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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

Primary Purpose

Cholangiocarcinoma Non-resectable, Cholangiocarcinoma, Intrahepatic, Cholangiocarcinoma, Extrahepatic

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

PEGPH20

CIS

GEM

Atezolizumab

About this trial

This is an interventional treatment trial for Cholangiocarcinoma Non-resectable focused on measuring Extrahepatic Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Gallbladder Adenocarcinoma, PEGylated Recombinant Human Hyaluronidase, PEGylated Recombinant Human Hyaluronidase with atezolizumab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:
1. 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.
2. 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.
3. Or known cases of drug-induced hepatobiliary toxicities.
Active or history of autoimmune diseases
Uncontrolled hypercalcemia

Sites / Locations

Mayo Clinic of Arizona
University of Arizona
City of Hope
Scripps
USC/Norris Comprehensive Cancer Center
University of California Irvine Division of Hematology-Oncology, Department of Medicine UC Irvine Health
UC Davis
UCLA - David Geffen School of Medicine
The Oncology Institute of Hope and Innovation
Yale Cancer Center
Lombardi Cancer Center, Georgetown University
Johns Hopkins
Beth Israel Deaconess Medical Center
Washington University School of Medicine
Mount Sinai
University of Rochester Medical Center
Duke Cancer Institute
Gabrail Cancer Center
University of Pittsburgh Cancer Institute
Medical University of South Carolina
MD Anderson Cancer Center
UT Health Cancer Center
Huntsman Cancer Institute
Virginia Mason
Seattle Cancer Care Alliance
Froedtert Hospital And Medical College
Samsung Medical Center
Korea University Guro Hospital
Seoul National University Bundang Hospital
Seoul National University Hospital
The Catholic University of Korea Seoul St. Mary's Hospital
Severance Hospital, Yonsei University Health System
Asan Medical Center
Maharaj Nakorn Chiang Mai Hospital
King Chulalongkorn Memorial Hospital
Prince of Songkla University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Active Comparator

Arm Label

Run-in Portion: PEGCISGEM

Run-in Portion: PEGCISGEMATEZO

Expansion Portion: PEGCISGEM

Expansion Portion: PEGCISGEMATEZO Twice Weekly

Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly

Expansion Portion: CISGEM

Arm Description

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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'.

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'.

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'.

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'.

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.

Secondary Outcome Measures

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.

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.

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.

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.

Expansion Portion: Overall Survival (OS)

Overall survival was defined as the time from randomization until death from any cause.

Expansion Portion: OS by PD-L1 Expression Levels

Overall survival was defined as the time from randomization until death from any cause.

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'.

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'.

Expansion Portion: Number of Participants With Clinically Significant Abnormalities in ECG and Vital Signs

Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication

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.

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.

Run-in and Expansion Portion : Elimination Rate Constant (Kel) of PEGPH20

PK data were planned to be analyzed using a noncompartmental analysis approach.

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.

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.

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.

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.

Full Information

NCT ID

NCT03267940

First Posted

July 25, 2017

Last Updated

January 24, 2020

Sponsor

Halozyme Therapeutics

1. Study Identification

Unique Protocol Identification Number

NCT03267940

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2020

Overall Recruitment Status

Terminated

Why Stopped

Sponsor decision

Study Start Date

October 2, 2017 (Actual)

Primary Completion Date

November 11, 2019 (Actual)

Study Completion Date

November 11, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Halozyme Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

Extrahepatic Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Gallbladder Adenocarcinoma, PEGylated Recombinant Human Hyaluronidase, PEGylated Recombinant Human Hyaluronidase with atezolizumab

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

85 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Run-in Portion: PEGCISGEM

Arm Type

Experimental

Arm Description

Arm Title

Run-in Portion: PEGCISGEMATEZO

Arm Type

Experimental

Arm Description

Arm Title

Expansion Portion: PEGCISGEM

Arm Type

Experimental

Arm Description

Arm Title

Expansion Portion: PEGCISGEMATEZO Twice Weekly

Arm Type

Experimental

Arm Description

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.

Arm Title

Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly

Arm Type

Experimental

Arm Description

Arm Title

Expansion Portion: CISGEM

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

PEGPH20

Intervention Description

PEGPH20 will be administered as per the schedule specified in the respective arms.

Intervention Type

Drug

Intervention Name(s)

CIS

Intervention Description

CIS will be administered as per the schedule specified in the respective arms.

