Stage IV Pancreatic Cancer
Conditions
Keywords
pancreatic, Cancer, Stage IV, untreated
Brief summary
Phase 1B: Open label (all patients receive PEGPH20+gemcitabine), dose escalation, safety and tolerability study to determine the safe dose of PEGPH20 to use in combination with gemcitabine in Stage IV previously untreated pancreatic cancer patients. Phase 2: Randomized, double blind study to compare the effect of overall survival of gemcitabine plus PEGPH20 vs gemcitabine plus placebo in Stage IV previously untreated pancreatic cancer patients.
Detailed description
PEGPH20 is a PEGylated version of human recombinant PH20 hyaluronidase that, in preclinical studies, has been shown to remove HA from the extracellular matrix surrounding tumor cells by depolymerizing this substrate. 87% of pancreatic ductal adenocarcinomas (PDA) overexpress HA. PDA tumor tissue may be especially sensitive to the HA-degradation properties of PEGPH20 and thus more responsive to the cytotoxic effects of a given dose of gemcitabine. Modifying the extracellular environment to increase the penetration and efficacy of anti-cancer agents represents a novel approach to treating pancreatic cancer and may provide important therapeutic outcomes in patients with Stage IV Previously Untreated Pancreatic Cancer. This Phase 1B/2 study will assess safety, tolerability, treatment effect, and various PK/PD endpoints.
Interventions
DRUGGemcitabine
1000 mg/m2 given IV one time a week (Cycle 1: 7 weeks on treatment, 1 week off treatment; Cycle 2+: 3 Weeks on treatment, 1 week off treatment)
DRUGPEGPH20
(Cycle 1: 7 weeks on treatment/1 week off treatment; Cycle 2+: 3 Weeks on treatment/1 week off treatment). Doses start at 1.0 mcg/kg and modified until recommended Phase 2 dose is determined. Treatment continues until occurrence of significant treatment-related toxicity, progressive disease, or discontinuation criteria are met
DRUGPlacebo
(Cycle 1: 7 weeks on treatment/1 week off treatment; Cycle 2+: 3 Weeks on treatment/1 week off treatment).
Sponsors
Halozyme Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Patients with histologically confirmed Stage IV adenocarcinoma of the pancrease previously untreated for metastatic disease * One or more metastatic tumors measurable on CT scan per RECIST 1.1 criteria * Life expectancy of at least 3 months * Signed, written IRB/EC-approved informed consent * A negative serum pregnancy test, if female Key
Exclusion criteria
* Known brain metastasis * New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 12 months * Active, uncontrolled bacterial, viral, or fungal infection requiring systemic therapy * Known allergy to hyaluronidase * Women currently pregnant or breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Dose-limiting Toxicity (DLT) | first 4 weeks of Cycle 1 | 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. |
| Recommended Phase 2 Dose (RP2D) | first 4 weeks of Cycle 1 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Last Measurable Observed Plasma Concentration (Cmin) Following Single PEGPH20 Doses | Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given) | Blood samples were collected for pharmacokinetic assessment. |
| Cmin Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given) | Blood samples were collected for pharmacokinetic assessment. The 24-hour sample collected at the first visit was optional. |
| Time to Reach Cmax (Tmax) Following Single PEGPH20 Doses | Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given) | Blood samples were collected for pharmacokinetic assessment. |
| Tmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given) | Blood samples were collected for pharmacokinetic assessment. The 24-hour sample collected at the first visit was optional. |
| Apparent Half-life (t1/2) Following Single PEGPH20 Doses | Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given) | 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. |
| Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | up to the end of Cycle 10 (up to Week 44) | CA19-9 is a tumor marker. Blood samples (plasma) were collected for CA19-9 evaluations. |
| t1/2 Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given) | 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. |
| Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Measurable Plasma Concentration (AUC0-T) Following Single PEGPH20 Doses | Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given) | Blood samples were collected for pharmacokinetic assessment. AUC0-T was calculated by the linear trapezoidal rule. |
| AUC0-T Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given) | 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. |
| Plasma Hyaluronan (HA) Concentration at Baseline and After PEGPH20 Administration | Baseline; post-Baseline (average treatment duration of 94.6 days) | 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. |
| Observed Maximum Plasma Concentration (Cmax) Following Single PEGPH20 Doses | Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given) | Cmax is defined as the observed maximum plasma concentration after the first dose. Blood samples were collected for pharmacokinetic assessment. |
| Percent Change in in the Maximum Standardized Uptake Value (SUVmax), as an Assessment of Total Lesion Metabolic Activity | Baseline; up to 32 weeks for each individual participant (end of Cycle 7) | 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. |
| Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Baseline; 24 hours hours; end of Cycle 1 (Week 7) | 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. |
| Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Baseline; 24 hours hours; end of Cycle 1 (Week 7) | 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. |
| Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | up to the end of Cycle 10 (up to Week 44) | CA19-9 is a tumor marker. Blood samples (plasma) were collected for CA19-9 evaluations. |
| Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | up to approximately 2 years 4 months | 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 | up to approximately 2 years 4 months | 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 | up to approximately 2 years 4 months | 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. |
| Progression-free Survival (PFS) | from the first dose of PEGH20 until objective tumor progression or death (up to approximately 2 years 4 months) | 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 | from the time of the first dose of PEGPH20 until death (up to approximately 2 years 4 months) | Overall survival was defined as the time from the time of the first dose of PEGPH20 until death. |
| Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | up to the end of Cycle 10 (up to Week 44) | 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. |
| H-scores, as an Assessment of HA Staining Changes in Tumor Biopsies | Screening; Cycle 1 Week 7 | 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. |
| Cmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given) | 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. |
Countries
Russia, United States
Participant flow
Pre-assignment details
This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGylated Recombinant Human Hyaluronidase PH20 (PEGPH20).
Participants by arm
| Arm | Count |
|---|---|
| PEGPH20 1.0 μg/kg Participants received PEGylated Recombinant Human Hyaluronidase PH20 (PEGPH20) 1.0 micrograms per kilogram (μg/kg). PEGPH20 was administered twice weekly for 4 consecutive weeks and then once weekly for the next 3 weeks during Cycle 1. For each cycle thereafter, PEGPH20 was administered once weekly for 3 consecutive weeks. Participants received gemcitabine 1000 milligrams per meters squared (mg/m\^2) administered via intravenous (IV) infusion. Before the Recommend Phase 2 Dose (RP2D) was established, gemcitabine was administered 2 hours after the second dose of PEGPH20 during Weeks 1 to 4 of Cycle 1 and on the same day as PEGPH20 during each week thereafter. After the RP2D was established, gemcitabine was administered within 24 hours after the first dose of PEGPH20 during Weeks 1 to 4 of Cycle 1 and 2 to 24 hours after each PEGPH20 dose thereafter. Dexamethasone was administered approximately 1 hour prior to and 8 to 12 hours after PEGPH20 dosing. | 4 |
| PEGPH20 1.6 μg/kg Participants received PEGPH20 1.6 μg/kg. PEGPH20 was administered twice weekly for 4 consecutive weeks and then once weekly for the next 3 weeks during Cycle 1. For each cycle thereafter, PEGPH20 was administered once weekly for 3 consecutive weeks. Participants received gemcitabine 1000 mg/m\^2 administered via IV infusion. Before the RP2D was established, gemcitabine was administered 2 hours after the second dose of PEGPH20 during Weeks 1 to 4 of Cycle 1 and on the same day as PEGPH20 during each week thereafter. After the RP2D was established, gemcitabine was administered within 24 hours after the first dose of PEGPH20 during Weeks 1 to 4 of Cycle 1 and 2 to 24 hours after each PEGPH20 dose thereafter. Dexamethasone was administered approximately 1 hour prior to and 8 to 12 hours after PEGPH20 dosing. | 4 |
| PEGPH20 3.0 μg/kg Participants received PEGPH20 3.0 μg/kg. PEGPH20 was administered twice weekly for 4 consecutive weeks and then once weekly for the next 3 weeks during Cycle 1. For each cycle thereafter, PEGPH20 was administered once weekly for 3 consecutive weeks. Participants received gemcitabine 1000 mg/m\^2 administered via IV infusion. Before the RP2D was established, gemcitabine was administered 2 hours after the second dose of PEGPH20 during Weeks 1 to 4 of Cycle 1 and on the same day as PEGPH20 during each week thereafter. After the RP2D was established, gemcitabine was administered within 24 hours after the first dose of PEGPH20 during Weeks 1 to 4 of Cycle 1 and 2 to 24 hours after each PEGPH20 dose thereafter. Dexamethasone was administered approximately 1 hour prior to and 8 to 12 hours after PEGPH20 dosing. | 20 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 3 | 2 | 16 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | PEGPH20 1.0 μg/kg | PEGPH20 1.6 μg/kg | PEGPH20 3.0 μg/kg | Total |
|---|---|---|---|---|
| Age, Continuous | 50.5 years STANDARD_DEVIATION 8.06 | 59.0 years STANDARD_DEVIATION 8.72 | 60.3 years STANDARD_DEVIATION 13.5 | 58.7 years STANDARD_DEVIATION 12.48 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 18 Participants | 25 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 10 Participants | 14 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 10 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 4 | 4 / 4 | 17 / 20 |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 19 / 20 |
| serious Total, serious adverse events | 2 / 4 | 1 / 4 | 13 / 20 |
Outcome results
Primary
Number of Participants With a Dose-limiting Toxicity (DLT)
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.
