A Phase 1, Open-Label, Multicenter Study of INCB123667 as Monotherapy in Participants With Selected Advanced Solid Tumors

1. Ability to comprehend and willingness to sign a written ICF for the study.
2. Adults age 18 years or older at the time of signing the ICF. In France,
adult (age of at least 18 and up to 99 years) male or female participants.
3. Willing and able to conform to and comply with all Protocol requirements,
including all scheduled visits and Protocol procedures.
4. Life expectancy greater than 12 weeks.
5. ECOG performance status score of 0 or 1.
6. Disease progression on prior standard treatment, intolerance to or
ineligibility for standard treatment, or no available treatment to improve the
disease outcome.
7. Availability of a baseline archival tumor specimen or willingness to undergo
a pretreatment and an on-treatment tumor biopsy (core or excisional) as
applicable to obtain the specimen.
Note:
• For participants in Part 1a and Part 1b: Fresh pretreatment biopsy (within
the screening/prescreening period) or archival tissue (collected within 2 years
prior to C1D1) is required as described in the protocol and in the Laboratory
Manual.
• For participants in Part 1b only: At least 5 participants per disease group
will be required to provide an on-treatment tumor biopsy during the
third/fourth week of study drug treatment (to obtain paired biopsies).
8. Diagnoses as follows:
a. For participants in Part 1a (dose escalation): Histologically or
cytologically confirmed advanced or metastatic solid tumors. Documented CCNE1
amplification from a qualified local laboratory test is preferred but not
mandatory.
b. For participants in Part 1b (dose expansion): Tumor tissue with CCNE1
amplification as determined by a qualified local laboratory or central
confirmation of cyclin E1 overexpression as follows (this does not apply to
participants in disease group 5):
* Participants with documentation of CCNE1 amplification obtained from a
qualified local laboratory will be enrolled without central cyclin E1
overexpression prescreening but are still required to provide a tumor tissue
sample (fresh sample or archival tissue) for retrospective central cyclin E1
overexpression evaluation.
* Participants without documentation of CCNE1 amplification obtained from a
qualified local laboratory will provide a tumor tissue sample (a fresh sample
if archival tissue within 2 years prior to C1D1 is not available) for
prospective central cyclin E1 overexpression evaluation as part of eligibility
prescreening. Only participants with cyclin E1 overexpression confirmed at a
central laboratory using a CLIA assay will be allowed to enter the study. These
participants will be required to sign a specific prescreening consent form
before the prescreening tumor tissue is obtained; however, no other protocol
assessments will be performed under the prescreening consent.

and with any of the following histologically or cytologically confirmed
indications:
- Gynecologic malignancies
o Disease Group 1 (ovarian/fallopian/primary peritoneal cancer): Participants
with advanced platinum-based chemotherapy-refractory or - resistant epithelial
ovarian/fallopian/primary peritoneal carcinoma or clear cell ovarian cancer who
have received up to 4 prior lines of systemic therapy administered for advanced
or metastatic disease
or
o Disease Group 2 (endometrial/uterine cancer): Participants with advanced
endometrial adenocarcinoma, uterine carcinosarcoma, or uterine papillary serous
carcinoma who have received up to 3 prior lines of systemic therapy
administered for advanced or metastatic disease.
Note (applicable to both Disease Groups 1 and 2): Maintenance treatment with
bevacizumab or a poly (ADP-ribose) polymerase inhibitor following response to
chemotherapy will not be counted as a separate line of therapy. Unlimited prior
lines of endocrine therapy are allowed.

* Gastrointestinal malignancies
o Disease Group 3 (gastric, GEJ, and esophageal adenocarcinomas): Participants
with advanced gastric, GEJ, or esophageal adenocarcinomas who have received up
to 3 prior lines of systemic therapy administered for advanced or metastatic
disease

