Pharmacokinetic and Safety Study of Nab®-Paclitaxel (ABI-007) Plus Gemcitabine in Subjects With Advanced Pancreatic Cancer Who Have Cholestatic Hyperbilirubinemia

There are 2 treatment cohorts in this study based on the predose total bilirubin levels on
Cycle 1 Day 1 (Cohort 1 > 1.5 x Upper Limit of Normal [ULN] to 3 x ULN bilirubin and Cohort
2 > 3 x ULN to 5 x ULN). Enrollment of subjects into Cohort 2 will only proceed after a
review of the safety and pharmacokinetic (PK) data for all subjects in Cohort 1 has been
completed by the Safety Monitoring Committee. The study is following a 3+3 dose escalation
scheme within each dose level cohort group. A total of 3 subjects will initially be enrolled
to the starting dose level in each cohort. The dose of the study regimen in each cohort will
be escalated (or reduced) according to tolerability.

Inclusion Criteria:

1. Subject has definitive histologically or cytologically confirmed locally advanced
unresectable or metastatic pancreatic adenocarcinoma (islet cell neoplasms are
excluded) that is measurable by RECIST Version 1.1 guidelines.

2. Initial diagnosis of advanced stage disease must have occurred ≤ 6 weeks prior to
starting Cycle 1 Day 1. NOTE: The clock for this time interval starts with the date
of last evaluation confirming advanced disease (either biopsy or imaging results).

3. Subject has confirmed cholestatic hyperbilirubenemia due to bile duct obstruction.
Subjects who have liver dysfunction due to metastasis alone are excluded.

4. Subject must have received no prior therapy for the treatment of metastatic disease.
Prior treatment with 5-FU or gemcitabine administered as a radiation sensitizer
during and up to 4 weeks after radiation therapy is allowed. If a subject received
gemcitabine in the adjuvant setting, tumor recurrence must have occurred at least 6
months after completing the last dose of gemcitabine.

5. For those patients who had a biliary stent inserted, 2 stable bilirubin readings
within 48 to 72 hours of each other taken at least 5 days and not more than 14 days
post-stenting must be obtained. In addition, there should be no complications (eg,
infection) present and bilirubin levels should have stabilized (2 readings with total
bilirubin within 20% of each other) before administering first treatment.

6. Males and females ≥ 18 years of age at the time of signing the informed consent
document (ICD).

7. Subject has adequate biological parameters as demonstrated by the following blood
counts at screening (obtained ≤ 14 days prior to starting Cycle 1 Day 1):

- Absolute neutrophil count (ANC) ≥ 1500 (1.5 × 109/L) cells/mm3;

- Platelet count ≥ 100,000 (100 × 109/L) cells/mm3;

- Hemoglobin (Hgb) ≥ 9 g/dL.

8. Subject has the following blood chemistry levels at screening (obtained ≤ 14 days
prior to starting Cycle 1 Day 1):

- AST (SGOT), ALT (SGPT) ≤ 5 × ULN is allowed:

- Serum creatinine within normal limits or calculated clearance ≥ 50 mL/min/1.73
m2 for subjects with serum creatinine levels above or below the institutional
normal value. If using creatinine clearance, actual body weight should be used
for calculating creatinine clearance (eg, using the Cockroft-Gault formula). For
subjects with a body mass index (BMI) > 30 kg/m2, lean body weight should be
used instead.

9. Subject has acceptable coagulation studies (obtained ≤ 14 days prior to starting
Cycle 1 Day 1) partial thromboplastin time (PTT) < 1.2 x ULN and INR ≤ 1.5 x ULN.

10. Subject has no clinically significant abnormalities in urinalysis results (obtained ≤
14 days prior to starting Cycle 1 Day 1).

11. Subject has a Karnofsky performance status (KPS) ≥ 70%.

12. Significant or symptomatic amounts of ascites should be drained prior to Cycle 1 Day
1. Pain symptoms should be stable and should not require modifications in analgesic
management prior to Cycle 1 Day 1.

13. Females of childbearing potential (FCBP) (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:

1. Either commit to true abstinence* from heterosexual contact (which must be
reviewed on a monthly basis), or agree to use, and be able to comply with,
effective contraception without interruption, 28 days prior to starting IP
therapy (including dose interruptions), and while on study medication or for a
longer period if required by local regulations following the last dose of IP;
and

2. Have a negative serum pregnancy test (β -hCG) result at screening and agree to
ongoing pregnancy testing during the course of the study, and after the end of
study therapy. This applies even if the subject practices true abstinence* from
heterosexual contact.

14. Male subjects must practice true abstinence* or agree to use a condom during sexual
contact with a pregnant female or a female of childbearing potential while
participating in the study, during dose interruptions and for 6 months following IP
discontinuation, even if he has undergone a successful vasectomy.

* True abstinence is acceptable when this is in line with the preferred and usual
lifestyle of the subject. Note: Periodic abstinence (e.g, calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
contraception.

15. Understand and voluntarily sign an informed consent document prior to any study
related assessments/procedures being conducted.

16. Able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

1. Subject has known brain metastases.

2. Any other active malignancy. Any other previous malignancy is allowed providing that
the tumor was curatively resected and there is no evidence of recurrence within 12
months prior to enrolment to the study. In addition, adequately treated in-situ
carcinoma of the cervix, uteri, or non-melanonatous skin cancer are allowed provided
that all treatment was completed 6 months prior to enrollment.

3. Subject has active, uncontrolled bacterial, viral, or fungal infection(s) requiring
systemic therapy.

4. Subject has known historical or active infection with HIV (human immunodeficiency
virus), hepatitis B, or hepatitis C or subject receiving immunosuppressive or
myelosuppressive medications that would, in the opinion of the Investigator, increase
the risk of serious neutropenic complications.

5. Subject has undergone major surgery for any reason, other than diagnostic surgery
(ie, surgery done to obtain a biopsy for diagnosis without removal of an organ),
within 4 weeks prior to Cycle 1 Day 1 of treatment in this study.

6. Subject has a history of a myocardial infarction, severe/unstable angina pectoris,
coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class
III-IV heart failure, uncontrolled hypertension, clinically significant cardiac
dysrhythmia or electrocardiogram (ECG) abnormality, cerebrovascular accident,
transient ischemic attack, seizure disorder or clinically significant cardiac
dysrhythmia or electrocardiogram (ECG) abnormality, within 6 months prior to Cycle 1
Day 1.

7. Subject has a history of allergy or hypersensitivity to nab-paclitaxel or gemcitabine
or any of their excipients.

8. Subject uses medication known to be strong inducers of CYP3A4 and CYP2C8 (Section
9.2).

9. History of connective tissue disorders (eg, lupus, scleroderma, arteritis nodosa).

10. Subjects with a history of interstitial lung disease, history of slowly progressive
dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary
fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies.

11. History of chronic leukemias (eg, chronic lymphocytic leukemia).

12. Subject is enrolled in any other clinical protocol or investigational trial with an
interventional agent or assessments that may interfere with study procedures.

13. Subject is unwilling or unable to comply with study procedures.

14. Any significant medical condition, laboratory abnormality, or psychiatric illness
that would prevent the subject from participating in the study.

15. Any condition including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study.

16. Any condition that confounds the ability to interpret data from the study.