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

Study Overview
=================
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.

Official Title
-----------------
A Phase 1b/2 Multicenter, International, Randomized, Double Blind, Placebo-Controlled, Study of Gemcitabine Combined With PEGPH20 Compared to Gemcitabine Combined With Placebo in Patients With Stage IV Previously Untreated Pancreatic Cancer

Conditions
-----------------
Stage IV Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: Gemcitabine
* Drug: PEGPH20
* Drug: Placebo


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Gemcitabine<br>Gemcitabine + Placebo | Drug: Gemcitabine<br>* 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)<br>* Other names: Gemzar;Drug: Placebo<br>* (Cycle 1: 7 weeks on treatment/1 week off treatment; Cycle 2+: 3 Weeks on treatment/1 week off treatment).<br>* Other names: Saline;|
| Experimental: PEGPH20<br>PEGPH20+Gemcitabine | Drug: Gemcitabine<br>* 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)<br>* Other names: Gemzar;Drug: PEGPH20<br>* (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<br>* Other names: PEGylated Recombinant Human Hyaluronidase;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | first 4 weeks of Cycle 1 | 
| 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. | first 4 weeks of Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 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. | 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) | 
| Last Measurable Observed Plasma Concentration (Cmin) Following Single PEGPH20 Doses | Blood samples were collected for pharmacokinetic assessment. | 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) | 
| 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. | 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) | 
| Time to Reach Cmax (Tmax) Following Single PEGPH20 Doses | Blood samples were collected for pharmacokinetic assessment. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | Baseline; post-Baseline (average treatment duration of 94.6 days) | 
| 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. | Screening; Cycle 1 Week 7 | 
| 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. | Baseline; up to 32 weeks for each individual participant (end of Cycle 7) | 
| 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. | Baseline; 24 hours hours; end of Cycle 1 (Week 7) | 
| 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. | Baseline; 24 hours hours; end of Cycle 1 (Week 7) | 
| 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.) | up to approximately 2 years 4 months | 
| 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. | up to approximately 2 years 4 months | 
| 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. | up to approximately 2 years 4 months | 
| 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. | from the first dose of PEGH20 until objective tumor progression or death (up to approximately 2 years 4 months) | 
| Overall Survival | Overall survival was defined as the time from the time of the first dose of PEGPH20 until death. | from the time of the first dose of PEGPH20 until death (up to approximately 2 years 4 months) | 
| 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. | up to the end of Cycle 10 (up to Week 44) | 
| 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. | up to the end of Cycle 10 (up to Week 44) | 
| 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. | up to the end of Cycle 10 (up to Week 44) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pancreatic, Cancer, Stage IV, untreated