A Study of PEGylated Recombinant Human Hyaluronidase in Combination With Nab-Paclitaxel Plus Gemcitabine Compared With Placebo Plus Nab-Paclitaxel and Gemcitabine in Participants With Hyaluronan-High Stage IV Previously Untreated Pancreatic Ductal Adenocarcinoma

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy and safety of PEGylated Recombinant Human Hyaluronidase (PEGPH20) combined with nab-paclitaxel plus gemcitabine (PAG treatment), compared with placebo combined with nab-paclitaxel plus gemcitabine (AG treatment), in participants with hyaluronan (HA)-high Stage IV previously untreated pancreatic ductal adenocarcinoma (PDA).

Detailed Description
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Participants will be randomized in a 2:1 ratio to PAG or AG treatment.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) in Combination With Nab-Paclitaxel Plus Gemcitabine Compared With Placebo Plus Nab-Paclitaxel and Gemcitabine in Subjects With Hyaluronan-High Stage IV Previously Untreated Pancreatic Ductal Adenocarcinoma

Conditions
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Pancreatic Ductal Carcinoma

Intervention / Treatment
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* Other: Biological: PEGylated Recombinant Human Hyaluronidase (PEGPH20)
* Drug: Placebo
* Drug: nab-Paclitaxel
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants must satisfy all the following inclusion criteria to be enrolled in the study: Signed, written Institutional Review Board/Ethics Committee-approved Informed Consent Form (ICF). Stage IV PDA with histological or cytological confirmation of PDA. Participants must be determined to be HA-high based on archived or fresh tumor core biopsy or sample obtained after the participant has documented metastatic disease. Biopsies/samples must meet the following requirements: Pancreas tumor biopsies/samples obtained on or after the date that metastatic disease is documented or tumor biopsies/samples from a metastatic lesion are acceptable. Tumor biopsies or samples must meet the requirements provided in the Study Laboratory Manual with regard to tumor tissue architecture. Note: cytology samples from fine needle aspirates without maintained tissue architecture or brushing biopsies are not acceptable. Tumor tissue (formalin-fixed paraffin-embedded [FFPE] block preferred) must include enough tumor to make a minimum of 5-10 unstained, consecutive FFPE slides (10 slides are preferred) of 1 archival block that meet specific tissue sample requirements. Radiographic confirmation of Stage IV PDA with at least 1 tumor metastasis measurable on computed tomography (CT) scan or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, excluding the primary pancreatic lesion. If a participant has had adjuvant/neoadjuvant therapy and/or therapy for locally advanced disease (chemotherapy for non-metastatic pancreatic cancer in combination with or without radiation therapy), tumor recurrence or disease progression must have occurred no sooner than 6 months after completing the last dose of the aforementioned therapies, provided all toxicities have returned to baseline or less than or equal to (≤) Grade 1. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Life expectancy greater than or equal to (≥) 3 months. Age ≥18 years. A negative urine or serum pregnancy test within 7 days before Cycle 1, Day 1 (C1D1; first dose of study medication) if female participant is of childbearing potential. Screening clinical laboratory values as follows: Total bilirubin ≤1.5 times upper limit of normal (ULN) (participants with Gilbert syndrome are eligible independent of bilirubin levels). Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvate transaminase) ≤2.5 times ULN, (if liver metastases are present, then ≤5 times ULN is allowed). Serum creatinine ≤2.0 milligrams/deciliter (mg/dL) or calculated creatinine clearance ≥40 milliliters/minute (mL/min). Serum albumin ≥2.5 grams/deciliter (g/dL). Prothrombin time or international normalized ratio (INR) within normal limits (±15%), unless participant takes warfarin, in which case prothrombin time or INR result must be within therapeutic range. Partial thromboplastin time (PTT) within normal limits (±15%). Hemoglobin ≥9 g/dL (transfusion and erythropoietic agents allowed). Absolute neutrophil count ≥1,500 cells/cubic millimeter (cells/mm^3). Platelet count ≥100,000/mm^3. For women of childbearing potential (WOCBP) and for men, agreement to use a highly effective contraceptive method from the time of screening throughout the study until 1 month (WOCBP) or 6 months (men) after administration of the last dose of any study medication. Highly effective contraceptive methods consist of prior sterilization, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), oral or injectable contraceptives, barrier methods, and/or true sexual abstinence. Exclusion criteria: Participants are ineligible for enrollment if they meet any of the following exclusion criteria: Clinical evidence of deep vein thrombosis (DVT), pulmonary embolism (PE) or other known thromboembolic (TE) event present during the screening period. Participants with superficial vein thrombosis are eligible. Participants with visceral/splanchnic vein thrombosis are still eligible if, in the opinion of the Investigator, the visceral/splanchnic vein thrombosis is primarily associated with the anatomic location of the underlying disease of metastatic pancreatic cancer (there must be primary or metastatic disease in reasonable proximity to the thrombosis, and the Investigator determines that the thrombosis is due to a local tumor event and not a coagulation issue). Previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease. a. Palliative radiotherapy for pain control of metastatic bone lesions is allowed. Known central nervous system involvement or brain metastases. New York Heart Association Class III or IV cardiac disease or myocardial infarction within the past 12 months. History of cerebrovascular accident or transient ischemic attack. Clinically significant pre-existing carotid artery disease. Known infection with human immunodeficiency virus, or active infection with hepatitis B or hepatitis C within the past 12 months. Known allergy to hyaluronidase. Current use of megestrol acetate or megestrol acetate-containing drugs (use within 10 days of Day 1). Contraindication to heparin as per institutional guidelines. Women currently pregnant or breastfeeding. Intolerance to dexamethasone. History of another primary cancer within the last 3 years with the exception of non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical carcinoma in-situ. Any other disease, active, uncontrolled bacterial, viral or fungal infection requiring systemic therapy, metabolic dysfunction, physical examination finding or clinical laboratory finding that leads to reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, or that may affect the interpretation of the results, or that may render the participant at high risk for treatment complications. Immunization with a live vaccine up to 2 weeks prior to Day 1. Hypersensitivity to the active substance or ingredients of PEGPH20, gemcitabine, and nab-paclitaxel. Inability to comply with study and follow-up procedures as judged by the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PAG: PEGPH20 + nab-Paclitaxel + Gemcitabine<br>Participants will receive 3.0 micrograms/kilogram (μg/kg) PEGPH20 as an intravenous (IV) infusion, twice weekly for Weeks 1 to 3 of Cycle 1 (each cycle consisting of 4 weeks [Week 4 of every cycle will be a rest week with no treatment]), then once weekly for Weeks 1 to 3 of Cycle 2 and beyond in combination with 125 milligrams/square meter (mg/m^2) nab-paclitaxel as an IV infusion and 1000 mg/m^2 gemcitabine as an IV infusion, once weekly for Weeks 1 to 3 of all treatment cycles. Treatment will continue until disease progression, unacceptable toxicity, death, or withdrawal of consent. | Other: Biological: PEGylated Recombinant Human Hyaluronidase (PEGPH20)<br>* PEGPH20 will be administered as per the dose and schedule specified in the respective arms.<br>Drug: nab-Paclitaxel<br>* Nab-paclitaxel will be administered as per the dose and schedule specified in the respective arms.<br>* Other names: Abraxane®;Drug: Gemcitabine<br>* Gemcitabine will be administered as per the dose and schedule specified in the respective arms.<br>* Other names: Gemzar®;|
| Placebo Comparator: AG: Placebo + nab-Paclitaxel + Gemcitabine<br>Participants will receive placebo matching to PEGPH20 as an IV infusion, twice weekly for Weeks 1 to 3 of Cycle 1 (each cycle consisting of 4 weeks [Week 4 of every cycle will be a rest week with no treatment]), then once weekly for Weeks 1 to 3 of Cycle 2 and beyond in combination with 125 mg/m^2 nab-paclitaxel as an IV infusion and 1000 mg/m^2 gemcitabine as an IV infusion, once weekly for Weeks 1 to 3 of all treatment cycles. Treatment will continue until disease progression, unacceptable toxicity, death, or withdrawal of consent. | Drug: Placebo<br>* Matching placebo for PEGPH20<br>Drug: nab-Paclitaxel<br>* Nab-paclitaxel will be administered as per the dose and schedule specified in the respective arms.<br>* Other names: Abraxane®;Drug: Gemcitabine<br>* Gemcitabine will be administered as per the dose and schedule specified in the respective arms.