Study of PEGPH20 With Cisplatin (CIS) and Gemcitabine (GEM); PEGPH20 With Atezolizumab (ATEZO), CIS, and GEM; and CIS and GEM Alone in Participants With Previously Untreated, Unresectable, Locally Advanced, or Metastatic Intrahepatic and Extrahepatic Cholangiocarcinoma and Gallbladder Adenocarcinoma

Study Overview
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Brief Summary
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The study is being conducted to assess the safety and tolerability of (1) PEGPH20 in combination with CIS and GEM (PEGCISGEM), and (2) PEGPH20 in combination with CIS, GEM, and atezolizumab (PEGCISGEMATEZO) compared with (3) cisplatin and gemcitabine (CISGEM).

Detailed Description
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The study will have a Run-in portion and an Expansion portion. The Run-in portion will be used to evaluate the safety profile of the PEGCISGEM and PEGCISGEMATEZO treatments prior to evaluating the efficacy and safety of PEGCISGEM and PEGCISGEMATEZO treatments compared with CISGEM treatment in the Expansion portion of the study. Treatment in both portions of the study will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity.

Official Title
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A Phase 1B, Randomized, Open-Label Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) in Combination With Cisplatin Plus Gemcitabine and PEGPH20 in Combination With Atezolizumab and Cisplatin Plus Gemcitabine Compared With Cisplatin Plus Gemcitabine in Subjects With Previously Untreated, Unresectable, Locally Advanced, or Metastatic Intrahepatic and Extrahepatic Cholangiocarcinoma and Gallbladder Adenocarcinoma

Conditions
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Cholangiocarcinoma Non-resectable, Cholangiocarcinoma, Intrahepatic, Cholangiocarcinoma, Extrahepatic, Gallbladder Adenocarcinoma

Intervention / Treatment
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* Drug: PEGPH20
* Drug: CIS
* Drug: GEM
* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For both portions of the study, participants must satisfy all of the following inclusion criteria to be enrolled in the study: Written Institutional Review Board/Ethics Committee-approved informed consent form (ICF), signed by participant or legally authorized representative. Participants must be determined to have histologically confirmed unresectable, locally advanced or metastatic adenocarcinoma of the intra- and/or extra-hepatic bile ducts and/or gallbladder. Participants must have sufficient tissue with architectural integrity, including tumor and associated stroma, available for retrospective biomarker testing. One or more lesions measurable on computed tomography (CT) scan/magnetic resonance imaging (MRI) scan per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). Participants having Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. Life expectancy ≥3 months. Males and females aged ≥18 years. Screening clinical laboratory values within pre-determined parameters Female participants of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 7 days before Day 1 (first dose of study medication). For WOCBP and for men, agreement to use a highly effective contraceptive method from the time of screening throughout the study until 5 months (WOCBP) or 6 months (men) after administration of the last dose of any study medication. Highly effective contraceptive methods consist of prior sterilization, intrauterine device (IUD), intrauterine hormone releasing system (IUS), oral or injectable contraceptives, barrier methods, and/or true sexual abstinence. Exclusion Criteria: Participants are ineligible for enrollment if they meet any of the following exclusion criteria: Clinical evidence of deep vein thrombosis or pulmonary embolism present during the screening period New York Heart Association Class III or IV cardiac disease, atrial fibrillation, unstable angina, or myocardial infarction within the past 12 months before screening. Participants with known brain metastases History of cerebrovascular accident or transient ischemic attack History of active bleeding within the last 3 months prior to screening requiring transfusion. Participants must have received no previous radiotherapy, surgery, chemotherapy or investigational therapy for treatment of metastatic or locally advanced disease. Intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen (HBsAg) test at screening Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at screening History of: Idiopathic pulmonary fibrosis, organizing pneumonia (for example, bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. Or known cases of hepatobiliary diseases (for example, primary biliary cholangitis, primary sclerosing cholangitis, history of immune-mediated cholangitis); Participants with cholangitis attributed to infectious etiology (for example, ascending cholangitis, bacterial cholangitis) are eligible if the infection has been fully resolved prior to the screening visit. Or known cases of drug-induced hepatobiliary toxicities. Active or history of autoimmune diseases Uncontrolled hypercalcemia

