PEGPH20 Plus Nab-Paclitaxel Plus Gemcitabine Compared With Nab-Paclitaxel Plus Gemcitabine in Participants With Stage IV Untreated Pancreatic Cancer

• Sponsor: Halozyme Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01839487
• Collaborator: (none)
• Enrollment: 279
• Locations: 51
• Arms: 6
• Actual Duration (Months): 64.4
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is designed to compare the treatment effect of PEGPH20 combined with nab-paclitaxel (NAB) and gemcitabine (GEM) [PAG] to NAB and GEM [AG] in participants with Stage IV previously untreated pancreatic ductal adenocarcinoma (PDA).

The study will have 2 run-in phases, one for each formulation of PEGPH20 (original and new formulations), and a Phase 2 portion. The 2 run-in phases will evaluate the safety and tolerability of the PAG treatment using the original and new succinic acid PEGPH20 formulation, respectively, compared with AG treatment. Phase 2 will have 2 stages due to a partial clinical hold that occurred from April through July 2014. The participants will be randomized in 3:1 for the run-in phases. The first stage will randomize participants in a 1:1 ratio. The second stage will randomize participants in a 2:1 ratio (PAG:AG).

This is an open-label study. To minimize bias to the progression-free survival endpoint, disease progression will be based on the assessment of the Central Imaging Reader (CIR). Determination of clinical progression by the Investigator without corresponding CIR confirmation will be documented with the relevant signs and symptoms.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Pancreatic Cancer	Drug: PEGPH20; Drug: Nab-paclitaxel; Drug: Gemcitabine; Drug: Dexamethasone; Drug: Enoxaparin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 279 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Multicenter Study of PEGPH20 (PEGylated Recombinant Human Hyaluronidase) Combined With Nab-Paclitaxel Plus Gemcitabine Compared With Nab-Paclitaxel Plus Gemcitabine in Subjects With Stage IV Previously Untreated Pancreatic Cancer
• Actual Study Start Date: May 14, 2013
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: Sep 26, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Run-in Phase - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine Participants will receive 3.0 micrograms/kilogram (mcg/kg) PEGPH20 with 125 milligrams/square meter (mg/m^2) NAB and 1000 mg/m^2 GEM as intravenous (IV) infusion. In Cycle 1 Week 1, PEGPH20 will be administered alone on Days 1 and 4 and NAB+GEM will be given on Day 2 at approximately 24 hours after first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 will be given twice/week on Days 8, 11, 15 and 18 and NAB+GEM will be given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and15. In Cycle 2 onwards, PEGPH20, NAB, and GEM will be given once/week on Days 1 8 and 15. NAB+GEM will be given 2 to 4 hours after PEGPH20 dose. Each cycle will be of 4-weeks with Week 4 of every cycle as a rest week (no treatment will be given). Treatment will continue until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg will be given in each cycle within 2 hours prior and 8 to 12 hours after completion of each PEGPH20 infusion.	Drug: PEGPH20; PEGPH20 will be administered as per the dose and schedule specified in the respective arms.; Drug: Nab-paclitaxel; Nab-paclitaxel will be administered as per the dose and schedule specified in the respective arms.; Other Names: Abraxane ; Drug: Gemcitabine; Gemcitabine will be administered as per the dose and schedule specified in the respective arms.; Other Names: Gemzar ; Drug: Dexamethasone; Dexamethasone will be administered as per the dose and schedule specified in the respective arms.
Active Comparator: Run-in Phase - AG: Nab-paclitaxel + Gemcitabine Participants will receive 125 mg/m^2 NAB and 1000 mg/m^2 GEM, as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle will be of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment will be given). Treatment will continue until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg will be given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.	Drug: Nab-paclitaxel; Nab-paclitaxel will be administered as per the dose and schedule specified in the respective arms.; Other Names: Abraxane ; Drug: Gemcitabine; Gemcitabine will be administered as per the dose and schedule specified in the respective arms.; Other Names: Gemzar ; Drug: Dexamethasone; Dexamethasone will be administered as per the dose and schedule specified in the respective arms.
Experimental: Phase 2: Stage 1 - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine Participants will receive 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 will be given alone on Days 1 and Day 4 and NAB+GEM will be given on Day 2 at approximately 24 hours after first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 will be given twice/week on Days 8, 11, 15, and 18 and NAB+GEM will be given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM will be given once/week on Days 1, 8, and 15. NAB+GEM will be given 2 to 4 hours after dose of PEGPH20. Each cycle will be of 4-weeks with Week 4 of every cycle as a rest week (no treatment will be given). Treatment will continue until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg will be given in each cycle within 2 hours prior to the beginning and 8 to 12 hours after the completion of each PEGPH20 infusion.	Drug: PEGPH20; PEGPH20 will be administered as per the dose and schedule specified in the respective arms.; Drug: Nab-paclitaxel; Nab-paclitaxel will be administered as per the dose and schedule specified in the respective arms.; Other Names: Abraxane ; Drug: Gemcitabine; Gemcitabine will be administered as per the dose and schedule specified in the respective arms.; Other Names: Gemzar ; Drug: Dexamethasone; Dexamethasone will be administered as per the dose and schedule specified in the respective arms.
Active Comparator: Phase 2: Stage 1 - AG: Nab-paclitaxel + Gemcitabine Participants will receive 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle will be of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment will be given). Treatment will continue until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg will be given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.	Drug: Nab-paclitaxel; Nab-paclitaxel will be administered as per the dose and schedule specified in the respective arms.; Other Names: Abraxane ; Drug: Gemcitabine; Gemcitabine will be administered as per the dose and schedule specified in the respective arms.; Other Names: Gemzar ; Drug: Dexamethasone; Dexamethasone will be administered as per the dose and schedule specified in the respective arms.
Experimental: Phase 2: Stage 2 - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine Participants will receive 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 will be given alone on Days 1 and 4 and NAB+GEM will be given on Day 2 at approximately 24 hours after first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 will be given twice/week on Days 8, 11, 15, and 18 and NAB+GEM will be given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM will be given once/week on Days 1, 8, and 15. NAB+GEM will be given 2 to 4 hours after dose of PEGPH20. Each cycle will be of 4-weeks with Week 4 of every cycle as a rest week (no treatment will be given). Treatment will continue until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg will be given in each cycle within 2 hours prior to beginning and 8 to 12 hours after completion of each PEGPH20 infusion. Enoxaparin 40 mg/day or 1 mg/kg/day will be given subcutaneously (SC).	Drug: PEGPH20; PEGPH20 will be administered as per the dose and schedule specified in the respective arms.; Drug: Nab-paclitaxel; Nab-paclitaxel will be administered as per the dose and schedule specified in the respective arms.; Other Names: Abraxane ; Drug: Gemcitabine; Gemcitabine will be administered as per the dose and schedule specified in the respective arms.; Other Names: Gemzar ; Drug: Dexamethasone; Dexamethasone will be administered as per the dose and schedule specified in the respective arms.; Drug: Enoxaparin; Enoxaparin will be administered as per the dose and schedule specified in the respective arms.
Active Comparator: Phase 2: Stage 2 - AG: Nab-paclitaxel + Gemcitabine Participants will receive 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle will be of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment will be given). Treatment will continue until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg will be given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion. Enoxaparin 40 mg/day or 1 mg/kg/day will be given SC.	Drug: Nab-paclitaxel; Nab-paclitaxel will be administered as per the dose and schedule specified in the respective arms.; Other Names: Abraxane ; Drug: Gemcitabine; Gemcitabine will be administered as per the dose and schedule specified in the respective arms.; Other Names: Gemzar ; Drug: Dexamethasone; Dexamethasone will be administered as per the dose and schedule specified in the respective arms.; Drug: Enoxaparin; Enoxaparin will be administered as per the dose and schedule specified in the respective arms.

