ZN-c3 + Gemcitabine in Pancreatic Cancer

Inclusion Criteria:

• Participants must have a pathologically confirmed advanced pancreatic adenocarcinomathat is not curable with standard approaches based on the judgement of the treatinginvestigator. Patients with metastatic pancreatic cancer and unresectable pancreaticcancer are eligible.

• Patients must have progressed or not tolerated a platinum-based regimen prior toenrolling on the trial.

• Patients must have received no more than 1 prior lines of platinum-basedchemotherapy in the metastatic setting. Therapy given in the adjuvant or neoadjuvantsetting is counted as a prior therapy if it occurred less than 6 months beforecancer recurrence or progression.

• Age ≥ 18 years. As no dosing or adverse event data are currently available inparticipants < 18 years of age, children and adolescents are excluded from thisstudy.

• ECOG performance status of 0 or 1 (see Appendix A) with no deterioration over theprevious 2 weeks prior to day of first dosing (Cycle 1, Day 1).

• Participants must have adequate organ and marrow function as defined below:

• Absolute neutrophil count ≥ 1,500/mm3

• Platelets ≥ 100,000/mm3 excluding measurements obtained within 3 days aftertransfusion of platelets

• Hemoglobin ≥ 9 g/dL

• Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN); or totalbilirubin ≤3.0 x ULN with direct bilirubin WNL in patients with documentedGilbert's Syndrome.

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) Albumin ≤2.5 x institutional ULN; ≤ 5 × institutional ULN if liver metastases ≥ 2.7g/dL

• Creatinine clearance (CrCl) ≥ 50 ml/min based on Cockroft-Gault method

• Participants must have measurable disease by RECIST v. 1.1 criteria and be willingto undergo a pre-treatment and on-treatment tumor biopsy. The biopsy requirement canbe waived only with approval from the sponsor-investigator.

• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated, unless thereis a drug-drug interaction with study medication.

• Patient has read and understands the informed consent form (ICF) and has been givenwritten ICF prior to any study procedures which includes compliance with therequirements and restrictions listed in the ICF and in this protocol.

• Female patients who are not of child-bearing potential* and women of childbearingpotential who agree to use adequate contraceptive measures prior to the first doseand for 90 days after the last dose of ZN-c3, and who have a negative serum or urinepregnancy test within 14 days prior to the start of study treatment.

--Evidence of non-childbearing status, defined as below:

• Women who are surgically sterile (i.e., have undergone bilateral salpingectomy,bilateral oophorectomy, or complete hysterectomy).

• Age ≥50 years with any one or more of the conditions below:

• Amenorrheic for 12 months or more following cessation of all hormonalreplacement therapy

• Had radiation-induced menopause with last menses >1 year ago

• Had chemotherapy-induced menopause with last menses >1 year ago

• Age <50 if amenorrhoeic for 12 months or more following cessation of allhormonal replacement therapy and if luteinizing hormone and follicle-stimulating hormone levels are in the post-menopausal range per institutionalstandards of practice.

• Male patients should be willing to abstain or use barrier contraception (i.e.,condoms) for the duration of the study drug exposure and for 90 days after the lastdose of ZN- c3 after study treatment discontinuation.

• Participants with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For participants with HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load, unlessthere is a drug-drug interaction with study medication.

Exclusion Criteria:

• Patients who have previously received a WEE1 inhibitor are not eligible.

• Patients who received gemcitabine for incurable pancreatic cancer (locally advancedunresectable or metastatic) or patients progressing within 6 months of receivingneoadjuvant/adjuvant gemcitabine.

• Use of an anti-cancer treatment drug ≤ 21 days or 5 half-lives (whichever isshorter) prior to the first dose of ZN-c3.

• Active use of treatment prescription or non-prescription drugs, or food and herbalsupplements, that are strong/moderate CYP3A4 inhibitors, P-gp inhibitors, or strongCYP3A4 inducers.

• Any prior palliative radiation to ≥5% of the bone marrow, and must have beencompleted and recovered from adverse effects of therapy at least 21 days prior tothe first dose of ZN-c3.

• Participants who have undergone major surgical procedures ≤ 28 days, or minorsurgical procedures ≤ 7 days, of the first dose of ZN-c3. No waiting period isrequired following port-a-cath or other central venous access placement.

• Presence of CTCAE v5.0 Grade >1 toxicity from prior therapy (except alopecia,anorexia or CTCAE grade 2 peripheral neuropathy).

• Patient is unable to swallow oral medications. Note: Patient may not have apercutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteralnutrition (TPN).

• Participants with known malignant central nervous system (CNS) disease other thanneurologically stable, treated brain metastases - defined as metastasis having noevidence of progression or hemorrhage for at least 2 weeks after the completion oftreatment (including brain radiotherapy). Must be off any systemic corticosteroidsfor the treatment of brain metastases for at least 14 days prior to enrollment.

• History of hypersensitivity to compounds of similar chemical or biologic compositionto gemcitabine or ZN-c3.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection*, uncontrolled major seizure disorder, unstable spinal cord compression,superior vena cava syndrome, or psychiatric illness/social situations that wouldlimit compliance with study requirements.

• Recurrent, active or suspected infection and/or patients who are predisposed to anincreased risk of severe infection. Patients with infections that requireantibiotics or antifungal agents may be eligible, provided that infection isresolved and treatment is completed at least 7 days prior to study treatment start.

• Participants with a clinically significant gastrointestinal disorder that in theopinion of the treating investigator could impact the absorption of the study drugs,including but not limited to refractory nausea and vomiting, chronicgastrointestinal disease, inability to swallow the formulated product, or previoussignificant bowel resection that would preclude adequate absorption, distribution,metabolism, or excretion of ZN-c3.

• Participants with a history of a clinically relevant second primary malignancywithin the past 2 years. Exceptions include: resected basal and squamous cellcarcinomas of the skin and completely resected carcinoma in situ of any type.

• Administration of strong or moderate CYP3A4 inhibitors or inducers and P-gpinhibitors. (See Appendix B)

• Pregnant or lactating women are excluded from this study because gemcitabine/ZN- c3are anti-cancer agents with the potential for teratogenic or abortifacient effects.Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with gemcitabine/ZN-c3, breastfeeding should bediscontinued if the mother is treated with gemcitabine/ZN-c3.

• Any of the following cardiac diseases currently or within 6 months of the first doseof ZN-c3:

• 12-lead ECG demonstrating a corrected QT interval using Fridericia's formula (QTcF) of >470 ms, except for subjects with atrioventricular pacemakers orother conditions (e.g., right bundle branch block) that render the QTmeasurement invalid.