Phase II Trial of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients With Cholangiocarcinoma

Advanced cholangiocarcinomas (CCAs) are aggressive tumors with median survival time after
diagnosis of less than 12 months, and five-year overall survival (OS) of ~5% with systemic
chemotherapy. Currently available systemic therapies for CCA are largely ineffective, thus
the rationale for the proposed research is to investigate targeted delivery of chemotherapy.

The goal of this study is to evaluate the efficacy of gemcitabine plus nab-paclitaxel in
patients with advanced CCA. This is based on the premise that nab-paclitaxel binds to SPARC
(secreted protein acidic and rich in cysteine) through its interaction with albumin, leading
to an increase in intra-tumoral concentration of gemcitabine through decreased deoxycytidine
deaminase (CDA) enzyme. We hope to improve on the OS of patients with advanced CCA through
the use of the synergistic combination of nab-paclitaxel and gemcitabine to specifically
target the SPARC protein in the peri-tumoral stroma. We aim to provide critical data to
further develop pharmacologic strategies to target the desmoplastic stroma in order to
increase chemotherapy responsiveness of CCAs.

We will also examine whether circulating tumor cell (CTC) levels with targeted gene
expression analysis and stromal SPARC levels correlate with patient outcome and thus serve as
prognostic biomarkers. We will evaluate the role of Human Equilibrative Nucleoside
Transporter 1 (hENT1), CDA and tumor fibrosis as additional prognostic and predictive
biomarkers in CCA. This clinical trial hopes to improve on the poor prognosis of patients
with advanced CCA by establishing the activity of a platinum-free doublet, nab-paclitaxel
plus gemcitabine that has shown clear clinical benefit in pancreatic cancer which has close
biological parallels to CCA.

A maximum of 70 patients will be enrolled to attain 67 eligible/evaluable patients. Stage I
will enroll 37 patients. If 21 or more patients are alive and progression-free at 6 months,
the study will proceed to Stage II and an additional 33 patients will be enrolled.

Procurement of archived tissue, if available, from a previous diagnostic biopsy is mandatory
for enrollment. If not available, this will not preclude participation in the trial, nor will
additional biopsies be performed for research purposes only.

Optional blood samples will be requested.

Inclusion Criteria:

- Must have histologically-confirmed diagnosis of cholangiocarcinoma Stage II, III, or
IV CCA (intra-hepatic, extra-hepatic and perihilar) that is not eligible for curative
resection, transplantation, or ablative therapies. Tumors of mixed histology are not
allowed.

- Must have radiographically measurable disease in at least one site not previously
treated with radiation, chemoembolization, radioembolization, or other local ablative
procedures; a new area of tumor progression within or adjacent to a previously-treated
lesion, if clearly measurable by a Radiologist, is acceptable.

- May have received prior radiation, chemoembolization, radioembolization, or other
local ablative therapies, or hepatic resection if completed ≥ 4 weeks prior to
registration AND if patient has recovered to ≤ grade 1 toxicity. NOTE: Measurable
disease (as required above) must still be present.

- May have received prior radiation for bone or brain metastases if patient is now
asymptomatic and has completed all radiation and steroid therapy (if applicable) ≥ 2
weeks prior to registration.

- Age ≥ 18 years.

- Child-Pugh score of A or B with ≤ 7 points.

- Eastern Cooperative Oncology Group performance status of 0-1.

- Willing to provide archived tissue, if available, from a previous diagnostic biopsy.

- Must be able to tolerate CT and/or MRI with contrast.

- Adequate organ function obtained ≤ 2 weeks prior to registration:

- Absolute Neutrophil Count ≥ 1500/mm³

- Hemoglobin ˃9.0 g/dL

- Platelets ˃100,000/mm³

- Serum Creatinine ≤ 1.5x Upper Limit Normal (ULN)

- Creatinine Clearance ≥ 50 mL/min

- Albumin ≥ 2.8 g/dL

- Total Bilirubin ≤ 1.5 mg/dL or ≤ 1.5x ULN

- Aspartate Aminotransaminase (AST)/Alanine Aminotransaminase (ALT) ≤ 2.5x ULN (≤
5x ULN in patients with liver metastases)

- International Normalized Ratio (INR) <1.5x the ULN [INR ≥ 1.5 is allowed if
anticoagulation is used.]

- Women must not be pregnant or breastfeeding since nab-paclitaxel and/or gemcitabine
may harm the fetus or child.

- Must not have received prior systemic cytotoxic chemotherapy or targeted therapy for
this cancer.

- Must not be receiving treatment with other investigational agents.

- Must not have a pre-existing >grade 2 peripheral neuropathy.

- Must not be receiving immunosuppressive medications, including systemic
corticosteroids, aside from the following exceptions: used for adrenal replacement,
appetite stimulation, therapy for asthma, bronchitis exacerbation (≤ 2 weeks),
anti-emesis, or pre-medication for procedures (i.e. CT scan).

- No known Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV)
seropositivity.

- Must not have undergone liver transplantation.

- Must not have serious non-healing wound, ulcer, bone fracture, or abscess.

- Must not have undergone a major surgical procedure <4 weeks prior to registration.

- Must not have possible histories of pneumonitis or pneumonitis risk factors.

- Must not have an active second malignancy other than non-melanoma skin cancer or
cervical carcinoma in situ.

- Must have no ongoing or active, uncontrolled infections.

- Must have no evidence of significant, uncontrolled concomitant diseases including, but
not limited to: symptomatic congestive heart failure, unstable angina pectoris,
uncontrolled cardiac arrhythmia, myocardial infarction within preceding 12 months,
uncontrolled peripheral vascular disease, cerebrovascular accident within preceding 12
months, pulmonary disease impairing functional status or requiring oxygen, connective
tissue disease including lupus.

- Must not have any history of allergic reaction(s) attributed to compounds of similar
composition to nab-paclitaxel or gemcitabine.