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) [From the date of randomization until disease progression or death from any cause (maximum exposure: 30.72 months for PAG, and 20.27 months for AG)]

   PFS: time from randomization until first occurrence of disease progression, either by central radiologic determination (Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) or by clinical progression determined by Investigator, or death during treatment period from any cause. Radiological 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 (KM) method.

2. Percentage of Participants in the PAG Arm Who Experienced Any Thromboembolic (TE) Event in Stage 2 of the Study [From first exposure to any study drug (PEGPH20, NAB, GEM) through 30 days after end of treatment visit (maximum exposure: 30.72 months for PAG)]

   TE events were identified by applying the Medical Dictionary for Regulatory Activities (MedDRA) Standardized MedDRA Queries (SMQ) search strategy for 3 SMQs: TE arterial, TE venous, and TE vessel type unspecified and mixed arterial and venous. TE events were considered by the Sponsor to be adverse events (AEs) of special interest. All TE events, regardless of type of event, severity, or seriousness were reported. Participants with multiple events were counted only once. A summary of serious and all other non-serious adverse events regardless of causality is located in the 'Reported AE section'.

Secondary Outcome Measures

1. PFS in Relation to Tumor Hyaluronan (HA) Levels [From the date of randomization until disease progression or death from any cause (maximum exposure: 30.72 months for PAG, and 20.27 months for AG)]

   PFS was defined as time from randomization until first occurrence of disease progression, either by central radiologic determination (RECIST version 1.1) or by clinical progression determined by Investigator, or death during treatment period from any cause. Disease progression was defined as at least a 20% 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 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 KM method. PFS was measured in HA-high and HA-low participants.

2. Objective Response Rate (ORR): Percentage of Participants With Objective Response [From the date of randomization until last date on study treatment (maximum exposure: 30.72 months for PAG, and 20.27 months for AG)]

   ORR was defined as percentage of participants who achieved either a complete response (CR) or partial response (PR) regardless of confirmation, as assessed by 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.

3. Overall Survival [From randomization until death from any cause (maximum exposure: 30.72 months for PAG, and 20.27 months for AG)]

   Overall survival was defined as the time from randomization until death from any cause. Participants who died or were lost to follow-up by the date of analysis data cutoff were censored at their last contact date.

4. Percentage of Participants With AEs [From first exposure to any study drug (PEGPH20, NAB, GEM) through 30 days after end of treatment visit (maximum exposure: 30.72 months for PAG and 20.27 months for AG)]

   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. 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'.

5. Maximum Observed Plasma Concentration (Cmax) of PEGPH20 [Pre-PEGPH20 dosing and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing on Days 1 and 15 of Cycle 1]

   Samples were analyzed for PEGPH20 concentration using a validated electrochemiluminescence immunoassay. Plasma samples to assess the potential effects of NAB+GEM on PEGH20 pharmacokinetic (PK) were collected in the PAG treatment group in the run-in phases (Run-in Phase 1: Original PEGPH20 formulation [3.5 mg/mL], and Run-in Phase 2: New PEGPH20 formulation [0.3 mg/mL]).

6. Time to Reach Cmax (Tmax) of PEGPH20 [Pre-PEGPH20 dosing and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing on Days 1 and 15 of Cycle 1]

   Samples were analyzed for PEGPH20 concentration using a validated electrochemiluminescence immunoassay. Plasma samples to assess the potential effects of NAB+GEM on PEGH20 PK were collected in the PAG treatment group in the run-in phases (Run-in Phase 1: Original PEGPH20 formulation [3.5 mg/mL], and Run-in Phase 2: New PEGPH20 formulation [0.3 mg/mL]).

7. Area Under the Concentration-Time Curve From Time 0 to Last Quantifiable Concentration (AUC0-last) of PEGPH20 [Pre-PEGPH20 dosing and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing on Days 1 and 15 of Cycle 1]

   Samples were analyzed for PEGPH20 concentration using a validated electrochemiluminescence immunoassay. Plasma samples to assess the potential effects of NAB+GEM on PEGH20 PK were collected in the PAG treatment group in the run-in phases (Run-in Phase 1: Original PEGPH20 formulation [3.5 mg/mL], and Run-in Phase 2: New PEGPH20 formulation [0.3 mg/mL]).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Signed Informed consent.

• Histologically confirmed Stage IV PDA with documented disseminated neoplasm to liver and /or lung. Must have archival or fresh tissue (block /slides) available pre-dose.

• One or more metastatic tumors measurable on computed tomography (CT) scan per RECIST v.1.1 , excluding the primary pancreatic lesion.

• No previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease.

• Karnofsky Performance Status greater than or equal to (≥) 70%.

• Life expectancy ≥3 months.

• Age ≥18 years.

• Screening laboratory values of hemoglobin, platelets, absolute neutrophil count (ANC), bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine, serum albumin, prothrombin time/international normalized ratio (INR), and partial thromboplastin time (PTT) within specified values/criteria per protocol prior to dosing.

Key Exclusion Criteria:

• Non-metastatic PDA.

• Evidence of deep vein thrombosis (DVT), pulmonary embolism (PE), or other known thromboembolic event present during screening period.

• Known central nervous system involvement or brain metastasis.

• New York (NY) Heart Association Class III or IV cardiac disease or myocardial infarction within the past 12 months.

• Prior history of cerebrovascular accident or transient ischemic attack.

• Pre-existing carotid artery disease.

• Active, uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.

• Current use of megestrol acetate (use within 10 days of Day 1).

• Known infection with human immunodeficiency virus, Hepatitis B, or Hepatitis C.

• History of another primary cancer within the last 3 years with the exception of non-melanoma skin cancer, early state prostate cancer, or curatively-treated cervical cancer in-situ.

• Contraindication to heparin as per National Comprehensive Cancer Network (NCCN) guidelines.

• Previous major bleed (bleeding requiring transfusion of red blood cells) on low-molecular weight heparin (LMWH).

• Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that leads to reasonable suspicion of disease or condition that contraindicates the use of an investigational drug, that may affect interpretation of results, or render the participant at a high risk of treatment complications.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Oncology	Birmingham	Alabama	United States	35213
2	University of South Alabama Mitchell Cancer Institute	Mobile	Alabama	United States	36604
3	Banner MD Anderson Cancer Center	Gilbert	Arizona	United States	85234
4	Mayo Clinic - Scottsdale	Scottsdale	Arizona	United States	85259
5	Arizona Oncology Associates, PC	Tucson	Arizona	United States	85704
6	Highlands Oncology Group	Fayetteville	Arkansas	United States	72703
7	Providence St Joseph Medical Center	Burbank	California	United States	91505
8	Scripps Cancer Center	La Jolla	California	United States	92037
9	UCSD - Moore's Cancer Center	La Jolla	California	United States	92093
10	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
11	University of California Medical Center	Orange	California	United States	92868
12	Saint Helena Hospital	Saint Helena	California	United States	94574
13	Pacific Hematology Oncology Associates	San Francisco	California	United States	94115
14	The Oncology Institute of Hope and Innovation	Whittier	California	United States	90603
15	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
16	Rocky Mountain Cancer Center	Denver	Colorado	United States	80218
17	Stamford Hospital	Stamford	Connecticut	United States	06902
18	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
19	University of Miami, Sylvester comprehensive Cancer Center	Miami	Florida	United States	33136
20	H. Lee Moffit Cancer Center	Tampa	Florida	United States	33612
21	Piedmont Hospital	Atlanta	Georgia	United States	30318
22	Loyola University Medical Center	Maywood	Illinois	United States	60153
23	Norton Cancer Institute - Norton HealthCare Pavilion	Louisville	Kentucky	United States	40202
24	Johns Hopkins University Hospital	Baltimore	Maryland	United States	21231
25	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
26	Lahey Clinic	Burlington	Massachusetts	United States	01805
27	University of Mass Medical School	Worcester	Massachusetts	United States	01655
28	University of Michigan	Ann Arbor	Michigan	United States	48109
29	Virginia Piper Cancer Institute	Minneapolis	Minnesota	United States	55407
30	Unniversity of Minnesota	Minneapolis	Minnesota	United States	55455
31	Research Medical Center	Kansas City	Missouri	United States	64132
32	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
33	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
34	St. Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
35	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
36	North Shore Long Island Jewish Health System	Lake Success	New York	United States	11042
37	Mount Sinai Medical Center	New York	New York	United States	10029
38	Columbia University Medical Center	New York	New York	United States	10032
39	University of Rochester	Rochester	New York	United States	14642
40	Gabrail Cancer Center	Canton	Ohio	United States	44718
41	University of Oklahoma Health Science Center	Oklahoma City	Oklahoma	United States	73104
42	UPMC Cancer Center	Pittsburgh	Pennsylvania	United States	15213
43	Greenville Health System	Greenville	South Carolina	United States	29605
44	Texas Oncology - Baylor	Dallas	Texas	United States	75246
45	Cancer Care Centers of South Texas	New Braunfels	Texas	United States	78130
46	Texas Oncology	Tyler	Texas	United States	75702
47	Columbia Basin Hematology and Oncology	Kennewick	Washington	United States	99336
48	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
49	NorthWest Medical Specialties, PLLC	Tacoma	Washington	United States	98405
50	University of Wisconsin Hospitals and Clinics	Madison	Wisconsin	United States	53792
51	Froedtert Hospital, Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Halozyme Therapeutics

Investigators

• Study Director: VP, Clinical Development, Halozyme Therapeutics

Study Documents (Full-Text)

• Study Protocol - Feb 9, 2018
• Statistical Analysis Plan - Dec 12, 2016

More Information

Additional Information:

• Reflects interim analysis conducted on mature data when 95% of participants had discontinued from the study.

Publications

None provided.

• Responsible Party: Halozyme Therapeutics
• ClinicalTrials.gov Identifier: NCT01839487
• Other Study ID Numbers: HALO-109-202
• First Posted: Apr 25, 2013
• Last Update Posted: Jul 20, 2020
• Last Verified: Jul 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Halozyme Therapeutics: pancreatic ductal carcinoma(PDA); Pancreatic ductal carcinoma; PEGPH20; Gemcitabine; Nab-paclitaxel
• Additional relevant MeSH terms: Pancreatic Neoplasms; Gemcitabine; Dexamethasone; Paclitaxel; Enoxaparin

Study Results

Participant Flow

Recruitment Details	Study had 2 run-in phases (for evaluating safety and tolerability of PAG [PEGPH20 + Nab-paclitaxel {NAB} + Gemcitabine {GEM}] treatment), one for each formulation of PEGPH20 (original and new formulations [injectable solution containing 3.5 milligrams/milliliter {mg/mL} and 0.3 mg/mL PEGPH20, respectively]), and a Phase 2 (Stage 1 and 2) portion.
Pre-assignment Detail	Study was on partial clinical hold from April to July 2014 due to higher incidence of thromboembolic events (TE) in PAG arm participants. Study enrollment (Stage 2) was reopened in June 2014 after excluding participants with high-risk of TE and adding enoxanparin prophylasis. Participants of PAG and AG arm both received AG during clinical hold.

Arm/Group Title	Run-in Phase - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine	Run-in Phase - AG: Nab-paclitaxel + Gemcitabine	Phase 2: Stage 1 - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine	Phase 2: Stage 1 - AG: Nab-paclitaxel + Gemcitabine	Phase 2: Stage 2 - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine	Phase 2: Stage 2 - AG: Nab-paclitaxel + Gemcitabine
Arm/Group Description	Participants received 3.0 micrograms/kilogram (mcg/kg) PEGPH20 with 125 milligrams/square meter (mg/m^2) nab-paclitaxel (NAB) and 1000 mg/m^2 gemcitabine (GEM) as intravenous (IV) infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after PEGPH20 dose. Each cycle was of 4-weeks with Week 4 of every cycle as a rest week (no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to beginning and 8 to 12 hours after completion of each PEGPH20 infusion.	Participants received 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after the first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, and 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were administered once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after the dose of PEGPH20. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning and 8 to 12 hours after the completion of each PEGPH20 infusion.	Participants received 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after the first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, and 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after dose of PEGPH20. Each cycle was of 4-weeks with Week 4 of every cycle as a rest week (no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to beginning and 8 to 12 hours after completion of each PEGPH20 infusion. Enoxaparin 40 mg/day or 1 mg/kg/day was given subcutaneously (SC).	Participants received 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion. Enoxaparin 40 mg/day or 1 mg/kg/day was given SC.
Period Title: Run-in Phase (Maximum Exposure:295 Days)
STARTED	16	7	0	0	0	0
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	16	7	0	0	0	0
Period Title: Run-in Phase (Maximum Exposure:295 Days)
STARTED	0	0	61	62	89	44
COMPLETED	0	0	0	0	1	0
NOT COMPLETED	0	0	61	62	88	44

Baseline Characteristics

Arm/Group Title	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine	AG: Nab-paclitaxel + Gemcitabine	Total
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after the first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, and 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after the dose of PEGPH20. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning and 8 to 12 hours after the completion of each PEGPH20 infusion.	Participants received 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.	Total of all reporting groups
Overall Participants	166	113	279
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.3 (9.72)	65.0 (8.82)	64.6 (9.35)
Sex: Female, Male (Count of Participants)
Female	65 39.2%	58 51.3%	123 44.1%
Male	101 60.8%	55 48.7%	156 55.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 2.4%	9 8%	13 4.7%
Not Hispanic or Latino	160 96.4%	104 92%	264 94.6%
Unknown or Not Reported	2 1.2%	0 0%	2 0.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.6%	1 0.9%	2 0.7%
Asian	5 3%	5 4.4%	10 3.6%
Native Hawaiian or Other Pacific Islander	1 0.6%	0 0%	1 0.4%
Black or African American	11 6.6%	9 8%	20 7.2%
White	146 88%	91 80.5%	237 84.9%
More than one race	1 0.6%	7 6.2%	8 2.9%
Unknown or Not Reported	1 0.6%	0 0%	1 0.4%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS: time from randomization until first occurrence of disease progression, either by central radiologic determination (Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) or by clinical progression determined by Investigator, or death during treatment period from any cause. Radiological 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 (KM) method.
Time Frame	From the date of randomization until disease progression or death from any cause (maximum exposure: 30.72 months for PAG, and 20.27 months for AG)

Outcome Measure Data

Analysis Population Description

Efficacy evaluable (EE) population: all randomized participants who received at least 1 dose of any study drug, who had measurable disease at baseline, and had a post-baseline response assessment, or had clinical disease progression without a post-baseline computed tomography (CT) scan, or had died on or prior to 14 days after the last dose date.

