A Trial of YL-13027 in Combination With Gemcitabine and Nab-paclitaxel in Patients With Refractory Metastatic Pancreatic Cancer

Inclusion Criteria:

1. Age ≥18 years.

2. Ability to understand and the willingness to sign a written informed consentdocument. 3. Ability to comply with the study protocol, in the investigator'sjudgment.

3. Participants with histologically confirmed metastatic pancreatic adenocarcinoma.

4. Refractory to one prior line of therapy in the metastatic setting. Participants arealso eligible if they finished adjuvant/neoadjuvant therapy in the last 6 months andhad disease recurrence.

5. Measurable disease with at least one lesion amenable to response assessment per theRECIST v1.1 (Appendix 2).

6. Eastern Cooperative Oncology Group performance status of 0 or 1 (Appendix 3).

7. Adequate organ and marrow function as defined below :

• Hemoglobin ≥8.0 g/dL o Absolute neutrophil count ≥1500/mm3

• Platelets ≥100,000/mm3

• Total bilirubin ≤1.5 × upper limit of normal (ULN) or direct bilirubin ≤ ULN forparticipants with total bilirubin levels >1.5 × ULN

• AST/ALT ≤2.5 × institutional ULN or ≤5 × ULN for patients with liver metastases

• Measured or calculated creatinine clearance (CrCl; Cockcroft-Gault) ≥50 mL/min/1.73m2. NOTE: For participants determined to be overweight or obese, actual body weightwill be used to estimate CrCl.

• For participants not receiving therapeutic anticoagulation: international normalizedratio or activated partial thromboplastin time ≤1.5 × ULN. For participantsreceiving therapeutic anticoagulation: stable anticoagulant regimen for at least 2weeks before study entry.

• Albumin ≥ 3 g/dL. 9. Participants must have adequate washout from prior therapy atthe time of study treatment initiation: ≥4 weeks from major surgery (excludingbiopsy; NOTE: If a participant received major surgery, she/he must have recoveredadequately from the toxicity and/or complications from the intervention prior tostudy treatment initiation); and ≥2 weeks or 5 half-lives (whichever is shorter)from prior therapy.

10. Women of childbearing potential (WOCBP) must agree to use a highly effectivemethod of contraception from the screening visit until 6 months after the lastdose of study treatment. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she shouldinform her treating physician immediately. Refer to Appendix 4 forcontraception guidance.

11. Male participants of childbearing potential must agree to use a highlyeffective method of contraception and refrain from donating sperm from thescreening visit until 3 months after the last dose of study treatment. Refer toAppendix 4 for contraception guidance.

12. WOCBP must have a negative serum pregnancy test result within 72 hours prior tostudy treatment initiation.

13. Participants with secondary malignancies are eligible if the malignancy doesnot have the potential to interfere with the safety or efficacy assessment ofthe study treatment. In addition, participants receiving hormonal therapy areeligible if the hormonal therapy does not interfere with the study treatment.

Exclusion Criteria:

1. Prior therapy with a TGF-β pathway-targeted agent.

2. Prior treatment with gemcitabine, nab-paclitaxel, or the combination of gemcitabineand nab-paclitaxel.

3. Unresolved toxicities from prior therapy (defined as having not resolved to NCICTCAE v.5.0 Grade ≤1 or baseline) or any other toxicity that is deemed irreversibleby the investigator. Exceptions include endocrinopathies from prior therapy ordisease and successfully treated (such as hypothyroidism, diabetes mellitus),alopecia, vitiligo, and Grade ≤2 peripheral neuropathy.

4. Known symptomatic brain metastases or primary CNS malignancy. Participants who havestable symptoms and are requiring steroids of 4 mg/day dexamethasone equivalent orless for 2 weeks prior to enrollment are permitted.

5. Live vaccines within 30 days prior to study treatment initiation.

6. Human immunodeficiency virus (HIV) infection with a current history of acquiredimmunodeficiency syndrome-defining illness or HIV infection with CD4+ T cell count <350 cells/µL and HIV viral load more than 400 copies/µL.

7. Participants with active viral (any etiology) hepatitis are excluded. However,participants with serologic evidence of chronic hepatitis B virus (HBV) infection (positive hepatitis B surface antigen test and a positive hepatitis B core antibodytest) who have a viral load below the limit quantification (HBV DNA titer <1000cps/mL or 200 IU/mL) and are not currently on viral suppressive therapy may beeligible and should be discussed with the principal investigators (PIs) and INDSponsor. The addition of HBV suppressive medication (i.e., entecavir) should beconsidered during the period of study treatment. Participants with a history ofhepatitis C virus infection who have completed curative antiviral treatment and havea viral load below the limit of quantitation may be eligible and should be discussedwith the PIs and Investigational New Drug (IND) Sponsor.

8. Any of the following cardiac criteria experienced currently or within 6 months priorto enrollment: a. Congestive heart failure (New York Heart Association FunctionalClassification of ≥ Class 2) b. Acute coronary syndrome c. Clinically significantcardiac arrhythmia

9. Mean QTcF >470 ms at screening.

10. Left ventricular ejection fraction <50% or the lower limit of normal (perinstitutional standard) at screening.

11. Use of strong CYP3A inhibitors or inducers are prohibited within 14 days or 5halflives, whichever is longer, prior to study treatment initiation and during thestudy treatment. For a comprehensive list of CYP3A inhibitors/inducers, refer to:https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-anddrug-interactions-table-substrates-inhibitors-and-inducers.

12. Evidence of severe or uncontrolled systemic comorbidities (e.g., active bleedingdiatheses or active infection), as determined by the investigator.

13. Participants who are pregnant or breastfeeding or expecting to conceive within theprojected duration of the study, starting with the screening visit through 3 monthsafter the last dose of study treatment.

14. Any condition that impairs a participant's ability to swallow whole pills orpresence of active GI disease or other condition that will significantly interferewith the absorption, distribution, metabolism, or excretion of YL-13027, asdetermined by the investigator.

15. Any known psychiatric, substance abuse, or other disorder that would interfere withcooperation with the requirements of the study, in the opinion of the investigator.

16. Participants who are receiving any other investigational agents.

17. History of allergic reactions attributed to compounds of similar chemical orbiologic composition to the study drugs.