Study of Gemcitabine + PEGPH20 vs Gemcitabine Alone in Stage IV Previously Untreated Pancreatic Cancer

The safety and tolerability profile of PEGPH20 used in combination with gemcitabine was assessed by measuring the number of participants with a DLT during the dose-escalation phase of the study. A DLT was defined as any treatment-emergent National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE), Version 4.0, Grade 3 or greater event occurring within the first 4 weeks of treatment that was considered related to PEGPH20. Any PEGPH20 treatment-related AE that resulted in a drug interruption or reduction might have been considered a DLT at the Investigator's or Sponsor's discretion. Hypersensitivity/infusion reactions related to PEGPH20 dosing were not considered DLTs.

The safety and tolerability profile of PEGPH20 used in combination with gemcitabine was assessed by determining the RP2D, the highest dose level at which no more than 1 of 6 evaluable participants experienced a DLT in the first 4 weeks of treatment (considered a safe dose). The RP2D was determined based on review of safety and pharmacokinetic (PK) data from participants enrolled during the dose-escalation phase of the study.

Cmax is defined as the observed maximum plasma concentration after the first dose. Blood samples were collected for pharmacokinetic assessment.

Cmax is defined as the observed maximum plasma concentration after the first dose. Blood samples were collected for pharmacokinetic assessment. The 24-hour sample collected at the first visit was optional.

Blood samples were collected for pharmacokinetic assessment.

Blood samples were collected for pharmacokinetic assessment. The 24-hour sample collected at the first visit was optional.

Blood samples were collected for pharmacokinetic assessment.

Blood samples were collected for pharmacokinetic assessment. The 24-hour sample collected at the first visit was optional.

The apparent half-life calculated by ln(2)/λ, where λ was the rate constant for the log-linear portion of the terminal phase. A minimum of 3 values in the postdistribution phase of the plasma concentration-time curve were required for calculation of λ. Blood samples were collected for pharmacokinetic assessment. t1/2 is expressed as harmonic mean and pseudo standard deviation.

The apparent half-life calculated by ln(2)/λ, where λ was the rate constant for the log-linear portion of the terminal phase. A minimum of 3 values in the postdistribution phase of the plasma concentration-time curve were required for calculation of λ. Blood samples were collected for pharmacokinetic assessment. The 24-hour sample collected at the first visit was optional. t1/2 is expressed as harmonic mean and pseudo standard deviation.

Blood samples were collected for pharmacokinetic assessment. AUC0-T was calculated by the linear trapezoidal rule.

Blood samples were collected for pharmacokinetic assessment. The 24-hour sample collected at the first visit was optional. AUC0-T was calculated by the linear trapezoidal rule.

The pharmacodynamic activity of PEGPH20 was evaluated by measuring plasma concentrations of HA after PEGPH20 dosing. Peak HA concentrations are the highest concentrations measured after a single dose of PEGPH20. HA samples were collected in Cycle 1 at the following time points: 1) Week 1/Day 1 (first visit) and Week 4 (first visit): predose and 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing (24-hour sample optional for Week 4); 2) all other visits in Cycle 1: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given). HA samples were collected in Cycles 2+ at the following time points: Week 3 of each cycle pre-PEGPH20 dose and 1 to 2 hours post-PEGPH20 dose.

An H-score approach methodology was developed and used to analyze staining in the tumor pericellular regions and the stroma separately. The H-score calculation was the sum of the products of the percentage of positive staining areas and the staining intensity (0, 1, 2 or 3), and ranged from 0 to 300. For example: [90% * 1 (weak)] + [10% * 2 (moderate)] + [0% * 3 (strong)] = 110. A score of 0 represents the absence of expression, and an H-score of 300 represents maximum expression. A larger decrease in H-score correlated with a greater target engagement of PEGPH20. As HA is a secreted protein, the scoring was performed in the immediate areas surrounding tumor (pericellular areas) as well as in stroma.

PEGPH20's effect on the metabolic activities of the tumor was assessed as the percent change in SUVmax (a measure of total lesion metabolic activity) using fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT). Assessment was done for the entire cohort of participants, not per treatment group.