Time frame: first 4 weeks of Cycle 1
Population: The DLT Evaluable Population: all participants enrolled during the dose escalation portion of the study who received at least 6 of 8 planned doses of PEGPH20 and 3 of 4 doses of gemcitabine in the first 4 weeks or had a DLT in the first 4 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PEGPH20 1.0 μg/kg | Number of Participants With a Dose-limiting Toxicity (DLT) | 0 Participants |
| PEGPH20 1.6 μg/kg | Number of Participants With a Dose-limiting Toxicity (DLT) | 0 Participants |
| PEGPH20 3.0 μg/kg | Number of Participants With a Dose-limiting Toxicity (DLT) | 0 Participants |
Primary
Recommended Phase 2 Dose (RP2D)
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.
Time frame: first 4 weeks of Cycle 1
Population: The DLT Evaluable Population: all participants enrolled during the dose escalation portion of the study who received at least 6 of 8 planned doses of PEGPH20 and 3 of 4 doses of gemcitabine in the first 4 weeks or had a DLT in the first 4 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PEGPH20 1.0 μg/kg | Recommended Phase 2 Dose (RP2D) | 3.0 micrograms per kilogram (μg/kg) |
Secondary
Apparent Half-life (t1/2) Following Single PEGPH20 Doses
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.
Time frame: Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed. t1/2 values were not calculated for the 1.0 μg/kg dose because there were insufficient data points in the profiles due to low concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PEGPH20 1.6 μg/kg | Apparent Half-life (t1/2) Following Single PEGPH20 Doses | 18.6 hours | Standard Deviation 0.255 |
| PEGPH20 3.0 μg/kg | Apparent Half-life (t1/2) Following Single PEGPH20 Doses | 8.24 hours | Standard Deviation 8.03 |
Secondary
Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Measurable Plasma Concentration (AUC0-T) Following Single PEGPH20 Doses
Blood samples were collected for pharmacokinetic assessment. AUC0-T was calculated by the linear trapezoidal rule.
Time frame: Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given)
Population: Intent-to-Treat Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PEGPH20 1.0 μg/kg | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Measurable Plasma Concentration (AUC0-T) Following Single PEGPH20 Doses | 1.39 Units*hour/milliliter | Standard Deviation 1.57 |
| PEGPH20 1.6 μg/kg | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Measurable Plasma Concentration (AUC0-T) Following Single PEGPH20 Doses | 13.6 Units*hour/milliliter | Standard Deviation 11.8 |
| PEGPH20 3.0 μg/kg | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Measurable Plasma Concentration (AUC0-T) Following Single PEGPH20 Doses | 31.5 Units*hour/milliliter | Standard Deviation 18 |
Secondary
AUC0-T Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks
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.
Time frame: Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PEGPH20 1.0 μg/kg | AUC0-T Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 2.99 Units*hour/milliliter | Standard Deviation 0.607 |
| PEGPH20 1.6 μg/kg | AUC0-T Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 21.5 Units*hour/milliliter | Standard Deviation 11.9 |
| PEGPH20 3.0 μg/kg | AUC0-T Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 35.2 Units*hour/milliliter | Standard Deviation 23.5 |
Secondary
Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders
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.