Arm/Group Title	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine	AG: Nab-paclitaxel + Gemcitabine
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after the first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, and 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after the dose of PEGPH20. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning and 8 to 12 hours after the completion of each PEGPH20 infusion.	Participants received 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.
Measure Participants	139	92
Median (95% Confidence Interval) [months]	6.05	5.26

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine, AG: Nab-paclitaxel + Gemcitabine
	Comments	Hazard ratio PAG/AG was based on Cox proportional hazards model stratified by the Karnofsky Performance Status (KPS) category (70-80% and 90-100%) at screening using AG as the reference arm.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments	Threshold for significance at 0.1 level.
	Method	Log Rank
	Comments	P-value was based on stratified log-rank test with the KPS category at screening as the stratification factor.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.54 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Percentage of Participants in the PAG Arm Who Experienced Any Thromboembolic (TE) Event in Stage 2 of the Study
Description	TE events were identified by applying the Medical Dictionary for Regulatory Activities (MedDRA) Standardized MedDRA Queries (SMQ) search strategy for 3 SMQs: TE arterial, TE venous, and TE vessel type unspecified and mixed arterial and venous. TE events were considered by the Sponsor to be adverse events (AEs) of special interest. All TE events, regardless of type of event, severity, or seriousness were reported. Participants with multiple events were counted only once. A summary of serious and all other non-serious adverse events regardless of causality is located in the 'Reported AE section'.
Time Frame	From first exposure to any study drug (PEGPH20, NAB, GEM) through 30 days after end of treatment visit (maximum exposure: 30.72 months for PAG)

Outcome Measure Data

Analysis Population Description

Safety population of Stage 2 included all participants enrolled in Stage 2 of Phase 2 of study after the clinical hold, and who received at least 1 dose of study drug. This outcome was planned to be reported only for PAG arm as pre-specified in protocol.

Arm/Group Title	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after the first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, and 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after the dose of PEGPH20. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning and 8 to 12 hours after the completion of each PEGPH20 infusion.
Measure Participants	86
Number [percentage of participants]	14.0 8.4%

3. Secondary Outcome

Title	PFS in Relation to Tumor Hyaluronan (HA) Levels
Description	PFS was defined as time from randomization until first occurrence of disease progression, either by central radiologic determination (RECIST version 1.1) or by clinical progression determined by Investigator, or death during treatment period from any cause. Disease progression was defined as at least a 20% 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 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 KM method. PFS was measured in HA-high and HA-low participants.
Time Frame	From the date of randomization until disease progression or death from any cause (maximum exposure: 30.72 months for PAG, and 20.27 months for AG)

Outcome Measure Data

Analysis Population Description

Intent-to -treat (ITT) population included all participants who were randomized, including the run-in phases. 'Number analyzed'=participants with HA-high or HA-low levels.

Arm/Group Title	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine	AG: Nab-paclitaxel + Gemcitabine
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after the first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, and 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after the dose of PEGPH20. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning and 8 to 12 hours after the completion of each PEGPH20 infusion.	Participants received 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.
Measure Participants	153	93
HA-High	9.23	5.19
HA-Low	5.59	5.26

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine, AG: Nab-paclitaxel + Gemcitabine
	Comments	Hazard ratio PAG/AG for HA-high was based on Cox proportional hazards model stratified by the KPS category (70-80% and 90-100%) at screening using AG as the reference arm.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.092
	Comments	Threshold for significance at 0.1 level.
	Method	Log Rank
	Comments	P-value was based on stratified log-rank test with the KPS category at screening as the stratification factor.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.30 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine, AG: Nab-paclitaxel + Gemcitabine
	Comments	Hazard ratio PAG/AG for HA-low was based on Cox proportional hazards model stratified by the KPS category (70-80% and 90-100%) at screening using AG as the reference arm.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.514
	Comments	Threshold for significance at 0.1 level.
	Method	Log Rank
	Comments	P-value was based on stratified log-rank test with the KPS category at screening as the stratification factor.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Objective Response Rate (ORR): Percentage of Participants With Objective Response
Description	ORR was defined as percentage of participants who achieved either a complete response (CR) or partial response (PR) regardless of confirmation, as assessed by 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.
Time Frame	From the date of randomization until last date on study treatment (maximum exposure: 30.72 months for PAG, and 20.27 months for AG)

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized, including the run-in phases.

Arm/Group Title	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine	AG: Nab-paclitaxel + Gemcitabine
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after the first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, and 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after the dose of PEGPH20. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning and 8 to 12 hours after the completion of each PEGPH20 infusion.	Participants received 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.
Measure Participants	166	113
Number (95% Confidence Interval) [percentage of participants]	40.4 24.3%	32.7 28.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine, AG: Nab-paclitaxel + Gemcitabine
	Comments	p-Value and relative risk were based on a stratified Cochran-Mantel-Haenszel method using KPS category at screening as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.225
	Comments	Threshold for significance at 0.1 level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from randomization until death from any cause. Participants who died or were lost to follow-up by the date of analysis data cutoff were censored at their last contact date.
Time Frame	From randomization until death from any cause (maximum exposure: 30.72 months for PAG, and 20.27 months for AG)

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized, including the run-in phases.

Arm/Group Title	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine	AG: Nab-paclitaxel + Gemcitabine
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after the first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, and 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after the dose of PEGPH20. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning and 8 to 12 hours after the completion of each PEGPH20 infusion.	Participants received 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.
Measure Participants	166	113
Median (95% Confidence Interval) [months]	9.59	9.23

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine, AG: Nab-paclitaxel + Gemcitabine
	Comments	Hazard ratio PAG/AG was based on Cox proportional hazards model stratified by the KPS category (70-80% and 90-100%) at screening using AG as the reference arm.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.495
	Comments	Threshold for significance at 0.1 level.
	Method	Log Rank
	Comments	P-value was based on stratified log-rank test with the KPS category at screening as the stratification factor.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With AEs
Description	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. 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'.
Time Frame	From first exposure to any study drug (PEGPH20, NAB, GEM) through 30 days after end of treatment visit (maximum exposure: 30.72 months for PAG and 20.27 months for AG)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of study drug.