Dynamic control enhanced-magnetic resonance imaging (DCE-MRI) provides a measure of the exchange of small-molecule contrast agents between the intracellular and extracellular spaces. Using a 2-compartment pharmacokinetic model, an estimate of tissue (tumor) perfusion can be obtained by determining the exchange rate constant (Ktrans) of contrast exchange. Ktrans is defined as the volume transfer constant between extravascular/extracellular space to plasma space and is a measure of blood flow, vascular permeability, or both. Mean Ktrans values across scan sites are reported per participant. DCE-MRI was performed before the first dosing visit (Week 1/Day 1), 24 hours after the first dose of PEGPH20 in Cycle 1, and 24 hours after the last dose of PEGPH20 in Cycle 1 (Week 7). Assessment was done for the entire cohort of participants, not per treatment group.

DCE-MRI provides a measure of the exchange of small-molecule contrast agents between the intracellular and extracellular spaces. Ve is defined as the extravascular-extracellular volume fraction and is a measure of extracellular, extravascular space. Mean Ve values across scan sites are reported per participant. DCE-MRI was performed before the first dosing visit (Week 1/Day 1), 24 hours after the first dose of PEGPH20 in Cycle 1, and 24 hours after the last dose of PEGPH20 in Cycle 1 (Week 7). Assessment was done for the entire cohort of participants, not per treatment group.

Target lesions (TLs), complete response (CR): Disappearance of all TLs. Partial response (PR): >=30% decrease in the sum of diameters of TLs, referencing baseline sums. Progressive disease (PD): >= 20% increase in the sum of diameters of TLs, referencing the smallest sum (including baseline sum). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of >=5 mm. (The appearance of >=1 new lesions is considered progression.) Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient to qualify for PD, referencing the smallest sum diameters. For nontarget lesions (NTLs), CR: Disappearance of all NTLs and normalization of tumor marker level. All lymph nodes must be nonpathological in size (short axis <10 mm). Incomplete response/SD: Persistence of >=1 NTLs and/or maintenance of tumor marker level above normal limits. PD: Unequivocal progression of existing NTLs. (The appearance of >=1 new lesions is considered progression.)

Objective Response Rate is defined as the number of participants with a complete response plus the number of participants with a partial response, per RECIST, Version 1.1. For TLs, CR: Disappearance of all TLs. PR: >=30% decrease in the sum of diameters of TLs, referencing baseline sums. For NTLs, CR: Disappearance of all NTLs and normalization of tumor marker level. All lymph nodes must be nonpathological in size (short axis <10 mm). Incomplete response/SD: Persistence of >=1 NTLs and/or maintenance of tumor marker level above normal limits.

Disease Control Rate is defined as the sum of the number of participants with a complete response, the number of participants with a partial response, and the number of participants with stable disease per RECIST, Version 1.1. For TLs, CR: Disappearance of all TLs. PR: >=30% decrease in the sum of diameters of TLs, referencing baseline sums. SD: Neither sufficient shrinkage to qualify for PR nor sufficient to qualify for PD, referencing the smallest sum diameters. For NTLs, CR: Disappearance of all NTLs and normalization of tumor marker level. All lymph nodes must be nonpathological in size (short axis <10 mm). Incomplete response/SD: Persistence of >=1 NTLs and/or maintenance of tumor marker level above normal limits.

PFS duration was defined as the time from the first dose of PEGPH20 until objective tumor progression or death. Per RECIST, Version 1.1, for the evaluation of target lesions, progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters. Note: the appearance of 1 or more new lesions is also considered progression. For the evaluation of nontarget lesions, progressive disease is defined as the unequivocal progression of existing nontarget lesions. Note: The appearance of 1 or more new lesions is also considered progression.

Overall survival was defined as the time from the time of the first dose of PEGPH20 until death.

CA19-9 is a tumor marker. Blood samples (plasma) were collected for CA19-9 evaluations.

CA19-9 is a tumor marker. Blood samples (plasma) were collected for CA19-9 evaluations.

CA19-9 is a tumor marker. Blood samples (plasma) were collected for CA19-9 evaluations. Responders are defined as participants who had a complete response or partial response, and non-responders are defined as participants who had stable disease, progressive disease, or an unknown tumor response, per RECIST, Version 1.1.