A Phase 1/2 Dose Escalation and Dose Expansion Study of ZN-c3 in Combination with Gemcitabine in Adult and Pediatric Subjects with Relapsed or Refractory Osteosarcoma.

An individual must meet all the following criteria to participate in this
study:
1. Provision of written informed consent by subjects and/or their
parents or legally authorized
representatives; assent, when appropriate, will be obtained according to
institutional
guidelines.
2. Age >=12 years old at the time of informed consent.
3. Body weight >=40 kg.
4. Histologically documented relapsed or metastatic osteosarcoma, as
confirmed at the local study site.
a) The disease must have failed standard therapy and there is no known curative
therapy available, or any available standard of care therapy was not tolerated.
b) The Investigator must confirm that gemcitabine is an appropriate
treatment approach.
c) Subjects may have had any number of prior therapies and prior
treatment with gemcitabine is allowed.
5. Must have measurable disease according to RECIST v1.1 criteria.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) <=2 for
subjects
>=16 years of age or Lansky PS >=50 for subjects <16 years of age.
7. Adequate hematologic and organ function.
8. Ability and willingness to take oral medication.
9. Willingness to release archival tissue (less than 2 years old and of
adequate tumor cellularity
as described in Laboratory Manual; other cases may be considered after
discussion with the Sponsor) for research purposes and/or to undergo a tumor
tissue biopsy prior to dosing on Cycle 1 Day 1 if >=18 years old.
Biopsy samples of tumor tissue should be obtained if, in the judgment of the
Investigator, the procedure is considered to be free of unacceptable risk. If
in the opinion of the investigator a tumor tissue biopsy is not freeof
unacceptable risk and archival tissue is not available, eligible patients may
be allowed onto the trial on a case-by-case basis after consultation with the
sponsor.
10. Female subjects of childbearing potential must have a negative
serum beta human chorionic
gonadotropin (β-hCG) test.
11. Female subjects of childbearing potential and male subjects must
agree to use a highly effective method of contraception from the start of
Screening period and for 6 months after the last dose of ZN-c3 and/or
gemcitabine.
12. Willingness and ability to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.

Individuals meeting any of the following criteria will be excluded from this
study:
1. Any of the following treatment interventions within the specified timeframe
prior to Cycle 1 Day 1:
a. Major surgery <28 days (the surgical incision should be fully healed prior
to study drug administration).
b. Any chemotherapy <21 days or 5 half-lives (whichever is shorter).
c. Prior radiotherapy <14 days.
d. Any investigational drug therapy <28 days or 5 half-lives (whichever is
shorter).
e. Inability to discontinue treatment with prescription or non-
prescription drugs, or to discontinue consumption of food and herbal
supplements, that are strong and moderate CYP3A inhibitors and
inducers, or P-gp inhibitors at least 14 days prior to Cycle 1 Day1.
2. Unresolved toxicity of Grade >1 attributed to any prior therapies
(excluding Grade neuropathy, alopecia, or skin pigmentation).
3. Prior therapy with a WEE1 inhibitor.
4. Known hypersensitivity to gemcitabine or its excipients.
5. Known hypersensitivity to any drugs similar to ZN-c3 in class.
6. A serious illness or medical condition(s) including, but not limited to,
the following:
a. Brain metastases that require immediate treatment or are clinically
orradiologically unstable (i.e., have been stable for <1 month). If
receivingsteroids, subjects must be receiving a stable dose or a decreasing
corticosteroid dose during at least 1 week before enrollment.
b. Leptomeningeal disease that requires or is anticipated to require
immediate treatment.
c. Myocardial impairment of any cause (e.g., cardiomyopathy, ischemic heart
disease, significant valvular dysfunction, hypertensive heart
disease, and congestive heart failure) resulting in heart failure by New York
Heart Association Criteria (Class III or IV).
d. Other severe acute or chronic medical or psychiatric condition or
laboratory abnormality that may increase the risk associated with study
participation or study drug administration, or may interfere with the
interpretation of study results, and in the judgment of the Investigator would
make the subject inappropriate for entry into this study.
e. Significant gastrointestinal abnormalities, requirement for IV
alimentation, active peptic ulcer, chronic diarrhea, or vomiting
considered to be clinically significant in the judgment of the
Investigator, or prior surgical procedures affecting absorption.
f. Active or uncontrolled infection. Subjects with an infection receiving
treatment (antibiotic, antifungal, or antiviral treatment) must have
completed such treatment and the infection must be considered
controlled/resolved by the investigator before enrollment.
7. Pregnant or lactating females or females of childbearing potential
who have a positive serum pregnancy test within 14 days prior to Cycle 1Day 1.
8. Subjects with active (uncontrolled, metastatic) second malignancies or
requiring therapy.
9. Individuals who are judged by the Investigator to be unsuitable as
study subjects.
10. 12-lead ECG demonstrating a corrected QT interval using Fridericia s
formula (QTcF) of
>470 ms, except for subjects with atrioventricular pacemakers or other
conditions (e.g., right bundle branch block) that render the QT measurement
invalid.
11. History or current evidence of congenital or family history of long QT
syndrome or Torsades de Pointes (TdP).