Vactosertib With Nal-IRI/FL in Metastatic Pancreatic Ductal Adenocarcinoma.

Phase 1b Study of Vactosertib (TEW-7197) in Combination With Nal-IRI／FL in Patients With Metastatic Pancreatic Ductal Adenocarcinoma Who Have Failed First-Line Gemcitabine／Nab-Paclitaxel

To determine recommended phase 2 dose and to evaluate the safety of vactosertib in combination with nal-IRI/FL in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) who have failed first-line gemcitabine and nab-paclitaxel

• Number of patients : Total 24 patients (6-12 patients in phase 1 part and 12 patients in expansion cohort )

• Treatment :

  • Vactosertib* 100-300 mg bid for 5 days

  • Liposomal Irinotecan (Onivyde) 70mg/m2 on D1

  • LV 200mg/m2 IV bolus on D1

  • 5-FU 2400mg/m2 CIV over 46 hours on D1

    • Vactosertib will be kindly provided by MedPacto.

• Disease evaluation: Tumor assessment will be conducted at screening and before Day 1 of every third cycle starting with Cycle 4

• Period : Approximately 24 months from the date of Institutional Review Board (IRB) approval

• Primary endpoint : To determine recommended phase 2 dose and to evaluate the safety of vactosertib in combination with nal-IRI/FL in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) who have failed first-line gemcitabine and nab-paclitaxel

• Secondary endpoint :

  • Progression-Free Survival (PFS) (RECIST 1.1 criteria)
  • Overall Survival (OS)
  • Objective Response Rate (ORR) (RECIST 1.1 criteria)
  • Disease Control Rate (DCR) (RECIST 1.1 criteria)

• Exploratory endpoint

  • Pharmacokinetic assessment: before treatment, post treatment 1.5h, 4.5h, and 8hPharmacodynamic assessment: to evaluate changes in the amount of p-SMAD in PBMC.
  • Biomarker analysis in pre-treated and post-treated tumor samples

Inclusion Criteria:

1. Subjects who are males or females ≥ 19 years of age

2. Subjects who have the following history of first-line gemcitabine-based chemotherapy among patients with cytologically or histologically proven metastatic pancreatic ductal adenocarcinoma

3. Subjects who can give written informed consent for participation in this trial after receiving explanations of this trial

4. Subjects who have the following laboratory test values:

   • bilirubin ≤ 1.5 x ULN (upper limit of normal)
   • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x ULN
   • serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 40 mL/min (Cockcroft-Gault)
   • partial thromboplastin time (aPTT) ≤ 1.5 x ULN
   • absolute neutrophil count (ANC) ≥ 1,500 cells/µL
   • platelet count ≥ 100,000/µL
   • hemoglobin ≥ 9.0 g/dL

5. Subjects who have at least a 12-week life expectancy at the Investigator's discretion

6. Subjects who have Eastern Cooperative Oncology Group (ECOG)Performance Status 0-1

Exclusion Criteria:

1. Subjects who were treated with surgery, radiotherapy, chemotherapy or investigational therapy within 2 weeks (note: placement of biliary stent is allowed)

2. Subjects who have uncontrolled CNS metastases (patients who require steroids should be on a stable or decreasing dose for at least 2 weeks)

3. Subjects who have any contraindications for 5-FU, leucovorin, or nal-IRI

4. Subjects who have moderate or severe cardiovascular disease

   • Subjects who have myocardial infarction, unstable angina pectoris, New York Heart Association (NYHA) Class III/IV congestive heart failure, or uncontrolled hypertension within 6 months before screening
   • Subjects who have major abnormalities at the Investigator's discretion based on electrocardiogram (ECG)and Doppler ECHO results at screening or within 14 days before screening
   • Subjects who have increase in brain natriuretic peptide (BNP) or increase in troponin (over 99th percentile upper reference limit) at Screening (based on the normal range of relevant study center)
   • Subjects who have risk factors for ascending aortic aneurysm such as genetic disorder and trauma and risk factors for aortic stenosis
   • Subjects who have a history of heart or aorta surgery

5. Subjects who have clinically significant gastrointestinal bleeding within 4 weeks before screening

6. Subjects who have a known history or suspected hypersensitivity to any excipients of the investigational product or combination drug(s)

7. Subjects who have received prior treatment targeting the signaling pathway of TGF-β

8. Subjects who have a disease or condition that affects the mechanism of the investigational product, or are currently using or planning to use:

   • Drugs that are exclusively or primarily eliminated by cytochrome P-450 isozyme (CYP) including CYP1A2, CYP2B6, or CYP3A4
   • Drugs that are exclusively or primarily eliminated by UDP glucuronyltransferase (UGT) 1A1 (UGT1A1)
   • Drugs that are substrates for the drug transporter multidrug resistance protein 1 (MDR1) have a narrow therapeutic window or are strong inhibitors of drug transporter MDR1
   • Drugs that are strong inhibitors or inducers of CYP2D6 or CYP3A4

9. Subjects who are unable to swallow tablets

10. Subjects who have a history of or are suspected of drug abuse

11. Female subjects of child-bearing potential who have a positive result on a pregnancy test at screening or are unable to agree to use an effective barrier method of birth control to avoid pregnancy during the study period (e.g., sterilization, intrauterine contraceptive device, combination of oral contraception and barrier contraception, combination of other hormone delivery systems and barrier contraception, contraceptive cream, combination of cream, jelly, or form and diaphragm or condom)

12. Subjects, in the opinion of the Investigator, who are unsuitable to participate in the study

13. Subjects who were treated with other investigational products within 28 days before screening or within a period shorter than 5-timesthe half-life of the investigational product