Time frame: up to the end of Cycle 10 (up to Week 44)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 10, Week 4, Visit 1 | -154937 U/ml | — |
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 5, Week 4, Visit 1 | -22347.6 U/ml | Standard Deviation 65803.24 |
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 6, Week 4, Visit 1 | -39900.5 U/ml | Standard Deviation 76719.16 |
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 7, Week 4, Visit 1 | -77482.1 U/ml | Standard Deviation 109576.2 |
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 8, Week 4, Visit 1 | -77472.8 U/ml | Standard Deviation 109563 |
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 9, Week 4, Visit 1 | -154940 U/ml | — |
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 1, Week 4, Visit 1 | -15677.1 U/ml | Standard Deviation 45962.74 |
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 1, Week 8, Visit 1 | -16367.0 U/ml | Standard Deviation 47164.85 |
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 2, Week 4, Visit 1 | -21587.2 U/ml | Standard Deviation 53784.34 |
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 3, Week 4, Visit 1 | -28752.7 U/ml | Standard Deviation 61783.48 |
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 4, Week 4, Visit 1 | -19976.6 U/ml | Standard Deviation 54603.4 |
| PEGPH20 1.6 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 1, Week 4, Visit 1 | 675.7 U/ml | Standard Deviation 15184.14 |
| PEGPH20 1.6 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 3, Week 4, Visit 1 | 23830.5 U/ml | Standard Deviation 78609.44 |
| PEGPH20 1.6 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 1, Week 8, Visit 1 | -6227.9 U/ml | Standard Deviation 12527.76 |
| PEGPH20 1.6 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 5, Week 4, Visit 1 | -29200.0 U/ml | — |
| PEGPH20 1.6 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 2, Week 4, Visit 1 | 1377.1 U/ml | Standard Deviation 21979.93 |
| PEGPH20 1.6 μg/kg | Change From Baseline in CA19-9 in Participants Classified as Responders and Non-responders | Cycle 4, Week 4, Visit 1 | -32900.0 U/ml | — |
Secondary
Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml
CA19-9 is a tumor marker. Blood samples (plasma) were collected for CA19-9 evaluations.
Time frame: up to the end of Cycle 10 (up to Week 44)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PEGPH20 1.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 1, Week 4, Visit 1 | 19346.2 U/ml | Standard Deviation 27370.41 |
| PEGPH20 1.6 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 1, Week 4, Visit 1 | -23500.0 U/ml | — |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 1, Week 4, Visit 1 | -15018.9 U/ml | Standard Deviation 43611.09 |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 1, Week 8, Visit 1 | -18274.5 U/ml | Standard Deviation 44769.87 |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 2, Week 4, Visit 1 | -20724.4 U/ml | Standard Deviation 56673.61 |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 3, Week 4, Visit 1 | -16835.7 U/ml | Standard Deviation 85332.54 |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 4, Week 4, Visit 1 | -27530.1 U/ml | Standard Deviation 57504.01 |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 5, Week 4, Visit 1 | -32656.8 U/ml | Standard Deviation 71005.52 |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 6, Week 4, Visit 1 | -79800.9 U/ml | Standard Deviation 106251.1 |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 7, Week 4, Visit 1 | -154964 U/ml | — |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 8, Week 4, Visit 1 | -154946 U/ml | — |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 9, Week 4, Visit 1 | -154940 U/ml | — |
| PEGPH20 3.0 μg/kg | Change From Baseline in CA19-9 in Participants With a Baseline Value >=59 U/ml | Cycle 10, Week 4, Visit 1 | -154937 U/ml | — |
Secondary
Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9)
CA19-9 is a tumor marker. Blood samples (plasma) were collected for CA19-9 evaluations.