Arm/Group Title	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine	AG: Nab-paclitaxel + Gemcitabine
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after the first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, and 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after the dose of PEGPH20. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning and 8 to 12 hours after the completion of each PEGPH20 infusion.	Participants received 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.
Measure Participants	160	100
Number [percentage of participants]	99.4 59.9%	98.0 86.7%

7. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of PEGPH20
Description	Samples were analyzed for PEGPH20 concentration using a validated electrochemiluminescence immunoassay. Plasma samples to assess the potential effects of NAB+GEM on PEGH20 pharmacokinetic (PK) were collected in the PAG treatment group in the run-in phases (Run-in Phase 1: Original PEGPH20 formulation [3.5 mg/mL], and Run-in Phase 2: New PEGPH20 formulation [0.3 mg/mL]).
Time Frame	Pre-PEGPH20 dosing and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing on Days 1 and 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

PK analysis population included all participants who received any part of a dose of PEGPH20 and had measurable PEGPH20 concentrations in at least 1 sample collected for PK analysis. 'Number analyzed'=participants evaluable for this outcome at specified timepoints.

Arm/Group Title	Run-in Phase 1-PAG: PEGPH20 (Original Formulation) + NAB + GEM	Run-in Phase 2- PAG: PEGPH20 (New Formulation) + NAB + GEM
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB, and 1000 mg/m^2 GEM, as IV infusion. In Cycle 1 Week 1, PEGPH20 was administered alone on Day 1, 4, and NAB+GEM were administered on Day 2, approximately 24 hours after first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, 18, and NAB+GEM were given once/week, 2 to 4 hours after PEGPH20 administration on Days 8, 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, 15. NAB+GEM were given 2 to 4 hours after PEGPH20 dose. Each treatment cycle was of 4-weeks with Week 4 of every cycle as a rest week (no treatment). Treatment was continued until disease progression or unacceptable toxicity. Dexamethasone 8 mg was administered in each treatment cycle within 2 hours prior to beginning of each PEGPH20 infusion and 8 to 12 hours after completion of each PEGPH20 infusion.	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB, and 1000 mg/m^2 GEM, as IV infusion. In Cycle 1 Week 1, PEGPH20 was administered alone on Day 1, 4, and NAB+GEM were administered on Day 2, approximately 24 hours after first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, 18, and NAB+GEM were given once/week, 2 to 4 hours after PEGPH20 administration on Days 8, 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, 15. NAB+GEM were given 2 to 4 hours after PEGPH20 dose. Each treatment cycle was of 4-weeks with Week 4 of every cycle as a rest week (no treatment). Treatment was continued until disease progression or unacceptable toxicity. Dexamethasone 8 mg was administered in each treatment cycle within 2 hours prior to beginning of each PEGPH20 infusion and 8 to 12 hours after completion of each PEGPH20 infusion.
Measure Participants	6	8
Day 1	72.1 (16.90)	67.8 (17.60)
Day 15	82.9 (25.42)	84.1 (7.70)

8. Secondary Outcome

Title	Time to Reach Cmax (Tmax) of PEGPH20
Description	Samples were analyzed for PEGPH20 concentration using a validated electrochemiluminescence immunoassay. Plasma samples to assess the potential effects of NAB+GEM on PEGH20 PK were collected in the PAG treatment group in the run-in phases (Run-in Phase 1: Original PEGPH20 formulation [3.5 mg/mL], and Run-in Phase 2: New PEGPH20 formulation [0.3 mg/mL]).
Time Frame	Pre-PEGPH20 dosing and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing on Days 1 and 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

PK analysis population included all participants who received any part of a dose of PEGPH20 and had measurable PEGPH20 concentrations in at least 1 sample collected for PK analysis. 'Number analyzed'=participants evaluable for this outcome at specified timepoints.

Arm/Group Title	Run-in Phase 1-PAG: PEGPH20 (Original Formulation) + NAB + GEM	Run-in Phase 2- PAG: PEGPH20 (New Formulation) + NAB + GEM
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB, and 1000 mg/m^2 GEM, as IV infusion. In Cycle 1 Week 1, PEGPH20 was administered alone on Day 1, 4, and NAB+GEM were administered on Day 2, approximately 24 hours after first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, 18, and NAB+GEM were given once/week, 2 to 4 hours after PEGPH20 administration on Days 8, 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, 15. NAB+GEM were given 2 to 4 hours after PEGPH20 dose. Each treatment cycle was of 4-weeks with Week 4 of every cycle as a rest week (no treatment). Treatment was continued until disease progression or unacceptable toxicity. Dexamethasone 8 mg was administered in each treatment cycle within 2 hours prior to beginning of each PEGPH20 infusion and 8 to 12 hours after completion of each PEGPH20 infusion.	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB, and 1000 mg/m^2 GEM, as IV infusion. In Cycle 1 Week 1, PEGPH20 was administered alone on Day 1, 4, and NAB+GEM were administered on Day 2, approximately 24 hours after first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, 18, and NAB+GEM were given once/week, 2 to 4 hours after PEGPH20 administration on Days 8, 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, 15. NAB+GEM were given 2 to 4 hours after PEGPH20 dose. Each treatment cycle was of 4-weeks with Week 4 of every cycle as a rest week (no treatment). Treatment was continued until disease progression or unacceptable toxicity. Dexamethasone 8 mg was administered in each treatment cycle within 2 hours prior to beginning of each PEGPH20 infusion and 8 to 12 hours after completion of each PEGPH20 infusion.
Measure Participants	6	8
Day 1	0.430	0.865
Day 15	0.790	0.810

9. Secondary Outcome

Title	Area Under the Concentration-Time Curve From Time 0 to Last Quantifiable Concentration (AUC0-last) of PEGPH20
Description	Samples were analyzed for PEGPH20 concentration using a validated electrochemiluminescence immunoassay. Plasma samples to assess the potential effects of NAB+GEM on PEGH20 PK were collected in the PAG treatment group in the run-in phases (Run-in Phase 1: Original PEGPH20 formulation [3.5 mg/mL], and Run-in Phase 2: New PEGPH20 formulation [0.3 mg/mL]).
Time Frame	Pre-PEGPH20 dosing and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing on Days 1 and 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

PK analysis population included all participants who received any part of a dose of PEGPH20 and had measurable PEGPH20 concentrations in at least 1 sample collected for PK analysis. 'Number analyzed'=participants evaluable for this outcome at specified timepoints.

