Trial Outcomes & Findings for PEGPH20 Plus Nab-Paclitaxel Plus Gemcitabine Compared With Nab-Paclitaxel Plus Gemcitabine in Participants With Stage IV Untreated Pancreatic Cancer (NCT NCT01839487)

Last Updated: 2020-07-20

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

279 participants

Primary outcome timeframe

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)

Results posted on

2020-07-20

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Run-in Phase - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine 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.	Run-in Phase - AG: Nab-paclitaxel + Gemcitabine 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.	Phase 2: Stage 1 - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine 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.	Phase 2: Stage 1 - AG: Nab-paclitaxel + Gemcitabine 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.	Phase 2: Stage 2 - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine 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).	Phase 2: Stage 2 - AG: Nab-paclitaxel + Gemcitabine 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.
Run-in Phase (Maximum Exposure:295 Days) STARTED	16	7	0	0	0	0
Run-in Phase (Maximum Exposure:295 Days) COMPLETED	0	0	0	0	0	0
Run-in Phase (Maximum Exposure:295 Days) NOT COMPLETED	16	7	0	0	0	0
Phase 2 (Maximum Exposure:935 Days) STARTED	0	0	61	62	89	44
Phase 2 (Maximum Exposure:935 Days) COMPLETED	0	0	0	0	1	0
Phase 2 (Maximum Exposure:935 Days) NOT COMPLETED	0	0	61	62	88	44

Reasons for withdrawal

Reasons for withdrawal
Measure	Run-in Phase - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine 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.	Run-in Phase - AG: Nab-paclitaxel + Gemcitabine 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.	Phase 2: Stage 1 - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine 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.	Phase 2: Stage 1 - AG: Nab-paclitaxel + Gemcitabine 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.	Phase 2: Stage 2 - PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine 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).	Phase 2: Stage 2 - AG: Nab-paclitaxel + Gemcitabine 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.
Run-in Phase (Maximum Exposure:295 Days) Withdrawal by Subject	1	0	0	0	0	0
Run-in Phase (Maximum Exposure:295 Days) Death	14	6	0	0	0	0
Run-in Phase (Maximum Exposure:295 Days) Study Terminated by Sponsor	0	1	0	0	0	0
Run-in Phase (Maximum Exposure:295 Days) Other than specified	1	0	0	0	0	0
Phase 2 (Maximum Exposure:935 Days) Withdrawal by Subject	0	0	12	9	4	8
Phase 2 (Maximum Exposure:935 Days) Death	0	0	46	49	71	32
Phase 2 (Maximum Exposure:935 Days) Lost to Follow-up	0	0	2	0	1	0
Phase 2 (Maximum Exposure:935 Days) Study Terminated by Sponsor	0	0	0	1	10	3
Phase 2 (Maximum Exposure:935 Days) Other than specified	0	0	1	3	2	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine n=166 Participants 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.	AG: Nab-paclitaxel + Gemcitabine n=113 Participants 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 n=279 Participants Total of all reporting groups
Age, Continuous	64.3 years STANDARD_DEVIATION 9.72 • n=93 Participants	65.0 years STANDARD_DEVIATION 8.82 • n=4 Participants	64.6 years STANDARD_DEVIATION 9.35 • n=27 Participants
Sex: Female, Male Female	65 Participants n=93 Participants	58 Participants n=4 Participants	123 Participants n=27 Participants
Sex: Female, Male Male	101 Participants n=93 Participants	55 Participants n=4 Participants	156 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=93 Participants	9 Participants n=4 Participants	13 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	160 Participants n=93 Participants	104 Participants n=4 Participants	264 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=93 Participants	0 Participants n=4 Participants	2 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants
Race (NIH/OMB) Asian	5 Participants n=93 Participants	5 Participants n=4 Participants	10 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) Black or African American	11 Participants n=93 Participants	9 Participants n=4 Participants	20 Participants n=27 Participants
Race (NIH/OMB) White	146 Participants n=93 Participants	91 Participants n=4 Participants	237 Participants n=27 Participants
Race (NIH/OMB) More than one race	1 Participants n=93 Participants	7 Participants n=4 Participants	8 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants

PRIMARY outcome

Timeframe: 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)

Population: 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.

Outcome measures

Outcome measures
Measure	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine n=139 Participants 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.	AG: Nab-paclitaxel + Gemcitabine n=92 Participants 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.
Progression-Free Survival (PFS)	6.05 months Interval 5.36 to 7.2	5.26 months Interval 3.91 to 6.54

PRIMARY outcome

Timeframe: 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)

Population: 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.

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'.