Time frame: up to the end of Cycle 10 (up to Week 44)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PEGPH20 1.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 1, Week 8, Visit 1 | 0.0 Units per milliliter (U/ml) | — |
| PEGPH20 1.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 1, Week 4, Visit 1 | 12897.5 Units per milliliter (U/ml) | Standard Deviation 22345.65 |
| PEGPH20 1.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 2, Week 4, Visit 1 | 0.0 Units per milliliter (U/ml) | — |
| PEGPH20 1.6 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 4, Week 4, Visit 1 | 0.0 Units per milliliter (U/ml) | — |
| PEGPH20 1.6 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 1, Week 4, Visit 1 | -7833.9 Units per milliliter (U/ml) | Standard Deviation 13567.21 |
| PEGPH20 1.6 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 1, Week 8, Visit 1 | -1.9 Units per milliliter (U/ml) | Standard Deviation 2.69 |
| PEGPH20 1.6 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 2, Week 4, Visit 1 | -1.2 Units per milliliter (U/ml) | Standard Deviation 1.63 |
| PEGPH20 1.6 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 3, Week 4, Visit 1 | 0.0 Units per milliliter (U/ml) | — |
| PEGPH20 1.6 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 5, Week 4, Visit 1 | 0.0 Units per milliliter (U/ml) | — |
| PEGPH20 1.6 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 6, Week 4, Visit 1 | 0.0 Units per milliliter (U/ml) | — |
| PEGPH20 1.6 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 7, Week 4, Visit 1 | 0.0 Units per milliliter (U/ml) | — |
| PEGPH20 1.6 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 8, Week 4, Visit 1 | 0.0 Units per milliliter (U/ml) | — |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 4, Week 4, Visit 1 | -24089.1 Units per milliliter (U/ml) | Standard Deviation 54120.73 |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 10, Week 4, Visit 1 | -154937 Units per milliliter (U/ml) | — |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 5, Week 4, Visit 1 | -27214.3 Units per milliliter (U/ml) | Standard Deviation 64893.4 |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 8, Week 4, Visit 1 | -154946 Units per milliliter (U/ml) | — |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 6, Week 4, Visit 1 | -53200.6 Units per milliliter (U/ml) | Standard Deviation 88132.74 |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 1, Week 8, Visit 1 | -15464.1 Units per milliliter (U/ml) | Standard Deviation 41440.85 |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 9, Week 4, Visit 1 | -154940 Units per milliliter (U/ml) | — |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 2, Week 4, Visit 1 | -16581.0 Units per milliliter (U/ml) | Standard Deviation 50738.98 |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 7, Week 4, Visit 1 | -154964 Units per milliliter (U/ml) | — |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 3, Week 4, Visit 1 | -12628.0 Units per milliliter (U/ml) | Standard Deviation 72538.77 |
| PEGPH20 3.0 μg/kg | Change From Baseline in Carbohydrate Antigen 19-9 or Sialylated Lewis(a) Antigen (CA19-9) | Cycle 1, Week 4, Visit 1 | -11800.3 Units per milliliter (U/ml) | Standard Deviation 38780.49 |
Secondary
Cmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks
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.
Time frame: Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given)
Population: Intent-to-Treat Population: all enrolled participants. Only those participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PEGPH20 1.0 μg/kg | Cmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 1.08 units per milliliter | Standard Deviation 0.0878 |
| PEGPH20 1.6 μg/kg | Cmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 2.40 units per milliliter | Standard Deviation 0.542 |
| PEGPH20 3.0 μg/kg | Cmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 3.98 units per milliliter | Standard Deviation 1.16 |
Secondary
Cmin Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks
Blood samples were collected for pharmacokinetic assessment. The 24-hour sample collected at the first visit was optional.
Time frame: Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PEGPH20 1.0 μg/kg | Cmin Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 0.572 Units per milliliter | Standard Deviation 0.0781 |
| PEGPH20 1.6 μg/kg | Cmin Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 0.976 Units per milliliter | Standard Deviation 0.568 |
| PEGPH20 3.0 μg/kg | Cmin Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 1.52 Units per milliliter | Standard Deviation 0.767 |
Secondary
Disease Control Rate
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.
Time frame: up to approximately 2 years 4 months
Population: Intent-to-Treat Population. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PEGPH20 1.0 μg/kg | Disease Control Rate | 1 Participants |
| PEGPH20 1.6 μg/kg | Disease Control Rate | 4 Participants |
| PEGPH20 3.0 μg/kg | Disease Control Rate | 14 Participants |
95% CI: [1, 81]
95% CI: [40, 100]
95% CI: [46, 88]
Secondary
H-scores, as an Assessment of HA Staining Changes in Tumor Biopsies
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.