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Run-in Portion: PEGCISGEM<br>Participants will receive 3.0 micrograms per kilogram (mcg/kg) PEGPH20 on Days 1, 8, and 15 in combination with 25 milligrams per meter square (mg/m^2) of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by intravenous (IV) infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. | Drug: PEGPH20<br>* PEGPH20 will be administered as per the schedule specified in the respective arms.<br>Drug: CIS<br>* CIS will be administered as per the schedule specified in the respective arms.<br>Drug: GEM<br>* GEM will be administered as per the schedule specified in the respective arms.<br>|
| Experimental: Run-in Portion: PEGCISGEMATEZO<br>After 6 participants from the PEGCISGEM arm are treated for at least 1 cycle without significant toxicities, new participants will be enrolled in this arm to receive 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 1200 mg ATEZO (administered 1 to 3 hours after PEGPH20 on Day 1 of each 21-day cycle) plus 25 mg/m^2 of CIS and 1000 mg/m^2 GEM on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. | Drug: PEGPH20<br>* PEGPH20 will be administered as per the schedule specified in the respective arms.<br>Drug: CIS<br>* CIS will be administered as per the schedule specified in the respective arms.<br>Drug: GEM<br>* GEM will be administered as per the schedule specified in the respective arms.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arms.<br>|
| Experimental: Expansion Portion: PEGCISGEM<br>After the Investigators and the Sponsor considers the study treatment with PEGCISGEM during the Run-in portion safe and tolerable, new participants will be enrolled to receive 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 CIS and 1000 mg/m^2 GEM on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. | Drug: PEGPH20<br>* PEGPH20 will be administered as per the schedule specified in the respective arms.<br>Drug: CIS<br>* CIS will be administered as per the schedule specified in the respective arms.<br>Drug: GEM<br>* GEM will be administered as per the schedule specified in the respective arms.<br>|
| Experimental: Expansion Portion: PEGCISGEMATEZO Twice Weekly<br>After the Investigators and the Sponsor considers the study treatment with PEGCISGEM during the Run-in portion safe and tolerable, new participants will be enrolled to receive 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 1200 mg ATEZO (administered 1 to 3 hours after PEGPH20 on Day 1 of each 21-day cycle) plus 25 mg/m^2 of CIS and 1000 mg/m^2 GEM on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. | Drug: PEGPH20<br>* PEGPH20 will be administered as per the schedule specified in the respective arms.<br>Drug: CIS<br>* CIS will be administered as per the schedule specified in the respective arms.<br>Drug: GEM<br>* GEM will be administered as per the schedule specified in the respective arms.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arms.<br>|
| Experimental: Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly<br>After the implementation of Protocol Amendment #3 and as communicated to the Investigators via a letter dated 22 March 2019, participants will receive 3.0 mcg/kg PEGPH20 on Days 1, 4, 8, 11, 15 and 18 in combination with 1200 mg ATEZO (administered 1 to 3 hours after PEGPH20 on Day 1 Cycle 1) plus 25 mg/m^2 of CIS and 1000 mg/m^2 GEM on Days 2 and 9 of Cycle 1 (cycle length = 21 days) by IV infusion. Participants will receive 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 1200 mg ATEZO (administered 1 to 3 hours after PEGPH20 on Day 1 of each 21-day cycle) plus 25 mg/m^2 of CIS and 1000 mg/m^2 GEM on Days 2 and 9 of each 21-day cycle from Cycle 2 and beyond by IV infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. | Drug: PEGPH20<br>* PEGPH20 will be administered as per the schedule specified in the respective arms.<br>Drug: CIS<br>* CIS will be administered as per the schedule specified in the respective arms.<br>Drug: GEM<br>* GEM will be administered as per the schedule specified in the respective arms.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in the respective arms.<br>|
| Active Comparator: Expansion Portion: CISGEM<br>After the Investigators and the Sponsor considers the study treatment with PEGCISGEM during the run-in portion safe and tolerable, new participants will be enrolled to receive 25 mg/m^2 CIS and 1000 mg/m^2 GEM on Days 1 and 8 of each 21-day cycle by IV infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. | Drug: CIS<br>* CIS will be administered as per the schedule specified in the respective arms.<br>Drug: GEM<br>* GEM will be administered as per the 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 |
| --- | --- | --- |