Arm/Group Title	Run-in Phase 1-PAG: PEGPH20 (Original Formulation) + NAB + GEM	Run-in Phase 2- PAG: PEGPH20 (New Formulation) + NAB + GEM
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB, and 1000 mg/m^2 GEM, as IV infusion. In Cycle 1 Week 1, PEGPH20 was administered alone on Day 1, 4, and NAB+GEM were administered on Day 2, approximately 24 hours after first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, 18, and NAB+GEM were given once/week, 2 to 4 hours after PEGPH20 administration on Days 8, 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, 15. NAB+GEM were given 2 to 4 hours after PEGPH20 dose. Each treatment cycle was of 4-weeks with Week 4 of every cycle as a rest week (no treatment). Treatment was continued until disease progression or unacceptable toxicity. Dexamethasone 8 mg was administered in each treatment cycle within 2 hours prior to beginning of each PEGPH20 infusion and 8 to 12 hours after completion of each PEGPH20 infusion.	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB, and 1000 mg/m^2 GEM, as IV infusion. In Cycle 1 Week 1, PEGPH20 was administered alone on Day 1, 4, and NAB+GEM were administered on Day 2, approximately 24 hours after first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, 18, and NAB+GEM were given once/week, 2 to 4 hours after PEGPH20 administration on Days 8, 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, 15. NAB+GEM were given 2 to 4 hours after PEGPH20 dose. Each treatment cycle was of 4-weeks with Week 4 of every cycle as a rest week (no treatment). Treatment was continued until disease progression or unacceptable toxicity. Dexamethasone 8 mg was administered in each treatment cycle within 2 hours prior to beginning of each PEGPH20 infusion and 8 to 12 hours after completion of each PEGPH20 infusion.
Measure Participants	6	8
Day 1	1837.93575 (374.093974)	2143.30319 (491.270018)
Day 15	2807.94210 (687.004217)	2423.01690 (261.783892)