<br>* Other names: Gemzar®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from randomization until death from any cause. Overall survival was analyzed using Kaplan-Meier methods. | From randomization until death from any cause (maximum exposure: 150.1 weeks for PAG, and 83.9 weeks for AG) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS was defined as the time from randomization until the first occurrence of radiological disease progression, as determined by the blinded Central Imaging Vendor (CIV) based on Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, or death from any cause during the treatment period. Disease progression was defined as at least a 20 percent (%) increase in sum of diameters of target lesions, taking as reference the smallest sum on study thus far, nadir (this included baseline sum if that was the smallest on study); Sum must also demonstrate an absolute increase of at least 5 millimeters (mm); Appearance of one or more new lesions; Unequivocal progression of existing non-target lesions. Surviving participants without disease progression were censored for PFS analysis at the date of last evaluable post-baseline tumor assessment. Surviving participants without any post-baseline disease assessment were censored on Day 1. PFS was estimated using Kaplan-Meier method. | From the date of randomization until disease progression or death from any cause (maximum exposure: 150.1 weeks for PAG, and 83.9 weeks for AG) | 
| Objective Response Rate (ORR): Percentage of Participants With Objective Response | ORR was defined as percentage of participants who achieved either a complete response (CR) or partial response (PR) as determined by the blinded CIV based on RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions; Any pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From the date of randomization until CR or PR (maximum exposure: 150.1 weeks for PAG, and 83.9 weeks for AG) | 
| Duration of Response (DOR) | DOR was defined as the time from the first objective response of CR or PR until disease progression (as determined by the blinded CIV based on RECIST version 1.1) or death within 14 days of last dose of study treatment or randomization. CR was defined as disappearance of all target and non-target lesions; Any pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study thus far, the sum must also demonstrate an absolute increase of at least 5 mm, or the appearance of one or more new lesions; and unequivocal progression of existing non-target lesions. DOR was analyzed using Kaplan-Meier methods. | From date of first objective response (CR or PR) until date of first disease progression (maximum exposure: 150.1 weeks for PAG, and 83.9 weeks for AG) | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were defined as AEs that begin or worsen in severity during or after the participant's first dose of study treatment and no later than 30 days after the date of the last dose of study treatment and/or any treatment-related AE regardless of the onset date. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | From administration of first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 150.1 weeks for PAG, and 83.9 weeks for AG) | 
| Number of Participants With Worst Post-Baseline Hematology and Chemistry (Clinical Laboratory Parameters) Severity Grade During the Study | Severity grade associated with a laboratory parameter value was determined using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening. Grade 0 indicates evaluable lab records but not fall into any CTCAE grade for certain CTCAE term. A worst post-baseline grade shift was defined as the worst change that occurred at any measured timepoint during study. Hematology abnormalities: anemia(hemoglobin decreased), lymphocyte count decreased, lymphocyte count increased, neutropenia(neutrophil count decreased), thrombocytopenia(platelet count decreased), and leukopenia(white blood cell decreased). Chemistry abnormalities: hypoalbuminemia, alkaline phosphatase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hyperbilirubinemia, hypo- and hypercalcemia, creatinine increased, hypo- and hyperglycaemia, hypo- and hyperkalemia, hypo- and hypermagnesemia, hypo- and hypernatremia. | From administration of first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 150.1 weeks for PAG, and 83.9 weeks for AG) | 
| Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) | ECGs including clinical significance was evaluated by the Investigator. Criteria for clinical significance were as per investigator's discretion. | From administration of first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 150.1 weeks for PAG, and 83.9 weeks for AG) | 
| Number of Participants With Clinically Significant Abnormalities in Vital Signs | Vital signs included measurement of blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]), heart rate, and body weight. Criteria for clinical significance abnormalities were: Heart rate: <50 beats per minute (bpm), >120 bpm, >=30 bpm increase from baseline, >=30 bpm decrease from baseline. SBP: >140 millimeters of mercury (mmHg) and increase from baseline >20 mmHg, >180 mmHg, <90 mmHg and decrease from baseline >10 mmHg. DBP: >90 mmHg and increase from baseline >20 mmHg, >105 mmHg, <60 mmHg and decrease from baseline >10 mmHg. Change in weight: >=5% increase from baseline, >=5% decrease from baseline. | From administration of first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 150.1 weeks for PAG, and 83.9 weeks for AG) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic ductal adenocarcinoma (PDA), Pancreatic ductal carcinoma, PEGylated Recombinant Human Hyaluronidase (PEGPH20), Nab-paclitaxel, Gemcitabine, Metastatic, Stage IV