| Run-in Portion: Number of Participants With Adverse Events (AEs) | An AE is any unfavorable or unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product (for example, study drug), whether or not considered related to the pharmaceutical product. 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 study drug through 30 days after the end of treatment visit (maximum exposure: 508 days) | 
| Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters (Hematology and Blood Chemistry) | Laboratory parameters evaluation included hematology (hemoglobin, hematocrit, red blood cell count, white blood cell [WBC] count, neutrophils [ANC], lymphocytes, monocytes, eosinophils, basophils, granulocytes, mean corpuscular hemoglobin, mean corpuscular volume, and platelet count) and blood chemistry (glucose, blood urea nitrogen [BUN], albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase [AST], alanine aminotransferase [ALT], electrolytes [including sodium, potassium, calcium, magnesium, chloride, and bicarbonate], and creatinine) evaluation. Clinical significance was defined as per Investigator's discretion. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days) | 
| Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) and Vital Signs | Clinical significance of ECGs was defined as per Investigator's discretion. Assessment of vital signs was to include the measurement of blood pressure (systolic and diastolic), pulse, respiratory rate, and body temperature. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days) | 
| Run-in Portion: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication | Number of participants with AEs leading to dose reduction or interruption of any study medication (PEGPH20, CIS, GEM, or ATEZO) was reported. An AE is any unfavorable or unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product (for example, study drug), whether or not considered related to the pharmaceutical product. 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 study drug through the end of treatment visit (maximum exposure: 508 days) | 
| Expansion Portion: Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: Percentage of Participants With Objective Response | ORR was defined as percentage of participants who achieved either a complete response (CR) or partial response (PR). 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 millimeters (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 date of randomization until the date of first documented progression of disease or date of death from any cause, whichever came first (maximum exposure: 421 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Run-in Portion: ORR Based on RECIST v1.1: Percentage of Participants With Objective Response | ORR was defined as percentage of participants who achieved either a CR or PR. 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 <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 date of randomization until the date of first documented progression of disease or date of death from any cause, whichever came first (maximum exposure: 508 days) | 
| Expansion Portion: Duration of Response (DOR) Based on RECIST v1.1 | DOR was considered the time from date of the first CR or PR until the date of first documentation of disease progression or date of death based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review. CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. | From date of the first CR or PR until the date of first documentation of disease progression or date of death, whichever came first (maximum exposure: 421 days) | 
| Expansion Portion: Progression-Free Survival (PFS) Based on RECIST v1.1 | PFS was based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review and was defined as the time from randomization to radiological disease progression or death. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on or prior to the current assessment (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of greater than or equal to (≥) 5 mm. | From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days) | 
| Expansion Portion: Disease Control Rate (DCR) Based on RECIST v1.1: Percentage of Participants With CR, PR or Stable Disease (SD) | DCR was defined as the percentage of participants with CR, PR, or SD based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review. CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. | From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days) | 
| Expansion Portion: Overall Survival (OS) | Overall survival was defined as the time from randomization until death from any cause. | From randomization until death from any cause (maximum exposure: 421 days) | 
| Expansion Portion: OS by PD-L1 Expression Levels | Overall survival was defined as the time from randomization until death from any cause. | From randomization until death from any cause (maximum exposure: 421 days) | 