Intervention Type

Drug

Intervention Name(s)

GEM

Intervention Description

GEM will be administered as per the schedule specified in the respective arms.

Intervention Type

Drug

Intervention Name(s)

Atezolizumab

Intervention Description

Atezolizumab will be administered as per the schedule specified in the respective arms.

Primary Outcome Measure Information:

Title

Run-in Portion: Number of Participants With Adverse Events (AEs)

Description

Time Frame

From first exposure to study drug through 30 days after the end of treatment visit (maximum exposure: 508 days)

Title

Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters (Hematology and Blood Chemistry)

Description

Time Frame

From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)

Title

Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) and Vital Signs

Description

Time Frame

From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)

Title

Run-in Portion: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication

Description

Time Frame

From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)

Title

Expansion Portion: Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: Percentage of Participants With Objective Response

Description

Time Frame

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 Measure Information:

Title

Run-in Portion: ORR Based on RECIST v1.1: Percentage of Participants With Objective Response

Description

Time Frame

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)

Title

Expansion Portion: Duration of Response (DOR) Based on RECIST v1.1

Description

Time Frame

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)

Title

Expansion Portion: Progression-Free Survival (PFS) Based on RECIST v1.1

Description

Time Frame

From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days)

Title

Expansion Portion: Disease Control Rate (DCR) Based on RECIST v1.1: Percentage of Participants With CR, PR or Stable Disease (SD)

Description

Time Frame

From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days)

Title

Expansion Portion: Overall Survival (OS)

Description

Overall survival was defined as the time from randomization until death from any cause.

Time Frame

From randomization until death from any cause (maximum exposure: 421 days)

Title

Expansion Portion: OS by PD-L1 Expression Levels

Description

Overall survival was defined as the time from randomization until death from any cause.

Time Frame

From randomization until death from any cause (maximum exposure: 421 days)

Title

Expansion Portion: Number of Participants With AEs

Description

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'.

Time Frame

From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)

Title

Expansion Portion: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters (Hematology and Blood Chemistry)

Description

Time Frame

From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)

Title

Expansion Portion: Number of Participants With Clinically Significant Abnormalities in ECG and Vital Signs

Description

Time Frame

From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)

Title

Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication

Description

Time Frame

From first exposure to study drug through 30 days after the end of treatment visit (maximum exposure: 421 days)

Title

Run-in and Expansion Portion : Maximum Observed Plasma Concentration (Cmax) of PEGPH20, ATEZO, GEM, and CIS

Description

Plasma pharmacokinetic (PK) data were planned to be analyzed using a noncompartmental analysis approach.

Time Frame

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

Title

Run-in and Expansion Portion : Minimum Observed Plasma Concentration (Cmin) of PEGPH20 and ATEZO

Description

PK data were planned to be analyzed using a noncompartmental analysis approach.

Time Frame

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)

Title

Run-in and Expansion Portion : Elimination Rate Constant (Kel) of PEGPH20

Description

PK data were planned to be analyzed using a noncompartmental analysis approach.

Time Frame

Cycle 1: multiple timepoints on Days 1, 2, 8, 9, and 15

Title

Run-in and Expansion Portion : Terminal Elimination Plasma Half-life (t1/2) of PEGPH20, ATEZO, GEM, and CIS

Description

PK data were planned to be analyzed using a noncompartmental analysis approach.

Time Frame

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

Title

Run-in and Expansion Portion : Clearance (CL) of PEGPH20, ATEZO, GEM, and CIS

Description

PK data were planned to be analyzed using a noncompartmental analysis approach.

Time Frame

Title

Run-in and Expansion Portion : Volume of Distribution (Vd) of PEGPH20, ATEZO, GEM, and CIS

Description

PK data were planned to be analyzed using a noncompartmental analysis approach.

Time Frame

Title

Run-in and Expansion Portion: Area Under the Concentration Time Curve (AUC) of PEGPH20, ATEZO, GEM, and CIS

Description

PK data were planned to be analyzed using a noncompartmental analysis approach.