Time frame: Screening; Cycle 1 Week 7
Population: Intent-to-Treat Population. Only 1 participant had a screening and post-treatment specimen that qualified for staining. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PEGPH20 3.0 μg/kg | H-scores, as an Assessment of HA Staining Changes in Tumor Biopsies | Screening pericellular tumor H-score | 40 score on a scale |
| PEGPH20 3.0 μg/kg | H-scores, as an Assessment of HA Staining Changes in Tumor Biopsies | Screening stromal H-score | 260 score on a scale |
| PEGPH20 3.0 μg/kg | H-scores, as an Assessment of HA Staining Changes in Tumor Biopsies | Post-treatment pericellular tumor H-score | 15 score on a scale |
| PEGPH20 3.0 μg/kg | H-scores, as an Assessment of HA Staining Changes in Tumor Biopsies | Post-treatment stromal tumor H-score | 150 score on a scale |
Secondary
Last Measurable Observed Plasma Concentration (Cmin) Following Single PEGPH20 Doses
Blood samples were collected for pharmacokinetic assessment.
Time frame: Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PEGPH20 1.0 μg/kg | Last Measurable Observed Plasma Concentration (Cmin) Following Single PEGPH20 Doses | 0.626 units per milliliter | Standard Deviation 0.0607 |
| PEGPH20 1.6 μg/kg | Last Measurable Observed Plasma Concentration (Cmin) Following Single PEGPH20 Doses | 0.651 units per milliliter | Standard Deviation 0.155 |
| PEGPH20 3.0 μg/kg | Last Measurable Observed Plasma Concentration (Cmin) Following Single PEGPH20 Doses | 0.864 units per milliliter | Standard Deviation 0.375 |
Secondary
Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites
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.
Time frame: Baseline; 24 hours hours; end of Cycle 1 (Week 7)
Population: ITT Population. DCE-MRI scans were performed for 6 participants. Only participants with data available were analyzed. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 1, Baseline | 0.162 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 1, 24 hours | 0.327 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 1, End of Cycle 1 | NA milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 2, Baseline | 0.671 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 2, 24 hours | 0.386 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 2, End of Cycle 1 | NA milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 3, Baseline | 0.481 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 3, 24 hours | 0.389 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 3, End of Cycle 1 | NA milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 4, Baseline | 0.458 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 4, 24 hours | 0.788 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 4, End of Cycle 1 | 0.751 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 5, Baseline | 0.380 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 5, 24 hours | 0.395 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 5, End of Cycle 1 | 0.550 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 6, Baseline | 0.355 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 6, 24 hours | 0.825 milliliters |
| PEGPH20 1.0 μg/kg | Mean Extravascular-Extracellular Volume Fraction (Ve) for Scans Across Tissue Sites | Participant 6, End of Cycle 1 | 0.425 milliliters |
Secondary
Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites
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.
Time frame: Baseline; 24 hours hours; end of Cycle 1 (Week 7)
Population: ITT Population. DCE-MRI scans were performed for 6 participants. Only participants with data available were analyzed. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 1, Baseline | 0.124 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 1, 24 hours | 0.383 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 1, End of Cycle 1 | NA milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 2, Baseline | 0.430 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 2, 24 hours | 0.468 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 2, End of Cycle 1 | NA milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 3, Baseline | 0.402 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 3, 24 hours | 0.331 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 3, End of Cycle 1 | NA milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 4, Baseline | 0.564 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 4, 24 hours | 0.672 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 4, End of Cycle 1 | 0.646 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 5, Baseline | 0.135 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 5, 24 hours | 0.197 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 5, End of Cycle 1 | 0.133 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 6, Baseline | 0.249 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 6, 24 hours | 0.376 milliliters (mL) per minute per 100 mL |
| PEGPH20 1.0 μg/kg | Mean Volume Transfer Constant (Ktrans) for Scans Across Tissue Sites | Participant 6, End of Cycle 1 | 0.078 milliliters (mL) per minute per 100 mL |
Secondary
Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1
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.)