Adverse Events

Time Frame	From first exposure to any study drug (PEGPH20, NAB, GEM) through 30 days after end of treatment visit (maximum exposure: 30.72 months for PAG and 20.27 months for AG)
Adverse Event Reporting Description	AEs were analyzed on safety population, which included all participants who received at least 1 dose of study drug. AE data was collected and reported combined for both phases per treatment arm (PAG and AG). All-cause mortality was reported for all randomized participants.
Arm/Group Title	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine		AG: Nab-paclitaxel + Gemcitabine
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 with 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion. In Cycle 1 Week 1, PEGPH20 was given alone on Days 1 and 4 and NAB+GEM was given on Day 2 at approximately 24 hours after the first dose of PEGPH20. In Cycle 1 Weeks 2 and 3, PEGPH20 was given twice/week on Days 8, 11, 15, and 18 and NAB+GEM were given once/week at 2 to 4 hours after PEGPH20 administration on Days 8 and 15. In Cycle 2 onwards, PEGPH20, NAB, and GEM were given once/week on Days 1, 8, and 15. NAB+GEM were given 2 to 4 hours after the dose of PEGPH20. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning and 8 to 12 hours after the completion of each PEGPH20 infusion.		Participants received 125 mg/m^2 NAB and 1000 mg/m^2 GEM as an IV infusion once weekly on Days 1, 8, and 15 of each cycle. Each cycle was of 4-weeks (28 days) with Week 4 of every cycle as a rest week (that is; no treatment was given). Treatment was continued until documented disease progression or unacceptable toxicity. Dexamethasone 8 mg was given in each cycle within 2 hours prior to the beginning of each NAB infusion and 8 to 12 hours after the completion of GEM infusion.
All Cause Mortality
	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine		AG: Nab-paclitaxel + Gemcitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	131/166 (78.9%)		87/113 (77%)
Serious Adverse Events
	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine		AG: Nab-paclitaxel + Gemcitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	101/160 (63.1%)		58/100 (58%)
Blood and lymphatic system disorders
Anaemia	6/160 (3.8%)		5/100 (5%)
Neutropenia	7/160 (4.4%)		1/100 (1%)
Febrile neutropenia	5/160 (3.1%)		2/100 (2%)
Thrombocytopenia	4/160 (2.5%)		0/100 (0%)
Leukocytosis	1/160 (0.6%)		1/100 (1%)
Coagulopathy	0/160 (0%)		1/100 (1%)
Haemolytic uraemic syndrome	1/160 (0.6%)		0/100 (0%)
Leukopenia	1/160 (0.6%)		0/100 (0%)
Pancytopenia	1/160 (0.6%)		0/100 (0%)
Splenic haematoma	1/160 (0.6%)		0/100 (0%)
Cardiac disorders
Atrial fibrillation	8/160 (5%)		4/100 (4%)
Atrial flutter	2/160 (1.3%)		2/100 (2%)
Cardiac failure	1/160 (0.6%)		3/100 (3%)
Acute myocardial infarction	0/160 (0%)		2/100 (2%)
Cardio-respiratory arrest	2/160 (1.3%)		0/100 (0%)
Acute coronary syndrome	1/160 (0.6%)		0/100 (0%)
Angina pectoris	0/160 (0%)		1/100 (1%)
Arrhythmia	0/160 (0%)		1/100 (1%)
Bundle branch block left	1/160 (0.6%)		0/100 (0%)
Cardiac arrest	1/160 (0.6%)		0/100 (0%)
Coronary artery occlusion	0/160 (0%)		1/100 (1%)
Left ventricular failure	0/160 (0%)		1/100 (1%)
Myocardial infarction	1/160 (0.6%)		0/100 (0%)
Sinus tachycardia	1/160 (0.6%)		0/100 (0%)
Eye disorders
Retinal vascular disorder	0/160 (0%)		1/100 (1%)
Dry eye	0/160 (0%)		1/100 (1%)
Gastrointestinal disorders
Nausea	7/160 (4.4%)		4/100 (4%)
Vomiting	8/160 (5%)		2/100 (2%)
Abdominal pain	5/160 (3.1%)		3/100 (3%)
Diarrhoea	5/160 (3.1%)		2/100 (2%)
Constipation	3/160 (1.9%)		2/100 (2%)
Gastrointestinal haemorrhage	3/160 (1.9%)		1/100 (1%)
Haematemesis	0/160 (0%)		2/100 (2%)
Large intestinal obstruction	2/160 (1.3%)		0/100 (0%)
Mesenteric vein thrombosis	2/160 (1.3%)		0/100 (0%)
Retroperitoneal haemorrhage	2/160 (1.3%)		0/100 (0%)
Small intestinal obstruction	1/160 (0.6%)		1/100 (1%)
Ascites	0/160 (0%)		1/100 (1%)
Gastric ulcer	0/160 (0%)		1/100 (1%)
Gastric ulcer haemorrhage	0/160 (0%)		1/100 (1%)
Gastrooesophageal reflux disease	0/160 (0%)		1/100 (1%)
Intestinal perforation	0/160 (0%)		1/100 (1%)
Neutropenic colitis	0/160 (0%)		1/100 (1%)
Proctalgia	1/160 (0.6%)		0/100 (0%)
Stomatitis	1/160 (0.6%)		0/100 (0%)
Upper gastrointestinal haemorrhage	1/160 (0.6%)		0/100 (0%)
General disorders
Pyrexia	11/160 (6.9%)		2/100 (2%)
Asthenia	3/160 (1.9%)		1/100 (1%)
Fatigue	3/160 (1.9%)		1/100 (1%)
Generalised oedema	2/160 (1.3%)		1/100 (1%)
Non-cardiac chest pain	1/160 (0.6%)		1/100 (1%)
Oedema peripheral	1/160 (0.6%)		1/100 (1%)
Chills	0/160 (0%)		1/100 (1%)
Extravasation	1/160 (0.6%)		0/100 (0%)
Incarcerated hernia	0/160 (0%)		1/100 (1%)
Multiple organ dysfunction syndrome	0/160 (0%)		1/100 (1%)
Pain	1/160 (0.6%)		0/100 (0%)
Peripheral swelling	0/160 (0%)		1/100 (1%)
Hepatobiliary disorders
Cholangitis	4/160 (2.5%)		2/100 (2%)
Cholecystitis	1/160 (0.6%)		1/100 (1%)
Bile duct obstruction	1/160 (0.6%)		0/100 (0%)
Biliary dilatation	1/160 (0.6%)		0/100 (0%)
Cholecystitis acute	0/160 (0%)		1/100 (1%)
Hepatic failure	1/160 (0.6%)		0/100 (0%)
Hyperbilirubinaemia	0/160 (0%)		1/100 (1%)
Infections and infestations
Sepsis	13/160 (8.1%)		11/100 (11%)
Pneumonia	8/160 (5%)		2/100 (2%)
Bacteraemia	3/160 (1.9%)		4/100 (4%)
Urinary tract infection	3/160 (1.9%)		2/100 (2%)
Device related infection	3/160 (1.9%)		1/100 (1%)
Liver abscess	3/160 (1.9%)		1/100 (1%)
Cellulitis	2/160 (1.3%)		1/100 (1%)
Lung infection	1/160 (0.6%)		2/100 (2%)
Clostridium difficile infection	1/160 (0.6%)		1/100 (1%)
Neutropenic sepsis	1/160 (0.6%)		1/100 (1%)
Peritonitis	2/160 (1.3%)		0/100 (0%)
Urosepsis	1/160 (0.6%)		1/100 (1%)
Abdominal infection	0/160 (0%)		1/100 (1%)
Bronchitis	1/160 (0.6%)		0/100 (0%)
Device related sepsis	1/160 (0.6%)		0/100 (0%)
Gastroenteritis	0/160 (0%)		1/100 (1%)
Klebsiella bacteraemia	1/160 (0.6%)		0/100 (0%)
Klebsiella sepsis	1/160 (0.6%)		0/100 (0%)
Peritonitis bacterial	1/160 (0.6%)		0/100 (0%)
Pneumocystis jirovecii pneumonia	1/160 (0.6%)		0/100 (0%)
Pneumonia staphylococcal	0/160 (0%)		1/100 (1%)
Pneumonia streptococcal	0/160 (0%)		1/100 (1%)
Staphylococcal bacteraemia	0/160 (0%)		1/100 (1%)
Streptococcal sepsis	0/160 (0%)		1/100 (1%)
Injury, poisoning and procedural complications
Anastomotic ulcer	0/160 (0%)		1/100 (1%)
Infusion related reaction	1/160 (0.6%)		0/100 (0%)
Pelvic fracture	1/160 (0.6%)		0/100 (0%)
Transfusion-associated dyspnoea	1/160 (0.6%)		0/100 (0%)
Investigations
White blood cell count decreased	2/160 (1.3%)		0/100 (0%)
Electrocardiogram abnormal	1/160 (0.6%)		0/100 (0%)
International normalised ratio increased	1/160 (0.6%)		0/100 (0%)
Metabolism and nutrition disorders
Dehydration	12/160 (7.5%)		4/100 (4%)
Failure to thrive	3/160 (1.9%)		0/100 (0%)
Decreased appetite	0/160 (0%)		2/100 (2%)
Hyperglycaemia	1/160 (0.6%)		1/100 (1%)
Electrolyte imbalance	1/160 (0.6%)		0/100 (0%)
Fluid overload	0/160 (0%)		1/100 (1%)
Hypercalcaemia	0/160 (0%)		1/100 (1%)
Hyperkalaemia	0/160 (0%)		1/100 (1%)
Hypoglycaemia	0/160 (0%)		1/100 (1%)
Hypokalaemia	0/160 (0%)		1/100 (1%)
Hypovolaemia	1/160 (0.6%)		0/100 (0%)
Lactic acidosis	0/160 (0%)		1/100 (1%)
