PRIMARY OBJECTIVES:
I. To assess the progression free survival duration of patients treated with the combination
of pegylated recombinant human hyaluronidase PH20 (PEGPH20) and pembrolizumab.
SECONDARY OBJECTIVES:
I. To assess the safety and tolerability of the combination of PEGPH20 and pembrolizumab.
EXPLORATORY OBJECTIVES:
I. To evaluate objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors
(RECIST) and Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria,
duration of response (DOR), disease control rate (DCR), time to progression (TTP) and
progression-free survival (PFS) per RECIST and iRECIST as assessed by M.D. Anderson
investigators and overall survival (OS) of the combination of pembrolizumab and PEGPH20.
II. To explore the association between PD-L1 expression by immunohistochemistry (IHC), shed
PD-L1 level, hyaluronan (HA) levels, somatic gene expression profiling and antitumor efficacy
of the combination of pembrolizumab and PEGPH20 based on RECIST 1.1 as well as OS.
III. To explore the relationship between genomic variation and response to study treatment.
IV. To examine the effect of pembrolizumab and PEGPH20 on immune cell infiltration into
tumor.
V. To explore the effect of PEGPH20 on serum HA levels, and to compare changes in serum HA
with clinical efficacy.
VI. To determine the impact of the combination of pembrolizumab and PEGPH20 on circulating
immune cells.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 10 minutes on day 1 and pegylated
recombinant human hyaluronidase PH20 subcutaneously (SC) on days 1, 8, and 15. Cycles repeat
every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 9 and
12 weeks.
Inclusion Criteria:
- Have histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma
based on pathology report
- Be willing and able to provide written informed consent for the trial. The subject may
also provide consent for Future Biomedical Research. However, the subject may
participate in the main trial without participating in Future Biomedical Research.
- Have at least one measurable lesion and one lesion available for biopsy (not the
primary pancreatic lesion) based on RECIST 1.1. Target lesions situated in a
previously irradiated area are considered measurable if progression has been
demonstrated in such lesions
- Have had prior treatment with first-line therapy for metastatic disease for at least 4
months, and have had a radiologic response or stable disease at the most recent
imaging. Adjuvant therapy for resected disease will not count as first-line therapy.
Therapies that are derivative of others (e.g. fluorouracil/leucovorin
calcium/oxaliplatin [FOLFOX] vis-a-vis fuorouracil/irinotecan/leucovorin/oxaliplatin
[FOLFIRINOX]) will be counted as a single line of treatment for the purpose of
determining the number of prior therapies
- Be willing to undergo a core biopsy or excisional biopsy of tumor from a metastatic
site. Note that the biopsy itself will be done only after the patient has been found
to meet all other inclusion/exclusion criteria and the patient is otherwise prepared
to start therapy
- Be willing to provide (and have available) archival tissue from a surgical or biopsy
specimen obtained PRIOR to the most recent chemotherapy
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale
- Demonstrate adequate organ function. Specimens must be collected within 10 days prior
to the start of trial treatment
- Female subjects of childbearing potential must have a negative urine or serum
pregnancy test at screening (prior to biopsy) and again within 24 hours prior to
receiving the first dose of study medication. If the urine test is positive or cannot
be confirmed as negative, a serum pregnancy test will be required
- Male and female subjects of childbearing potential must agree to use an adequate
method of contraception starting with the first dose of trial therapy through 120 days
after the last dose of trial therapy. Note: Abstinence is acceptable if this is the
usual lifestyle and preferred contraception for the subject. Acceptable methods of
contraception are as follows:
- Single method (1 of the following is acceptable): intrauterine device (IUD),
vasectomy of a female subject's male partner, contraceptive rod implanted into
the skin
- Combination method (requires use of 2 of the following): diaphragm with
spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical
cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous
women only), male condom or female condom (cannot be used together), hormonal
contraceptive: oral contraceptive pill (estrogen/ progestin pill or
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or
subcutaneous (SC) contraceptive injection
Exclusion Criteria:
- Has pancreatic tumor other than adenocarcinoma, including: acinar cell carcinoma,
pancreaticoblastoma, malignant cystic neoplasms, endocrine neoplasms, squamous cell
carcinoma, ampulla of Vater, periampullary, duodenal, or common bile duct malignancies
- Has had more than one line of systemic chemotherapy for metastatic disease
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment
- Has had prior treatment with PEGPH20
- Has received prior systemic anti-cancer therapy that includes investigational agents
within 2 weeks prior to treatment
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Had a solid organ or hematologic transplant
- Has active autoimmune disease that has required systemic treatment in past 3 months
(i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive
drugs). Patients with autoimmune colitis (eg Crohn's disease) will be excluded. Any
relevant diseases not listed here are to be discussed with the study supporters.