| Expansion Portion: Number of Participants With AEs | An AE is any unfavorable or unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product (for example, study drug), whether or not considered related to the pharmaceutical product. 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 study drug through the end of treatment visit (maximum exposure: 421 days) | 
| Expansion Portion: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters (Hematology and Blood Chemistry) | Laboratory parameters evaluation included hematology (hemoglobin, hematocrit, red blood cell count, WBC count, neutrophils [ANC], lymphocytes, monocytes, eosinophils, basophils, granulocytes, mean corpuscular hemoglobin, mean corpuscular volume, and platelet count) and blood chemistry (glucose, BUN, albumin, total bilirubin, alkaline phosphatase, AST, ALT, electrolytes [including sodium, potassium, calcium, magnesium, chloride, and bicarbonate], and creatinine) evaluation. Clinical significance was defined as per Investigator's discretion. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days) | 
| Expansion Portion: Number of Participants With Clinically Significant Abnormalities in ECG and Vital Signs | Clinical significance of ECGs was defined as per Investigator's discretion. Assessment of vital signs was to include the measurement of blood pressure (systolic and diastolic), pulse, respiratory rate, and body temperature. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days) | 
| Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication | Number of participants with AEs leading to dose reduction or interruption of any study medication (PEGPH20, CIS, GEM, or ATEZO) was reported. An AE is any unfavorable or unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product (for example, study drug), whether or not considered related to the pharmaceutical product. 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 study drug through 30 days after the end of treatment visit (maximum exposure: 421 days) | 
| Run-in and Expansion Portion : Maximum Observed Plasma Concentration (Cmax) of PEGPH20, ATEZO, GEM, and CIS | Plasma pharmacokinetic (PK) data were planned to be analyzed using a noncompartmental analysis approach. | PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1, 2, 8, 9, 15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) (maximum exposure: 508 days for run-in and 421 days for expansion); CIS and GEM: Cycle 1: multiple timepoints on Days 2,9 | 
| Run-in and Expansion Portion : Minimum Observed Plasma Concentration (Cmin) of PEGPH20 and ATEZO | PK data were planned to be analyzed using a noncompartmental analysis approach. | PEGPH20 and ATEZO: Treatment Cycle 1: multiple timepoints on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent cycles and EOT visit (7 days after last 21-day cycle) (maximum exposure: 508 days for run-in portion and 421 days for expansion portion) | 
| Run-in and Expansion Portion : Elimination Rate Constant (Kel) of PEGPH20 | PK data were planned to be analyzed using a noncompartmental analysis approach. | Cycle 1: multiple timepoints on Days 1, 2, 8, 9, and 15 | 
| Run-in and Expansion Portion : Terminal Elimination Plasma Half-life (t1/2) of PEGPH20, ATEZO, GEM, and CIS | PK data were planned to be analyzed using a noncompartmental analysis approach. | PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1, 2, 8, 9, 15; ATEZO: Day 1 of subsequent cycles and EOT visit (maximum exposure: 508 days for run-in and 421 days for expansion portion); CIS and GEM: Cycle 1: multiple timepoints on Days 2, 9 | 
| Run-in and Expansion Portion : Clearance (CL) of PEGPH20, ATEZO, GEM, and CIS | PK data were planned to be analyzed using a noncompartmental analysis approach. | PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1, 2, 8, 9, 15; ATEZO: Day 1 of subsequent cycles and EOT visit (maximum exposure: 508 days for run-in and 421 days for expansion portion); CIS and GEM: Cycle 1: multiple timepoints on Days 2, 9 | 
| Run-in and Expansion Portion : Volume of Distribution (Vd) of PEGPH20, ATEZO, GEM, and CIS | PK data were planned to be analyzed using a noncompartmental analysis approach. | PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1, 2, 8, 9, 15; ATEZO: Day 1 of subsequent cycles and EOT visit (maximum exposure: 508 days for run-in and 421 days for expansion portion); CIS and GEM: Cycle 1: multiple timepoints on Days 2, 9 | 
| Run-in and Expansion Portion: Area Under the Concentration Time Curve (AUC) of PEGPH20, ATEZO, GEM, and CIS | PK data were planned to be analyzed using a noncompartmental analysis approach. | PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1, 2, 8, 9, 15; ATEZO: Day 1 of subsequent cycles and EOT visit (maximum exposure: 508 days for run-in and 421 days for expansion portion); CIS and GEM: Cycle 1: multiple timepoints on Days 2, 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extrahepatic Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Gallbladder Adenocarcinoma, PEGylated Recombinant Human Hyaluronidase, PEGylated Recombinant Human Hyaluronidase with atezolizumab