Time Frame

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

VP, Medical, Regulatory and Drug Safety

Organizational Affiliation

Halozyme Therapeutics

Official's Role

Study Director

Facility Information:

Facility Name

Mayo Clinic of Arizona

City

Phoenix

State/Province

Arizona

ZIP/Postal Code

85054

Country

United States

Facility Name

University of Arizona

City

Tucson

State/Province

Arizona

ZIP/Postal Code

85724

Country

United States

Facility Name

City of Hope

City

Duarte

State/Province

California

ZIP/Postal Code

91010

Country

United States

Facility Name

Scripps

City

La Jolla

State/Province

California

ZIP/Postal Code

92037

Country

United States

Facility Name

USC/Norris Comprehensive Cancer Center

City

Los Angeles

State/Province

California

ZIP/Postal Code

90033

Country

United States

Facility Name

University of California Irvine Division of Hematology-Oncology, Department of Medicine UC Irvine Health

City

Orange

State/Province

California

ZIP/Postal Code

92868

Country

United States

Facility Name

UC Davis

City

Sacramento

State/Province

California

ZIP/Postal Code

95817

Country

United States

Facility Name

UCLA - David Geffen School of Medicine

City

Santa Monica

State/Province

California

ZIP/Postal Code

90404

Country

United States

Facility Name

The Oncology Institute of Hope and Innovation

City

Whittier

State/Province

California

ZIP/Postal Code

90603

Country

United States

Facility Name

Yale Cancer Center

City

New Haven

State/Province

Connecticut

ZIP/Postal Code

06511

Country

United States

Facility Name

Lombardi Cancer Center, Georgetown University

City

Washington

State/Province

District of Columbia

ZIP/Postal Code

20007

Country

United States

Facility Name

Johns Hopkins

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

Facility Name

Beth Israel Deaconess Medical Center

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

Washington University School of Medicine

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Facility Name

Mount Sinai

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

Facility Name

University of Rochester Medical Center

City

Rochester

State/Province

New York

ZIP/Postal Code

14642

Country

United States

Facility Name

Duke Cancer Institute

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

Facility Name

Gabrail Cancer Center

City

Canton

State/Province

Ohio

ZIP/Postal Code

44718

Country

United States

Facility Name

University of Pittsburgh Cancer Institute

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15232

Country

United States

Facility Name

Medical University of South Carolina

City

Charleston

State/Province

South Carolina

ZIP/Postal Code

29425

Country

United States

Facility Name

MD Anderson Cancer Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

UT Health Cancer Center

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78229

Country

United States

Facility Name

Huntsman Cancer Institute

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84112

Country

United States

Facility Name

Virginia Mason

City

Seattle

State/Province

Washington

ZIP/Postal Code

98101

Country

United States

Facility Name

Seattle Cancer Care Alliance

City

Seattle

State/Province

Washington

ZIP/Postal Code

98109

Country

United States

Facility Name

Froedtert Hospital And Medical College

City

Milwaukee

State/Province

Wisconsin

ZIP/Postal Code

53226

Country

United States

Facility Name

Samsung Medical Center

City

Seoul

State/Province

Gangnam-gu

ZIP/Postal Code

06351

Country

Korea, Republic of

Facility Name

Korea University Guro Hospital

City

Seoul

State/Province

Guro-gu

ZIP/Postal Code

08308

Country

Korea, Republic of

Facility Name

Seoul National University Bundang Hospital

City

Seongnam-si

State/Province

Gyeonggi-do

ZIP/Postal Code

13620

Country

Korea, Republic of

Facility Name

Seoul National University Hospital

City

Seoul

State/Province

Jongno-gu

ZIP/Postal Code

03080

Country

Korea, Republic of

Facility Name

The Catholic University of Korea Seoul St. Mary's Hospital

City

Seoul

State/Province

Seocho-gu

ZIP/Postal Code

06591

Country

Korea, Republic of

Facility Name

Severance Hospital, Yonsei University Health System

City

Seoul

State/Province

Seodaemun-Gu

ZIP/Postal Code

03722

Country

Korea, Republic of

Facility Name

Asan Medical Center

City

Seoul

State/Province

Songpa-gu

ZIP/Postal Code

05505

Country

Korea, Republic of

Facility Name

Maharaj Nakorn Chiang Mai Hospital

City

Chiang mai

State/Province

Muang

ZIP/Postal Code

50200

Country

Thailand

Facility Name

King Chulalongkorn Memorial Hospital

City

Bangkok

State/Province

Patumwan

ZIP/Postal Code

10330

Country

Thailand

Facility Name

Prince of Songkla University

City

Hat Yai

State/Province

Songkla

ZIP/Postal Code

90110

Country

Thailand

12. IPD Sharing Statement

Plan to Share IPD

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