Time frame: up to approximately 2 years 4 months
Population: Intent-to-Treat Population. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PEGPH20 1.0 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | PD | 3 Participants |
| PEGPH20 1.0 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | SD | 1 Participants |
| PEGPH20 1.0 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | CR | 0 Participants |
| PEGPH20 1.0 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | PR | 0 Participants |
| PEGPH20 1.0 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | Unknown | 0 Participants |
| PEGPH20 1.6 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | SD | 2 Participants |
| PEGPH20 1.6 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | CR | 0 Participants |
| PEGPH20 1.6 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | PR | 2 Participants |
| PEGPH20 1.6 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | PD | 0 Participants |
| PEGPH20 1.6 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | Unknown | 0 Participants |
| PEGPH20 3.0 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | Unknown | 6 Participants |
| PEGPH20 3.0 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | PD | 0 Participants |
| PEGPH20 3.0 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | CR | 0 Participants |
| PEGPH20 3.0 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | SD | 6 Participants |
| PEGPH20 3.0 μg/kg | Number of Participants With the Indicated Best Response, Per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 | PR | 8 Participants |
Secondary
Objective Response Rate
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.
Time frame: up to approximately 2 years 4 months
Population: Intent-to-Treat Population. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PEGPH20 1.0 μg/kg | Objective Response Rate | 0 Participants |
| PEGPH20 1.6 μg/kg | Objective Response Rate | 2 Participants |
| PEGPH20 3.0 μg/kg | Objective Response Rate | 8 Participants |
95% CI: [0, 60]
95% CI: [7, 93]
95% CI: [19, 64]
Secondary
Observed Maximum Plasma Concentration (Cmax) Following Single PEGPH20 Doses
Cmax is defined as the observed maximum plasma concentration after the first dose. Blood samples were collected for pharmacokinetic assessment.
Time frame: Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given)
Population: Intent-to-Treat Population: all enrolled participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PEGPH20 1.0 μg/kg | Observed Maximum Plasma Concentration (Cmax) Following Single PEGPH20 Doses | 0.604 units per milliliter | Standard Deviation 0.438 |
| PEGPH20 1.6 μg/kg | Observed Maximum Plasma Concentration (Cmax) Following Single PEGPH20 Doses | 1.54 units per milliliter | Standard Deviation 0.491 |
| PEGPH20 3.0 μg/kg | Observed Maximum Plasma Concentration (Cmax) Following Single PEGPH20 Doses | 3.18 units per milliliter | Standard Deviation 1.28 |
Secondary
Overall Survival
Overall survival was defined as the time from the time of the first dose of PEGPH20 until death.
Time frame: from the time of the first dose of PEGPH20 until death (up to approximately 2 years 4 months)
Population: Intent-to-Treat Population. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PEGPH20 1.0 μg/kg | Overall Survival | 109.5 days |
| PEGPH20 1.6 μg/kg | Overall Survival | 199.5 days |
| PEGPH20 3.0 μg/kg | Overall Survival | 220.0 days |
Secondary
Percent Change in in the Maximum Standardized Uptake Value (SUVmax), as an Assessment of Total Lesion Metabolic Activity
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.
Time frame: Baseline; up to 32 weeks for each individual participant (end of Cycle 7)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PEGPH20 1.0 μg/kg | Percent Change in in the Maximum Standardized Uptake Value (SUVmax), as an Assessment of Total Lesion Metabolic Activity | Cycle 1 | -36.7 percent change | Standard Deviation 19.2 |
| PEGPH20 1.0 μg/kg | Percent Change in in the Maximum Standardized Uptake Value (SUVmax), as an Assessment of Total Lesion Metabolic Activity | Cycle 3 | -43.2 percent change | Standard Deviation 12.4 |
| PEGPH20 1.0 μg/kg | Percent Change in in the Maximum Standardized Uptake Value (SUVmax), as an Assessment of Total Lesion Metabolic Activity | Cycle 5 | -39.3 percent change | Standard Deviation 20.6 |
| PEGPH20 1.0 μg/kg | Percent Change in in the Maximum Standardized Uptake Value (SUVmax), as an Assessment of Total Lesion Metabolic Activity | Cycle 7 | -41.2 percent change | Standard Deviation 61 |
Secondary
Plasma Hyaluronan (HA) Concentration at Baseline and After PEGPH20 Administration
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.
