S1313, PEGPH20 in Treating Patients With Newly Diagnosed Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To assess the safety of modified leucovorin calcium, fluorouracil, irinotecan
hydrochloride and oxaliplatin (mFOLFIRINOX) in combination with PEGPH20 and select the
optimal dose of PEGPH20 for the phase II portion in patients with metastatic pancreatic
adenocarcinoma. (Phase I) II. To assess the overall survival of patients with metastatic
pancreatic adenocarcinoma treated with mFOLFIRINOX + PEGPH20 compared to those treated with
mFOLFIRINOX alone. (Phase II)

SECONDARY OBJECTIVES:

I. To assess progression free survival (PFS) in patients receiving mFOLFIRINOX with PEGPH20
and patients receiving mFOLFIRINOX alone in this patient population.

II. To assess objective tumor response (confirmed and unconfirmed, complete and partial) in
patients with measurable disease treated with mFOLFIRINOX with PEGPH20 and patients receiving
mFOLFIRINOX alone in this patient population.

III. To determine the frequency, severity, and tolerability of adverse events of mFOLFIRINOX
with PEGPH20.

TERTIARY OBJECTIVES:

I. To explore the correlation of maximum decrease in cancer antigen (CA) 19-9 levels and time
to maximum decrease in CA 19-9 levels with overall survival, progression-free survival and
response.

II. To explore the correlation of plasma hyaluronan (HA) and tumor expression of HA with
overall survival, progression-free survival and response.

OUTLINE: This is a phase I, dose de-escalation study of pegylated recombinant human
hyaluronidase followed by a randomized phase II study.

PHASE I: Patients receive pegylated recombinant human hyaluronidase intravenously (IV) over
10 minutes on day 1*; oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and
irinotecan hydrochloride IV over 1.5 hours on day 2; and fluorouracil IV over 46 hours on
days 2-4. Courses repeat every 14 days in the absence of disease progression or unacceptable
toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and
irinotecan hydrochloride IV over 1.5 hours on day 2, and fluorouracil IV over 46 hours on
days 2-4. Courses repeat every 14 days in the absence of disease progression or unacceptable
toxicity.

ARM II: Patients receive pegylated recombinant human hyaluronidase IV over 10 minutes on day
1* and oxaliplatin, leucovorin calcium, irinotecan hydrochloride, and fluorouracil as in Arm
I. Courses repeat every 14 days in the absence of disease progression or unacceptable
toxicity.

*NOTE: Some patients also receive pegylated recombinant human hyaluronidase on day 3 or 4 of
courses 1 and 2.

After completion of study treatment, patients are followed up for 3 years.

- Patients must have newly diagnosed, untreated metastatic histologically or
cytologically documented pancreatic adenocarcinoma; patients must not have known
history of brain metastases

- Patients must have measurable metastatic disease; computed tomography (CT) scans or
magnetic resonance imaging (MRI)s used to assess measurable disease must have been
completed within 28 days prior to registration; CT scans or MRIs used to assess
non-measurable disease must have been completed within 42 days prior to registration;
CT scans or MRIs must be assessed and documented on the Baseline Tumor Assessment Form
(Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)

- Patients must not have had any prior treatment with oxaliplatin or irinotecan within 3
years prior to registration; patients must not have had prior chemotherapy in
metastatic setting; prior abdominal radiation therapy is not allowed

- Patients must have a Zubrod performance status of 0-1

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< institutional upper limit of normal (IULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 2.5 X IULN
in the absence of liver metastases or =< 5.0 x IULN with liver metastasis

- Serum albumin >= 3 g/dL

- Serum creatinine =< ULN within 14 days prior to registration OR calculated creatinine
clearance > 50 ml/min; the serum creatinine value used in the calculation must have
been obtained within 14 days prior to registration

- Patients must have international normalized ratio (INR) =< 1.2 within 14 days prior to
registration; patients must not be receiving warfarin for therapeutic use, have
history of cerebrovascular accident (CVA), history of transient ischemic attack (TIA)
requiring intervention or treatment, pre-existing carotid artery disease requiring
intervention or treatment, or current use of megestrol acetate (use within 10 days of
registration)

- Patients must not be receiving chronic treatment (equivalent of prednisone > 10
mg/day) with systemic steroids or other immuno-suppressive agent

- Patients must not have liver disease such a cirrhosis, chronic active hepatitis or
chronic persistent hepatitis

- Patients must not have active bleeding or a pathological condition that is associated
with a high risk of bleeding

- Patients with a known history of human immunodeficiency virus (HIV) must not be on
active treatment for HIV

- Patients must have no non-malignant medical illnesses that are uncontrolled or whose
control may be jeopardized by the treatment with protocol therapy

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for five years

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; if at any point a previously
celibate patient chooses to become heterosexually active during the time period for
use of contraceptive measures outlined in the protocol, he/she is responsible for
beginning contraceptive measures

- Patients must have tumor (paraffin block or slides) available for submission and be
willing to submit tumor and blood samples

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system

- Patients planning to enroll in the phase I portion of this study must first have a
slot reserved in advance of the registration; all site staff will use OPEN to create a
slot reservation