Outcome measures

Outcome measures
Measure	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine n=86 Participants 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.	AG: Nab-paclitaxel + Gemcitabine 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.
Percentage of Participants in the PAG Arm Who Experienced Any Thromboembolic (TE) Event in Stage 2 of the Study	14.0 percentage of participants	—

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine n=153 Participants 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.	AG: Nab-paclitaxel + Gemcitabine n=93 Participants 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.
PFS in Relation to Tumor Hyaluronan (HA) Levels HA-High	9.23 months Interval 5.98 to 10.55	5.19 months Interval 3.52 to 6.54
PFS in Relation to Tumor Hyaluronan (HA) Levels HA-Low	5.59 months Interval 4.7 to 7.03	5.26 months Interval 3.78 to 7.33

SECONDARY outcome

Timeframe: From the date of randomization until last date on study treatment (maximum exposure: 30.72 months for PAG, and 20.27 months for AG)

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

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.

Outcome measures

Outcome measures
Measure	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine n=166 Participants 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.	AG: Nab-paclitaxel + Gemcitabine n=113 Participants 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.
Objective Response Rate (ORR): Percentage of Participants With Objective Response	40.4 percentage of participants Interval 32.83 to 48.24	32.7 percentage of participants Interval 24.21 to 42.21

SECONDARY outcome

Timeframe: From randomization until death from any cause (maximum exposure: 30.72 months for PAG, and 20.27 months for AG)

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

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.

Outcome measures

Outcome measures
Measure	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine n=166 Participants 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.	AG: Nab-paclitaxel + Gemcitabine n=113 Participants 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.
Overall Survival	9.59 months Interval 8.15 to 12.06	9.23 months Interval 7.59 to 10.71

SECONDARY outcome

Timeframe: 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)

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

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'.

Outcome measures

Outcome measures
Measure	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine n=160 Participants 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.	AG: Nab-paclitaxel + Gemcitabine n=100 Participants 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.
Percentage of Participants With AEs	99.4 percentage of participants	98.0 percentage of participants

SECONDARY outcome

Timeframe: Pre-PEGPH20 dosing and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing on Days 1 and 15 of Cycle 1

Population: 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.

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 \[0.3 mg/mL\]).

Outcome measures

Outcome measures
Measure	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine n=6 Participants 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.	AG: Nab-paclitaxel + Gemcitabine n=8 Participants 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.
Maximum Observed Plasma Concentration (Cmax) of PEGPH20 Day 1	72.1 nanograms/milliliter (ng/mL) Standard Deviation 16.90	67.8 nanograms/milliliter (ng/mL) Standard Deviation 17.60
Maximum Observed Plasma Concentration (Cmax) of PEGPH20 Day 15	82.9 nanograms/milliliter (ng/mL) Standard Deviation 25.42	84.1 nanograms/milliliter (ng/mL) Standard Deviation 7.70

SECONDARY outcome

Timeframe: 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 \[0.3 mg/mL\]).

Outcome measures

Outcome measures
Measure	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine n=6 Participants 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.	AG: Nab-paclitaxel + Gemcitabine n=8 Participants 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.
Time to Reach Cmax (Tmax) of PEGPH20 Day 1	0.430 hours Interval 0.33 to 4.17	0.865 hours Interval 0.33 to 4.2
Time to Reach Cmax (Tmax) of PEGPH20 Day 15	0.790 hours Interval 0.0 to 1.93	0.810 hours Interval 0.42 to 2.28

SECONDARY outcome

Timeframe: 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 \[0.3 mg/mL\]).

Outcome measures

Outcome measures
Measure	PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine n=6 Participants 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.	AG: Nab-paclitaxel + Gemcitabine n=8 Participants 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.
Area Under the Concentration-Time Curve From Time 0 to Last Quantifiable Concentration (AUC0-last) of PEGPH20 Day 1	1837.93575 hours*ng/mL Standard Deviation 374.093974	2143.30319 hours*ng/mL Standard Deviation 491.270018
Area Under the Concentration-Time Curve From Time 0 to Last Quantifiable Concentration (AUC0-last) of PEGPH20 Day 15	2807.94210 hours*ng/mL Standard Deviation 687.004217	2423.01690 hours*ng/mL Standard Deviation 261.783892

Adverse Events

PAG: PEGPH20 + Nab-paclitaxel + Gemcitabine

Serious events: 101 serious events

Other events: 157 other events

Deaths: 131 deaths

AG: Nab-paclitaxel + Gemcitabine

Serious events: 58 serious events

Other events: 98 other events

Deaths: 87 deaths

Serious adverse events

Other adverse events

Additional Information

VP, Clinical Development

Halozyme Therapeutics

Phone: 858-794-8889

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60