This is a multi-center, open-label, randomized, phase 2/3 trial of the bispecific antibody CTX-009 plus paclitaxel versus paclitaxel in patients with previously treated, unresectable advanced or metastatic biliary tract cancers.

INCLUSION CRITERIA

1. 18 years of age or older

2. Histologically or cytologically confirmed unresectable advanced, metastatic, or recurrent biliary tract cancers (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma)

3. Patients must have radiologically documented progression after a prior gemcitabine and platinum containing chemotherapy regimen as first line therapy for locally advanced unresectable or metastatic disease.

   1. Patients who received perioperative treatment (adjuvant and neoadjuvant) may be eligible, as determined by the Sponsor Medical Monitor.
   2. Patients whose first line regimen was modified due to toxicity before disease progression, may be eligible, as determined by the Sponsor Medical Monitor.

4. At least one lesion measurable as defined by RECIST v1.1

5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

6. Predicted life expectancy of at least 12 weeks

7. No evidence of ongoing infection and adequate biliary excretion or patients whose adequate biliary excretion can be confirmed with the following procedures:

   1. Patients who underwent endoscopic retrograde biliary drainage (ERBD) at least 1 week before the investigational drug treatment
   2. Patients with endobiliary stents are eligible, provided there is no evidence of obstruction
   3. Patients free of any signs of active or suspected uncontrolled infection after a drainage procedure
   4. Patients free of any risk of hemorrhage and with incision completely healed

8. Adequate bone marrow, hepatic, and renal function within 14 days of randomization as described below. (Patient must be free of G-CSF treatment and blood transfusion within 14 days prior to the lab test):

   1. Absolute neutrophil count (ANC) ≥ 1,500/mm3
   2. Hemoglobin ≥ 9.0 g/dL
   3. Platelet count ≥ 100,000/mm3
   4. Total bilirubin ≤ 1.5 X ULN
   5. AST/ALT ≤ 3.0 X ULN (≤5 X ULN in case of hepatic metastasis)
   6. Estimated creatinine clearance ≥ 30 mL/min based on Cockcroft-Gault
   7. Urine protein ≤ 1+ by Dipstick (Only when urinalysis shows a protein dipstick result of > 1 positive (+), the total protein volume (<1.0 g/24hr) can be confirmed with a 24-hour urine test.)
   8. Serum amylase and lipase level ≤ 3X ULN
   9. Serum Albumin ≥ 3.0 g/dL

9. Female patients who are women of childbearing potential (WCBP) must have a negative pregnancy test (serum-hCG or urine-hCG performed at the Investigator's discretion) within 14 days of randomization

10. Female patients must be surgically sterile (or have a monogamous partner who is surgically sterile) or be at least 2 years postmenopausal or commit to use 2 acceptable forms of birth control (defined as the use of an intrauterine device (IUD), a barrier method with spermicide, condoms, or any form of hormonal contraceptives) or abstinence for the duration of the study and for 6 months following the last dose of study treatment. Male patients must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study and for 6 months following the last dose of study treatment.

11. Signed and dated Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) before any protocol-directed screening procedures are performed

EXCLUSION CRITERIA

1. Patients who are eligible to be treated with a molecularly targeted therapy on a labelled regimen after receiving first-line chemotherapy. Patients who received a molecularly targeted therapy as part of their first line treatment may be eligible, as determined by the Sponsor Medical Monitor.

2. From the time point of screening,

   1. Less than 4 weeks have elapsed since patients had a surgery or major procedure
   2. Less than 2 weeks have elapsed from the last treatment date since patients had any radiation therapy

3. Patients with percutaneous transhepatic biliary drains (PTBD)

4. Prior to the initial treatment of study drug,

   1. Less than 2 weeks have elapsed since patients had chemotherapy or hormone therapy
   2. Less than 2 weeks have elapsed since patients had anticancer immunotherapy or investigational drug treatment
   3. Less than 4 weeks since cryotherapy, radiofrequency ablation, anhydrous alcohol therapy, or photodynamic therapy, including TACE and TARE

5. A history of the following cardiovascular diseases (please, consult the Sponsor Medical Monitor for a case by case evaluation):