* Breast Cancer
o Disease Group 4 (TNBC): Participants with locally recurrent/advanced or
metastatic TNBC who have received up to 2 prior lines of chemotherapy
administered for advanced or metastatic disease.
o Disease Group 5 (HR-positive/HER2-negative breast cancer after progression or
intolerant to a CDK4/6 inhibitor treatment): Participants with advanced
HR-positive/HER2-negative breast cancer who have had disease progression on or
been intolerant of a CDK4/6 inhibitor (HR+/HER2* defined as ER >1% and HER2
analysis will be conducted as per American Society of Clinical Oncology/College
of American Pathologists guidelines [Wolff et al 2018]).These participants do
not need to have documentation of CCNE1 amplification before enrollment in the
study.
* Other tumor indications
o Disease Group 6 (other tumor indications): Participants with advanced solid
tumors who have had disease progression on standard systemic therapies and
received up to 4 prior lines of systemic therapy administered for advanced or
metastatic disease

9. Measurable lesions by CT or MRI based on RECIST v1.1 criteria that are
considered nonamenable to surgery or other curative treatments or procedures.
Note: Locally advanced disease must not be amenable to resection with curative
intent or other curative treatments or procedures.
Note: Tumor lesions that are located in a previously irradiated area or in an
area subjected to other locoregional therapy should only be selected as target
lesions if progression has been demonstrated in such lesions.
Note: It is recommended that tumor lesions selected for biopsy not be selected
as target lesions.

10. Ability to swallow and retain oral medication.

1. History of clinically significant or uncontrolled cardiac disease, including
recent (within the last 12 months) unstable angina pectoris or acute myocardial
infarction, or New York Heart Association Class III or IV cardiac disease,
including preexisting clinically significant ventricular arrhythmia, congestive
heart failure, cardiomyopathy not controlled by medication, or other clinically
significant heart disease (ie, >= uncontrolled Grade 3 hypertension).
Participants with a pacemaker and well-controlled rhythm for at least 1 month
before the first dose of study drug will be allowed.
2. History or presence of an ECG abnormality that, in the investigator's
opinion, is clinically meaningful. Screening QTcF interval >450 milliseconds is
excluded; in the event that a single QTc is >450 milliseconds, the participant
may enroll if the average QTc for the 3 ECGs is <450 milliseconds.
3. Presence of chronic or current active infectious disease requiring systemic
antibiotic, antifungal, or antiviral treatment. Participants with acute
infection requiring antibiotic, antifungal, or antiviral treatment should delay
screening/enrollment until the course of antibiotic, antifungal, or antiviral
therapy has been completed and the infection is no longer active.
4. Untreated brain or CNS metastases or brain or CNS metastases that have
progressed (eg, evidence of new or enlarging brain metastasis or new
neurological symptoms attributable to brain or CNS metastases).
Note: Participants who have previously treated and clinically stable brain or
CNS metastases (without evidence of progression by imaging for at least 4 weeks
before the first dose of study drug and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastasis or CNS
edema, and have not required steroids for at least 7 days before study drug are
eligible.
5. Known additional malignancy that is progressing or requires active
treatment, or history of other malignancy within 2 years of the first dose of
study drug 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 for >1 year after
treatment with curative intent.
6. Participants with laboratory values at screening defined in the protocol.
7. Significant concurrent, uncontrolled medical condition, including but not
limited to the following:
a. Hepatic
* Known history of drug-induced liver injury; alcoholic liver disease;
nonalcoholic steatohepatitis; primary biliary cirrhosis; ongoing extrahepatic
obstruction caused by stones, cirrhosis of the liver, or portal hypertension.
b. Gastrointestinal
* Significant gastrointestinal disorder that could interfere with absorption,
metabolism, or excretion of study drug, including gastrectomy, partial
gastrectomy, or presence of a venting gastric tube that may interfere with
absorption of the study drug.
* Recent (<= 3 months) history or ongoing partial or complete bowel obstruction,
unless corrected by surgery.
* Any concomitant condition of the upper gastrointestinal tract that precludes
administration of oral medications.
8. Has not recovered to <= Grade 1 from toxic effects of prior therapy and/or
complications from prior surgical intervention before starting study drug.
Note: Participants with stable chronic conditions (<= Grade 2) not expected to
resolve (such as neuropathy, hypothyroidism, and alopecia) are exceptions and
may enroll.
9. Prior treatment with any CDK2 inhibitor.
10. Any change in endocrine therapy within 5 half-lives or 28 days (whichever
is shorter) before the first dose of study drug or any administration of
targeted therapy, antibody, or hypomethylating agent to treat the participant's
disease within 5 half-lives or 28 days (whichever is shorter) before the first
dose of study drug.