10
mg/day is permitted.
6. Known additional malignancy that is progressing or requires active
treatment, or history
of other malignancy within 2 years of the first dose of study treatment with
the exception
of cured basal cell or squamous cell carcinoma of the skin, superficial bladder
cancer,
prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other
noninvasive or
indolent malignancy, or cancers from which the participant has been disease
free > 1 year after treatment with curative intent.
7. Participants with exclusionary laboratory values at screening (see protocol)
8. Has not recovered to <= Grade 1 from toxic effects of prior therapy
(including prior immunotherapy) and/or complications from prior surgical
intervention before starting study treatment.
9. Evidence of interstitial lung disease, history of interstitial lung disease,
or active noninfectious pneumonitis.
10. Immune-related toxicity during prior immune therapy for which permanent
discontinuation of therapy is recommended (per product label or consensus
guidelines), OR any immune-related toxicity requiring intensive or prolonged
immunosuppression to manage (with the exception of endocrinopathy that is
well-controlled on replacement hormones).
11. Prior treatment with any adenosine pathway targeting drugs (eg, A2A
receptor and/or A2B receptor antagonists, anti-CD38, anti-CD39, anti-CD-73/CD73
antagonists).
12. Any prior chemotherapy, biological therapy, or targeted therapy to treat
the participant's disease within 5 half-lives or 28 days (whichever is shorter)
before the first dose of study treatment.
13. Any prior radiation therapy within 28 days before the first dose of study
treatment.
14. Undergoing treatment with another investigational medication or having been
treated with an investigational medication within 5 halflives or 28 days
(whichever is shorter) before the first dose of study treatment.
15. For participants to be enrolled in cohorts including INCB106385:
concomitant treatment with strong CYP3A4 inhibitors or inducers.
16. Receipt of a live virus vaccine within 30 days of the first dose of study
treatment.
17. Infection requiring parenteral antibiotics, antivirals, or antifungals
within 1 week of the first dose of study treatment.
18. Known or suspected SARS-CoV-2 infection at the time of enrollment.
19. Active HBV or HCV infection that requires treatment. HBV-DNA and HCV-RNA
must be undetectable. Participants who have cleared a prior HBV infection
(defined as HBsAg negative, HBsAg antibody positive, and anti-HBc antibody
positive) are eligible for the study.
20. Known history of HIV (HIV 1/2 antibodies).
21. History of organ transplant, including allogeneic stem-cell transplantation
or CAR-T cell therapy.
22. Known hypersensitivity or severe reaction to any component of study drug(s)
or formulation components.
23. For participants to be enrolled in cohorts including INCB106385: Inability
to swallow food or any concomitant condition of the upper GI tract that
precludes administration of oral medications.
24. Is pregnant or breastfeeding.
25. Any condition in the PIs judgment that will interfere with study
participation.