Gemcitabine, Cisplatin, and Nab-Paclitaxel Before Surgery in Patients With High-Risk Liver Bile Duct Cancer

PRIMARY OBJECTIVE:

To assess the feasibility of therapeutic approach that includes neoadjuvant chemotherapy
including gemcitabine hydrochloride (gemcitabine), cisplatin, and nab-paclitaxel for
high-risk but technically resectable intrahepatic cholangiocarcinoma and is completed with
surgical resection.

SECONDARY OBJECTIVES:

I. To assess the radiological response rate to neoadjuvant systemic chemotherapy according to
the Response Evaluation Criteria in Solid Tumors (RECIST).

II. To determine the R0 resection rate.

III. To determine patient recurrence-free survival (RFS).

IV. To identify patient overall survival (OS) rate.

OUTLINE:

Participants receive nab-paclitaxel intravenously (IV) over 30 minutes, cisplatin IV over 60
minutes, and gemcitabine IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days
for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Participants with stable disease (SD), partial response (PR), or complete response (CR) then
undergo standard of care hepatectomy with portal lymphadenectomy.

After completion of study treatment, participants are followed up every 4 months for 3 years.

Inclusion Criteria:

- Diagnosis of intrahepatic cholangiocarcinoma.

- High-quality cross-sectional imaging by computerized tomography (CT) or magnetic
resonant imaging (MRI) performed within 6 weeks prior to enrollment and showed a
resectable, but high-risk, intrahepatic cholangiocarcinoma (IHCCA) confined to the
liver, bile duct, and/or regional lymph nodes. Tumors will be considered high-risk if
the high-quality, contrast-enhanced CT and/or MRI +/- positron emission tomography
(PET) scan showed:

1. T-stage ≥ Ib (Ib-IV)

2. Solitary lesion > 5 cm

3. Multifocal tumors or satellite lesions present confined to the same lobe of the
liver as the dominant lesion but still technically resectable

4. Presence of major vascular invasion but still technically resectable

5. Suspicious or involved regional lymph nodes (N1)

6. No distant extrahepatic disease (M0)

- Able to give informed consent.

- Able to adhere to study visit schedule and other protocol requirements.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

- Absolute neutrophil count (ANC) ≥ 1,500 cells/μL

- Platelet count ≥ 100,000 cells/μL

- Hemoglobin ≥ 9 g/dL

- Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN

- Albumin ≥ 3 g/dL

- Creatinine ≤ 1.5 x ULN

- Non-pregnant and non-lactating.

- Women of child-bearing potential (defined as a sexually mature woman who [1] has not
undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy
[the surgical removal of both ovaries] or (2) has not been naturally postmenopausal
for at least 24 consecutive months [i.e., has had menses at any time during the
preceding 24 consecutive months]) must commit to true abstinence from heterosexual
contact or agree to use, and be able to comply with, effective contraception without
interruption for 28 days prior to starting gemcitabine/cisplatin/nab-paclitaxel
(including dose interruptions) until treatment with
gemcitabine/cisplatin/nab-paclitaxel is complete.

- Male subjects must practice true abstinence or agree to use a condom during sexual
contact with a female of childbearing potential or a pregnant female while on
treatment (including during dose interruptions) with
gemcitabine/cisplatin/nab-paclitaxel and for 6 months following
gemcitabine/cisplatin/nab-paclitaxel discontinuation, even if he has undergone a
successful vasectomy.

Exclusion Criteria:

- Peripheral neuropathy of grade 2 or greater by Common Terminology Criteria for Adverse
Events (CTCAE) 4.0. In CTCAE version 4.0 grade 2 sensory neuropathy is defined as
"moderate symptoms; limiting instrumental activities of daily living (ADLs)".

- Concurrent severe and/or uncontrolled medical conditions which could compromise
participation in the study such as unstable angina, myocardial infarction within 6
months, unstable symptomatic arrhythmia, symptomatic congestive heart failure,
uncontrolled diabetes, serious active, uncontrolled infection after inadequate biliary
drainage if tumor obstructing bile duct, or psychiatric illness/social situations.

- Pregnancy (positive pregnancy test) or lactation.

- Known central nervous system (CNS) disease, except for treated brain metastasis.
Treated brain metastases are defined as having no evidence of progression or
hemorrhage after treatment and no ongoing requirement for dexamethasone, as
ascertained by clinical examination and brain imaging (MRI or CT) during the screening
period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may
include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear
accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the
treating physician. Patients with CNS metastases treated by neurosurgical resection or
brain biopsy performed within 3 months prior to day 1 will be excluded.

- Previous (within the past 5 years) or concurrent presence of other cancer, except
non-melanoma skin cancer and in situ carcinomas.

- History of allergy or hypersensitivity to any of the study drugs.

- Current abuse of alcohol or illicit drugs.

- Inability or unwillingness to sign the informed consent form.