Study of Gemcitabine, Nab-paclitaxel, and Ficlatuzumab (AV-299) in Patients With Advanced Pancreatic Cancer

This research study is a Phase I dose-escalation clinical trial. It will test the safety and
tolerability of an investigational drug ficlatuzumab when combined with Nab-paclitaxel and
Gemcitabine, with the goal of determining the maximally tolerated dose of ficlatuzumab when
combined with gemcitabine and nab-paclitaxel.

Ficlatuzumab is a type of drug called a "monoclonal antibody." It is thought to work by
targeting hepatocyte growth factor (HGF) which is a HGF-c-Met inhibitor. The activation of
the receptor tyroside kinase c-Met via its ligand, HGF, mediates proliferation, motility, and
differentiation in a variety of cancers including pancreatic cancer.

Subjects must have a newly diagnosed stage 4 untreated metastatic pancreatic ductal cancer
and meet all inclusion/exclusion criteria.

Treatment consists of 4 week treatment cycles. Ficlatuzumab will be administered on day 1 and
15 of each cycle. Nab-paclitaxel and gemcitabine will be administered on days 1,8, and 15.

Subjects continue in study until disease progression, adverse event/toxicity, death or either
the subject or sponsor discontinues the study.

Inclusion Criteria:

- Cytologically- or histologically-confirmed pancreatic adenocarcinoma or poorly
differentiated pancreatic carcinoma that is metastatic to distant sites.

- Other histologies such as neuroendocrine and acinar cell carcinoma are excluded.

- No prior chemotherapy for locally advanced or metastatic pancreatic cancer.

- Patients are eligible if they received adjuvant treatment after surgical resection
with single-agent gemcitabine or gemcitabine/capecitabine or 5-fluorouracil/leucovorin
that was completed >12 months before enrollment. Similarly, adjuvant radiation +/-
chemosensitization with 5-fluorouracil, capecitabine, or gemcitabine is allowed if
completed >12 months before enrollment.

- Participants are required to have measurable disease (RECIST v1.1), defined as at
least one lesion that can be accurately measured in at least one dimension (longest
diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with
spiral CT scan. See section 11 for the evaluation of measurable disease.

- Participants enrolled must have disease that is accessible for tumor biopsies and must
agree to a pre-treatment tumor biopsy.

- Age ≥ 18 years. Because no dosing or adverse event data are currently available in
participants <18 years of age, children are excluded from this study but will be
eligible for future pediatric trials.

- ECOG performance status ≤2 (see Appendix A)

- Patients must have completed any major surgery or open biopsy ≥4 weeks from start of
treatment.

- Participants must have adequate organ and marrow function as defined below:

- Absolute neutrophil count ≥1,500/mcL

- Platelets ≥100,000/mcL

- Total bilirubin ≤1.5 × institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- Creatinine ≤1.5 × institutional upper limit of normal OR

- Creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels
above 1.5 × upper limit of normal.

- Negative serum pregnancy test for women of childbearing potential.

- The effects of ficlatuzumab on the developing human fetus are unknown. For this reason
and because Hepatocyte Growth Factor inhibitors as well as other therapeutic agents
used in this trial are known to be teratogenic, women of child-bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry, for the duration of study participation and
4 months after completion of ficlatuzumab administration.. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, she should inform her treating physician immediately.

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Prior chemotherapy or any other investigational agents for the treatment of locally
advanced or metastatic pancreatic cancer

- Concurrent use of any other anti-cancer therapy, including chemotherapy, targeted
therapy, immunotherapy, or biological agents.

- Participants with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.
Screening for brain metastases with head imaging is not required.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ficlatuzumab or other agents used in study.

- History of prior or current synchronous malignancy, except:

- Malignancy that was treated with curative intent and for which there has been no
known active disease for >3 years prior to enrollment

- Curatively treated non-melanoma skin cancer, cervical cancer in situ, or
prostatic intraepithelial neoplasia, without evidence of prostate cancer

- Pre-existing, clinically significant peripheral neuropathy, defined as CTCAE grade 2
or higher neurosensory or neuromotor toxicity, regardless of etiology

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, NYHA class III/IV congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements.

- Pregnant women are excluded from this study because ficlatuzumab is hepatocyte growth
factor inhibitor agent with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with ficlatuzumab, breastfeeding should be
discontinued if the mother is treated with ficlatuzumab. These potential risks may
also apply to other agents used in this study