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

Study Overview
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Brief Summary
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This study is designed to compare the treatment effect of PEGPH20 combined with nab-paclitaxel (NAB) and gemcitabine (GEM) [PAG] to NAB and GEM [AG] in participants with Stage IV previously untreated pancreatic ductal adenocarcinoma (PDA). The study will have 2 run-in phases, one for each formulation of PEGPH20 (original and new formulations), and a Phase 2 portion. The 2 run-in phases will evaluate the safety and tolerability of the PAG treatment using the original and new succinic acid PEGPH20 formulation, respectively, compared with AG treatment. Phase 2 will have 2 stages due to a partial clinical hold that occurred from April through July 2014. The participants will be randomized in 3:1 for the run-in phases. The first stage will randomize participants in a 1:1 ratio. The second stage will randomize participants in a 2:1 ratio (PAG:AG). This is an open-label study. To minimize bias to the progression-free survival endpoint, disease progression will be based on the assessment of the Central Imaging Reader (CIR). Determination of clinical progression by the Investigator without corresponding CIR confirmation will be documented with the relevant signs and symptoms.

Official Title
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A Phase 2, Randomized, Multicenter Study of PEGPH20 (PEGylated Recombinant Human Hyaluronidase) Combined With Nab-Paclitaxel Plus Gemcitabine Compared With Nab-Paclitaxel Plus Gemcitabine in Subjects With Stage IV Previously Untreated Pancreatic Cancer

Conditions
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Metastatic Pancreatic Cancer