Replacement hormone therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment and is allowed
- Has a diagnosed additional malignancy within 1 year prior to first dose of study
treatment, with the exception of curatively treated basal cell carcinoma of the skin,
squamous cell carcinoma of the skin and/or curatively resected tumors of low invasive
potential (e.g. in situ cervical and/or breast cancers)
- Has a history of central nervous system (CNS) metastases and/or carcinomatous
meningitis
- Has a history of (non-infectious) pneumonitis that required oral or IV steroids or
currently has pneumonitis
- Has an active infection requiring systemic therapy
- Chronic use of steroids for pain or emesis management
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 120 days
after the last dose of trial treatment
- Has received prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2
agents, or with an agent directed to another stimulatory or co-inhibitory T cell
receptor (eg, CTLA-4, OX-40, CD137), or has previously participated in Merck
pembrolizumab or PEGPH20 clinical trials
- Has a known history of human immunodeficiency virus (HIV) infection (HIV 1/2
antibodies) (HIV testing is required during screening)
- Has a history of the following liver diseases: hepatitis B (defined as hepatitis B
surface antigen [HBsAg] reactive), hepatitis C (defined as detectable hepatitis C
virus [HCV] ribonucleic acid [RNA]), primary biliary cholangitis, primary sclerosing
cholangitis, history of immune mediated cholangitis. Of note, patients with a history
of bacterial cholangitis are eligible if the infection has been fully resolved prior
to the screening visit. An exception is made for hepatitis C patients who have
undergone treatment and who have negative serologic testing for at least one year
- Has received a live vaccine within 30 days prior to the first dose of trial drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist) are live attenuated vaccines and are not allowed
- Has a known history of active TB (Bacillus tuberculosis)
- Is unable to tolerate a contrast enhanced computed tomography (CT) or magnetic
resonance imaging (MRI) for staging/restaging purposes
- Has not recovered (i.e., grade 1 or at baseline) from adverse events (AEs) due to
chemotherapy (neuropathy and alopecia are excluded)
- Has clinical evidence of a deep vein thrombosis (DVT), pulmonary embolism (PE), or
other known thrombotic event present during the screening period. Of note - this does
not apply to splanchnic vein (eg portal / superior mesenteric vein) thrombosis that,
in the opinion of the primary investigator, are primarily associated with the anatomic
location of the underlying disease
- Requires Megace (medroxyprogesterone acetate)
- In the estimation of the treating physician or primary investigator, have had a
clinical deterioration of their ECOG performance within the month prior to enrollment
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator
- Has unstable angina, new onset angina within the last 3 months, myocardial infarction
within the last 6 months, and current congestive heart failure New York Heart
Association class III or higher. Additionally, subjects with myocardial infarction or
atrial fibrillation within the past 12 months are excluded
- Has a history of a cerebrovascular accident or transient ischemic attack
- Known clinically significant pre-existing carotid artery disease
- Has a history of active bleeding requiring transfusion within a 3 month period prior
to screening
- Known allergy/intolerance to hyaluronidase or dexamethasone
- Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
- Contraindication to heparin or non-steroidal anti-inflammatory drugs (NSAIDs)
- Known cases of drug-induced hepatobiliary toxicities (other than a radiological
finding of fatty liver)