   1. Congestive heart failure (CHF) that corresponds to Class II or a higher class under New York Heart Association (NYHA) classification, or less than 50% of left ventricular ejection fraction (LVEF)
   2. Uncontrolled hypertension (SBP/DBP >140/90 mmHg) (e.g., patient with SBP/DBP >140/90 mmHg despite the best care including optimizing the anti-hypertensive medication regimen)
   3. Patients with any history of hypertensive crisis or pre-existing hypertensive encephalopathy
   4. Pulmonary hypertension
   5. Myocardial infarction
   6. Uncontrolled arrhythmia
   7. Unstable angina
   8. Patients with any significant vascular diseases (e.g., aortic aneurysm requiring surgery or recent peripheral artery thrombosis) within 6 months prior to the initial treatment of the investigational product

6. History of hypersensitivity reactions to any components of the investigational product or other drugs of the same class (humanized/human monoclonal antibody drugs) or paclitaxel

7. Patients with contraindications to paclitaxel therapy

8. Patients with persistent, clinically significant toxicities (excluding hair loss) from previous anticancer treatment that corresponds to Grade 2 or a higher grade under NCI-CTCAE v5.0

9. Symptomatic or uncontrolled central nervous system (CNS) metastasis (However, patients with asymptomatic CNS metastasis that have been treated with either surgery or radiation can participate provided that systemic corticosteroid treatment was discontinued at least 4 weeks prior to screening and that the patient is radiologically and neurologically stable or improving)

10. A history of the following hemorrhage-related or gastroenterological disease:

    1. Active hemorrhage, hemorrhagic diathesis, coagulopathy or tumor in great arteries
    2. History of clinically significant gastroenterological disease, such as peptic ulcer, GI bleeding, GI or non-GI fistula, perforation, abdominal abscess, clinical symptoms, and signs of GI obstruction, need for parenteral hydration or nutrition, or inflammatory bowel disease (IBD)

11. Current or recent (within 10 days prior to study treatment) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose will be excluded.

    a. Prophylactic (i.e., for the patency of venous access devices) use of low molecular weight heparin (i.e., enoxaparin 40 mg/day) is allowed if patient has INR < 2 or aPTT </=2x ULN within 14 days of study treatment

12. Patients with current or recent (within 10 days of study treatment) use of aspirin (>81 mg/day), or other nonsteroidal anti-inflammatory drugs (NSAIDs), or other antiplatelets (i.e., dipyramidole, ticlopidine, clopidogrel, and cilostazol) will be excluded.

13. Severe infection requiring ongoing systemic antibiotics, antivirus drugs, etc., or other uncontrolled acute active infectious diseases

14. Patients with evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients with positive HBsAg and/or detectable HBV DNA are eligible only if adequately controlled on antiviral therapy according to institutional standards and liver function eligibility criteria are also met. HCV patients showing sustained viral response or patients with immunity to HBV infection may enroll.

15. Patients with other severe diseases or uncontrolled illnesses that warrant the exclusion from the study (permitted only if medically controlled) including but not limited to:

    1. Pre-existing hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 28 days prior to screening
    2. Major, unhealed injury, active ulcer, or untreated fracture
    3. Pre-existing conditions of cerebrovascular incident (ischemic or hemorrhagic stroke), transient ischemic attack or subarachnoid hemorrhage within 6 months prior to screening.
    4. Moderate to severe ascites and/or pleural effusion. However, enrollment is permitted for patients with ascitic fluid as long as paracentesis is not required to improve the condition.
    5. Interstitial lung disease or pulmonary fibrosis

16. Patients expected to require anticancer treatment other than the investigational product during the clinical study

17. Pregnant or lactating patients, or patients planning to become pregnant during the clinical study

18. A history of primary malignancy other than BTC will be excluded, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate >90%). Prior malignancy history will be evaluated on a case-by-case basis by the Sponsor Medical Monitor.

19. Clinically significant abnormal ECG findings or history determined as clinically significant by the Investigator

20. QT interval (Fridericia's formula) (QTcF) interval > 450msec at the time of screening

A blinded independent review committee will be used to assess the primary study endpoint.