Intervention / Treatment
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* Drug: PEGPH20
* Drug: Nab-paclitaxel
* Drug: Gemcitabine
* Drug: Dexamethasone
* Drug: Enoxaparin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed Informed consent. Histologically confirmed Stage IV PDA with documented disseminated neoplasm to liver and /or lung. Must have archival or fresh tissue (block /slides) available pre-dose. One or more metastatic tumors measurable on computed tomography (CT) scan per RECIST v.1.1 , excluding the primary pancreatic lesion. No previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease. Karnofsky Performance Status greater than or equal to (≥) 70%. Life expectancy ≥3 months. Age ≥18 years. Screening laboratory values of hemoglobin, platelets, absolute neutrophil count (ANC), bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine, serum albumin, prothrombin time/international normalized ratio (INR), and partial thromboplastin time (PTT) within specified values/criteria per protocol prior to dosing. Key Exclusion Criteria: Non-metastatic PDA. Evidence of deep vein thrombosis (DVT), pulmonary embolism (PE), or other known thromboembolic event present during screening period. Known central nervous system involvement or brain metastasis. New York (NY) Heart Association Class III or IV cardiac disease or myocardial infarction within the past 12 months. Prior history of cerebrovascular accident or transient ischemic attack. Pre-existing carotid artery disease. Active, uncontrolled bacterial, viral, or fungal infection requiring systemic therapy. Current use of megestrol acetate (use within 10 days of Day 1). Known infection with human immunodeficiency virus, Hepatitis B, or Hepatitis C. History of another primary cancer within the last 3 years with the exception of non-melanoma skin cancer, early state prostate cancer, or curatively-treated cervical cancer in-situ. Contraindication to heparin as per National Comprehensive Cancer Network (NCCN) guidelines. Previous major bleed (bleeding requiring transfusion of red blood cells) on low-molecular weight heparin (LMWH). Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that leads to reasonable suspicion of disease or condition that contraindicates the use of an investigational drug, that may affect interpretation of results, or render the participant at a high risk of treatment complications.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS: time from randomization until first occurrence of disease progression, either by central radiologic determination (Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) or by clinical progression determined by Investigator, or death during treatment period from any cause. Radiological disease progression was defined as at least a 20 percent (%) increase in sum of diameters of target lesions, taking as reference the smallest sum on study thus far, nadir (this included baseline sum if that was the smallest on study); Sum must also demonstrate an absolute increase of at least 5 millimeters (mm); Appearance of one or more new lesions; Unequivocal progression of existing non-target lesions. Surviving participants without disease progression were censored for PFS analysis at the date of last evaluable post-baseline tumor assessment. Surviving participants without any post-baseline disease assessment were censored on Day 1. PFS was estimated using Kaplan-Meier (KM) method. | From the date of randomization until disease progression or death from any cause (maximum exposure: 30.72 months for PAG, and 20.27 months for AG) | 
| Percentage of Participants in the PAG Arm Who Experienced Any Thromboembolic (TE) Event in Stage 2 of the Study | TE events were identified by applying the Medical Dictionary for Regulatory Activities (MedDRA) Standardized MedDRA Queries (SMQ) search strategy for 3 SMQs: TE arterial, TE venous, and TE vessel type unspecified and mixed arterial and venous. TE events were considered by the Sponsor to be adverse events (AEs) of special interest. All TE events, regardless of type of event, severity, or seriousness were reported. Participants with multiple events were counted only once. A summary of serious and all other non-serious adverse events regardless of causality is located in the 'Reported AE section'. | From first exposure to any study drug (PEGPH20, NAB, GEM) through 30 days after end of treatment visit (maximum exposure: 30.72 months for PAG) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS in Relation to Tumor Hyaluronan (HA) Levels | PFS was defined as time from randomization until first occurrence of disease progression, either by central radiologic determination (RECIST version 1.1) or by clinical progression determined by Investigator, or death during treatment period from any cause. Disease progression was defined as at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study thus far, nadir (this included baseline sum if that was the smallest on study); Sum must also demonstrate an absolute increase of at least 5 mm; Appearance of one or more new lesions; Unequivocal progression of existing non-target lesions. Surviving participants without disease progression were censored for PFS analysis at the date of last evaluable post-baseline tumor assessment. Surviving participants without any post-baseline disease assessment were censored on Day 1. PFS was estimated using KM method. PFS was measured in HA-high and HA-low participants. | From the date of randomization until disease progression or death from any cause (maximum exposure: 30.72 months for PAG, and 20.27 months for AG) | 
| Objective Response Rate (ORR): Percentage of Participants With Objective Response | ORR was defined as percentage of participants who achieved either a complete response (CR) or partial response (PR) regardless of confirmation, as assessed by RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions; Any pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From the date of randomization until last date on study treatment (maximum exposure: 30.72 months for PAG, and 20.27 months for AG) | 
| Overall Survival | Overall survival was defined as the time from randomization until death from any cause. Participants who died or were lost to follow-up by the date of analysis data cutoff were censored at their last contact date. | From randomization until death from any cause (maximum exposure: 30.72 months for PAG, and 20.27 months for AG) | 
| Percentage of Participants With AEs | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | From first exposure to any study drug (PEGPH20, NAB, GEM) through 30 days after end of treatment visit (maximum exposure: 30.72 months for PAG and 20.27 months for AG) | 
| Maximum Observed Plasma Concentration (Cmax) of PEGPH20 | Samples were analyzed for PEGPH20 concentration using a validated electrochemiluminescence immunoassay. Plasma samples to assess the potential effects of NAB+GEM on PEGH20 pharmacokinetic (PK) were collected in the PAG treatment group in the run-in phases (Run-in Phase 1: Original PEGPH20 formulation [3.5 mg/mL], and Run-in Phase 2: New PEGPH20 formulation [0.3 mg/mL]). | Pre-PEGPH20 dosing and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing on Days 1 and 15 of Cycle 1 | 
| Time to Reach Cmax (Tmax) of PEGPH20 | Samples were analyzed for PEGPH20 concentration using a validated electrochemiluminescence immunoassay. Plasma samples to assess the potential effects of NAB+GEM on PEGH20 PK were collected in the PAG treatment group in the run-in phases (Run-in Phase 1: Original PEGPH20 formulation [3.5 mg/mL], and Run-in Phase 2: New PEGPH20 formulation [0.3 mg/mL]). | Pre-PEGPH20 dosing and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing on Days 1 and 15 of Cycle 1 | 
| Area Under the Concentration-Time Curve From Time 0 to Last Quantifiable Concentration (AUC0-last) of PEGPH20 | Samples were analyzed for PEGPH20 concentration using a validated electrochemiluminescence immunoassay. Plasma samples to assess the potential effects of NAB+GEM on PEGH20 PK were collected in the PAG treatment group in the run-in phases (Run-in Phase 1: Original PEGPH20 formulation [3.5 mg/mL], and Run-in Phase 2: New PEGPH20 formulation [0.3 mg/mL]). | Pre-PEGPH20 dosing and 15 minutes, 1 hour, 2 hours, and 4 hours post-PEGPH20 dosing on Days 1 and 15 of Cycle 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pancreatic ductal carcinoma(PDA), Pancreatic ductal carcinoma, PEGPH20, Gemcitabine, Nab-paclitaxel