Malnutrition	1/160 (0.6%)		0/100 (0%)
Metabolic acidosis	0/160 (0%)		1/100 (1%)
Vitamin K deficiency	0/160 (0%)		1/100 (1%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	1/160 (0.6%)		0/100 (0%)
Muscle spasms	1/160 (0.6%)		0/100 (0%)
Flank pain	0/160 (0%)		1/100 (1%)
Back pain	1/160 (0.6%)		0/100 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour necrosis	1/160 (0.6%)		0/100 (0%)
Nervous system disorders
Seizure	1/160 (0.6%)		0/100 (0%)
Posterior reversible encephalopathy syndrome	1/160 (0.6%)		0/100 (0%)
Cerebrovascular accident	4/160 (2.5%)		0/100 (0%)
Encephalopathy	0/160 (0%)		2/100 (2%)
Autonomic nervous system imbalance	0/160 (0%)		1/100 (1%)
Depressed level of consciousness	1/160 (0.6%)		0/100 (0%)
Metabolic encephalopathy	0/160 (0%)		1/100 (1%)
Neuralgia	0/160 (0%)		1/100 (1%)
Neuropathy peripheral	0/160 (0%)		1/100 (1%)
Product Issues
Device occlusion	0/160 (0%)		1/100 (1%)
Psychiatric disorders
Confusional state	1/160 (0.6%)		2/100 (2%)
Mental status changes	0/160 (0%)		2/100 (2%)
Substance-induced psychotic disorder	1/160 (0.6%)		0/100 (0%)
Renal and urinary disorders
Acute kidney injury	2/160 (1.3%)		4/100 (4%)
Nephrolithiasis	1/160 (0.6%)		0/100 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	12/160 (7.5%)		3/100 (3%)
Pleural effusion	4/160 (2.5%)		0/100 (0%)
Pneumonitis	1/160 (0.6%)		3/100 (3%)
Respiratory failure	2/160 (1.3%)		2/100 (2%)
Acute respiratory failure	1/160 (0.6%)		2/100 (2%)
Hypoxia	1/160 (0.6%)		2/100 (2%)
Dyspnoea	2/160 (1.3%)		0/100 (0%)
Pneumonia aspiration	1/160 (0.6%)		1/100 (1%)
Pneumothorax	0/160 (0%)		1/100 (1%)
Respiratory distress	0/160 (0%)		1/100 (1%)
Skin and subcutaneous tissue disorders
Dermatitis	0/160 (0%)		1/100 (1%)
Vascular disorders
Deep vein thrombosis	2/160 (1.3%)		2/100 (2%)
Hypotension	1/160 (0.6%)		2/100 (2%)
Orthostatic hypotension	0/160 (0%)		2/100 (2%)
Aortic aneurysm rupture	1/160 (0.6%)		0/100 (0%)
Hypertension	0/160 (0%)		1/100 (1%)
Malignant hypertension	0/160 (0%)		1/100 (1%)
Vena cava thrombosis	1/160 (0.6%)		0/100 (0%)
Venous thrombosis	1/160 (0.6%)		0/100 (0%)
Other (Not Including Serious) Adverse Events
	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine		AG: Nab-paclitaxel + Gemcitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	157/160 (98.1%)		98/100 (98%)
Blood and lymphatic system disorders
Anaemia	63/160 (39.4%)		41/100 (41%)
Leukopenia	15/160 (9.4%)		7/100 (7%)
Lymphopenia	8/160 (5%)		5/100 (5%)
Neutropenia	53/160 (33.1%)		18/100 (18%)
Thrombocytopenia	41/160 (25.6%)		17/100 (17%)
Cardiac disorders
Sinus tachycardia	6/160 (3.8%)		5/100 (5%)
Tachycardia	15/160 (9.4%)		7/100 (7%)
Eye disorders
Vision blurred	13/160 (8.1%)		5/100 (5%)
Gastrointestinal disorders
Abdominal distension	16/160 (10%)		9/100 (9%)
Abdominal pain	51/160 (31.9%)		28/100 (28%)
Abdominal pain lower	9/160 (5.6%)		3/100 (3%)
Abdominal pain upper	10/160 (6.3%)		5/100 (5%)
Ascites	13/160 (8.1%)		5/100 (5%)
Constipation	58/160 (36.3%)		36/100 (36%)
Diarrhoea	81/160 (50.6%)		49/100 (49%)
Dry mouth	11/160 (6.9%)		5/100 (5%)
Dyspepsia	7/160 (4.4%)		7/100 (7%)
Dysphagia	12/160 (7.5%)		2/100 (2%)
Gastrooesophageal reflux disease	10/160 (6.3%)		4/100 (4%)
Nausea	91/160 (56.9%)		53/100 (53%)
Stomatitis	19/160 (11.9%)		11/100 (11%)
Vomiting	51/160 (31.9%)		33/100 (33%)
General disorders
Asthenia	23/160 (14.4%)		17/100 (17%)
Chills	23/160 (14.4%)		9/100 (9%)
Fatigue	124/160 (77.5%)		72/100 (72%)
Gait disturbance	10/160 (6.3%)		5/100 (5%)
Influenza like illness	8/160 (5%)		1/100 (1%)
Mucosal inflammation	12/160 (7.5%)		5/100 (5%)
Non-cardiac chest pain	10/160 (6.3%)		1/100 (1%)
Oedema peripheral	119/160 (74.4%)		41/100 (41%)
Pain	8/160 (5%)		5/100 (5%)
Peripheral swelling	13/160 (8.1%)		5/100 (5%)
Pyrexia	47/160 (29.4%)		30/100 (30%)
Infections and infestations
Candida infection	16/160 (10%)		5/100 (5%)
Cellulitis	5/160 (3.1%)		6/100 (6%)
Oral candidiasis	14/160 (8.8%)		4/100 (4%)
Pneumonia	10/160 (6.3%)		1/100 (1%)
Upper respiratory tract infection	12/160 (7.5%)		7/100 (7%)
Urinary tract infection	22/160 (13.8%)		11/100 (11%)
Injury, poisoning and procedural complications
Contusion	10/160 (6.3%)		3/100 (3%)
Fall	15/160 (9.4%)		8/100 (8%)
Investigations
Alanine aminotransferase increased	33/160 (20.6%)		12/100 (12%)
Aspartate aminotransferase increased	26/160 (16.3%)		12/100 (12%)
Blood alkaline phosphatase increased	14/160 (8.8%)		11/100 (11%)
Blood bilirubin increased	14/160 (8.8%)		1/100 (1%)
Lymphocyte count decreased	12/160 (7.5%)		2/100 (2%)
Neutrophil count decreased	33/160 (20.6%)		22/100 (22%)
Platelet count decreased	38/160 (23.8%)		10/100 (10%)
Weight decreased	32/160 (20%)		17/100 (17%)
White blood cell count decreased	29/160 (18.1%)		9/100 (9%)
Metabolism and nutrition disorders
Decreased appetite	75/160 (46.9%)		39/100 (39%)
Dehydration	30/160 (18.8%)		22/100 (22%)
Hyperglycaemia	18/160 (11.3%)		12/100 (12%)
Hypoalbuminaemia	27/160 (16.9%)		2/100 (2%)
Hypocalcaemia	13/160 (8.1%)		6/100 (6%)
Hypokalaemia	38/160 (23.8%)		22/100 (22%)
Hypomagnesaemia	19/160 (11.9%)		13/100 (13%)
Hyponatraemia	26/160 (16.3%)		10/100 (10%)
Hypophosphataemia	3/160 (1.9%)		5/100 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	46/160 (28.8%)		14/100 (14%)
Back pain	20/160 (12.5%)		14/100 (14%)
Muscle spasms	92/160 (57.5%)		6/100 (6%)
Muscular weakness	19/160 (11.9%)		8/100 (8%)
Musculoskeletal pain	10/160 (6.3%)		1/100 (1%)
Myalgia	43/160 (26.9%)		12/100 (12%)
Pain in extremity	19/160 (11.9%)		7/100 (7%)
Nervous system disorders
Dizziness	39/160 (24.4%)		25/100 (25%)
Dysgeusia	48/160 (30%)		22/100 (22%)
Headache	13/160 (8.1%)		14/100 (14%)
Neuropathy peripheral	50/160 (31.3%)		32/100 (32%)
Paraesthesia	9/160 (5.6%)		2/100 (2%)
Peripheral sensory neuropathy	18/160 (11.3%)		15/100 (15%)
Syncope	3/160 (1.9%)		6/100 (6%)
Psychiatric disorders
Anxiety	18/160 (11.3%)		13/100 (13%)
Depression	17/160 (10.6%)		12/100 (12%)
Insomnia	31/160 (19.4%)		17/100 (17%)
Renal and urinary disorders
Dysuria	8/160 (5%)		2/100 (2%)
Pollakiuria	6/160 (3.8%)		7/100 (7%)
Urinary retention	8/160 (5%)		1/100 (1%)
Respiratory, thoracic and mediastinal disorders
Cough	32/160 (20%)		23/100 (23%)
Dysphonia	30/160 (18.8%)		2/100 (2%)
Dyspnoea	48/160 (30%)		31/100 (31%)
Dyspnoea exertional	5/160 (3.1%)		8/100 (8%)
Epistaxis	25/160 (15.6%)		14/100 (14%)
Hiccups	18/160 (11.3%)		7/100 (7%)
Hypoxia	5/160 (3.1%)		5/100 (5%)
Nasal congestion	8/160 (5%)		5/100 (5%)
Oropharyngeal pain	18/160 (11.3%)		8/100 (8%)
Pleural effusion	18/160 (11.3%)		4/100 (4%)
Productive cough	7/160 (4.4%)		8/100 (8%)
Pulmonary embolism	7/160 (4.4%)		5/100 (5%)
Skin and subcutaneous tissue disorders
Alopecia	61/160 (38.1%)		39/100 (39%)
Dry skin	8/160 (5%)		2/100 (2%)
Erythema	7/160 (4.4%)		5/100 (5%)
Night sweats	7/160 (4.4%)		9/100 (9%)
Pruritus	10/160 (6.3%)		8/100 (8%)
Rash	25/160 (15.6%)		21/100 (21%)
Rash maculo-papular	15/160 (9.4%)		7/100 (7%)
Vascular disorders
Deep vein thrombosis	12/160 (7.5%)		7/100 (7%)
Flushing	10/160 (6.3%)		0/100 (0%)
Hypertension	8/160 (5%)		3/100 (3%)
Hypotension	35/160 (21.9%)		18/100 (18%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.