Time frame: Baseline; post-Baseline (average treatment duration of 94.6 days)
Population: Intent-to-Treat Population. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PEGPH20 1.0 μg/kg | Plasma Hyaluronan (HA) Concentration at Baseline and After PEGPH20 Administration | Baseline | 123.7 nanograms per milliliter | Standard Deviation 137.6 |
| PEGPH20 1.0 μg/kg | Plasma Hyaluronan (HA) Concentration at Baseline and After PEGPH20 Administration | After PEGPH20 administration | 7288 nanograms per milliliter | Standard Deviation 10027 |
| PEGPH20 1.6 μg/kg | Plasma Hyaluronan (HA) Concentration at Baseline and After PEGPH20 Administration | Baseline | 982.3 nanograms per milliliter | Standard Deviation 1370 |
| PEGPH20 1.6 μg/kg | Plasma Hyaluronan (HA) Concentration at Baseline and After PEGPH20 Administration | After PEGPH20 administration | 27818 nanograms per milliliter | Standard Deviation 25866 |
| PEGPH20 3.0 μg/kg | Plasma Hyaluronan (HA) Concentration at Baseline and After PEGPH20 Administration | Baseline | 164.7 nanograms per milliliter | Standard Deviation 139.6 |
| PEGPH20 3.0 μg/kg | Plasma Hyaluronan (HA) Concentration at Baseline and After PEGPH20 Administration | After PEGPH20 administration | 128411 nanograms per milliliter | Standard Deviation 126357 |
Secondary
Progression-free Survival (PFS)
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.
Time frame: from the first dose of PEGH20 until objective tumor progression or death (up to approximately 2 years 4 months)
Population: Intent-to-Treat Population. This study was to consist of a Phase 1b and a randomized Phase 2 study. However, the randomized Phase 2 study was not conducted due to a change to the standard-of-care chemotherapy treatment to be used in combination with PEGPH20.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PEGPH20 1.0 μg/kg | Progression-free Survival (PFS) | 47.0 days |
| PEGPH20 1.6 μg/kg | Progression-free Survival (PFS) | 276.0 days |
| PEGPH20 3.0 μg/kg | Progression-free Survival (PFS) | 113.0 days |
Secondary
t1/2 Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks
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.
Time frame: Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PEGPH20 1.0 μg/kg | t1/2 Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 5.60 hours | Standard Deviation 3.08 |
| PEGPH20 1.6 μg/kg | t1/2 Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 19.5 hours | Standard Deviation 7.75 |
| PEGPH20 3.0 μg/kg | t1/2 Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 10.7 hours | Standard Deviation 4.06 |
Secondary
Time to Reach Cmax (Tmax) Following Single PEGPH20 Doses
Blood samples were collected for pharmacokinetic assessment.
Time frame: Cycle 1, Week 1, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PEGPH20 1.0 μg/kg | Time to Reach Cmax (Tmax) Following Single PEGPH20 Doses | 0.250 hours |
| PEGPH20 1.6 μg/kg | Time to Reach Cmax (Tmax) Following Single PEGPH20 Doses | 0.250 hours |
| PEGPH20 3.0 μg/kg | Time to Reach Cmax (Tmax) Following Single PEGPH20 Doses | 0.420 hours |
Secondary
Tmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks
Blood samples were collected for pharmacokinetic assessment. The 24-hour sample collected at the first visit was optional.
Time frame: Cycle 1, Week 4, Day 1: First visit: predose; 15 minutes, 1, 2, 4, and 24 hours post-PEGPH20 dosing; all other visits: pre-PEGPH20 dose, 1 to 2 hours post-PEGPH20 dose, and immediately after the dose of gemcitabine (on the days gemcitabine was given)
Population: Intent-to-Treat Population. Only those participants with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PEGPH20 1.0 μg/kg | Tmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 0.330 hours |
| PEGPH20 1.6 μg/kg | Tmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 0.325 hours |
| PEGPH20 3.0 μg/kg | Tmax Following Twice-weekly PEGPH20 Doses for 3 Consecutive Weeks | 0.420 hours |