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

Sponsor

Halozyme Therapeutics (Industry)

Overall Status

Terminated

CT.gov ID

NCT03267940

Collaborator

(none)

Enrollment

Locations

Arms

25.3

Actual Duration (Months)

2.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Cholangiocarcinoma Non-resectable Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Extrahepatic Gallbladder Adenocarcinoma	Drug: PEGPH20 Drug: CIS Drug: GEM Drug: Atezolizumab	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

85 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 2, 2017

Actual Primary Completion Date :

Nov 11, 2019

Actual Study Completion Date :

Nov 11, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Run-in Portion: PEGCISGEM 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 PEGPH20 will be administered as per the schedule specified in the respective arms. Drug: CIS CIS will be administered as per the schedule specified in the respective arms. Drug: GEM GEM will be administered as per the schedule specified in the respective arms.
Experimental: Run-in Portion: PEGCISGEMATEZO 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 PEGPH20 will be administered as per the schedule specified in the respective arms. Drug: CIS CIS will be administered as per the schedule specified in the respective arms. Drug: GEM GEM will be administered as per the schedule specified in the respective arms. Drug: Atezolizumab Atezolizumab will be administered as per the schedule specified in the respective arms.
Experimental: Expansion Portion: PEGCISGEM 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 PEGPH20 will be administered as per the schedule specified in the respective arms. Drug: CIS CIS will be administered as per the schedule specified in the respective arms. Drug: GEM GEM will be administered as per the schedule specified in the respective arms.
Experimental: Expansion Portion: PEGCISGEMATEZO Twice Weekly 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 PEGPH20 will be administered as per the schedule specified in the respective arms. Drug: CIS CIS will be administered as per the schedule specified in the respective arms. Drug: GEM GEM will be administered as per the schedule specified in the respective arms. Drug: Atezolizumab Atezolizumab will be administered as per the schedule specified in the respective arms.
Experimental: Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly 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 PEGPH20 will be administered as per the schedule specified in the respective arms. Drug: CIS CIS will be administered as per the schedule specified in the respective arms. Drug: GEM GEM will be administered as per the schedule specified in the respective arms. Drug: Atezolizumab Atezolizumab will be administered as per the schedule specified in the respective arms.
Active Comparator: Expansion Portion: CISGEM 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 CIS will be administered as per the schedule specified in the respective arms. Drug: GEM GEM will be administered as per the schedule specified in the respective arms.

Outcome Measures

Primary Outcome Measures

Run-in Portion: Number of Participants With Adverse Events (AEs) [From first exposure to study drug through 30 days after the end of treatment visit (maximum exposure: 508 days)]
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) [From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)]
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 [From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)]
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 [From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)]
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 [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)]
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 [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)]
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 [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)]
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 [From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days)]
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) [From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days)]
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) [From randomization until death from any cause (maximum exposure: 421 days)]
Overall survival was defined as the time from randomization until death from any cause.
Expansion Portion: OS by PD-L1 Expression Levels [From randomization until death from any cause (maximum exposure: 421 days)]
Overall survival was defined as the time from randomization until death from any cause.
Expansion Portion: Number of Participants With AEs [From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)]
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) [From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)]
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 [From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)]
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'.
Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication [From first exposure to study drug through 30 days after the end of treatment visit (maximum exposure: 421 days)]
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'.
Run-in and Expansion Portion : Maximum Observed Plasma Concentration (Cmax) of PEGPH20, ATEZO, GEM, and CIS [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]
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 [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)]
PK data were planned to be analyzed using a noncompartmental analysis approach.
Run-in and Expansion Portion : Elimination Rate Constant (Kel) of PEGPH20 [Cycle 1: multiple timepoints on Days 1, 2, 8, 9, and 15]
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 [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]
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 [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]
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 [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]
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 [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]
PK data were planned to be analyzed using a noncompartmental analysis approach.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic of Arizona	Phoenix	Arizona	United States	85054
2	University of Arizona	Tucson	Arizona	United States	85724
3	City of Hope	Duarte	California	United States	91010
4	Scripps	La Jolla	California	United States	92037
5	USC/Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
6	University of California Irvine Division of Hematology-Oncology, Department of Medicine UC Irvine Health	Orange	California	United States	92868
7	UC Davis	Sacramento	California	United States	95817
8	UCLA - David Geffen School of Medicine	Santa Monica	California	United States	90404
9	The Oncology Institute of Hope and Innovation	Whittier	California	United States	90603
10	Yale Cancer Center	New Haven	Connecticut	United States	06511
11	Lombardi Cancer Center, Georgetown University	Washington	District of Columbia	United States	20007
12	Johns Hopkins	Baltimore	Maryland	United States	21287
13	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
14	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
15	Mount Sinai	New York	New York	United States	10029
16	University of Rochester Medical Center	Rochester	New York	United States	14642
17	Duke Cancer Institute	Durham	North Carolina	United States	27710
18	Gabrail Cancer Center	Canton	Ohio	United States	44718
19	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania	United States	15232
20	Medical University of South Carolina	Charleston	South Carolina	United States	29425
21	MD Anderson Cancer Center	Houston	Texas	United States	77030
22	UT Health Cancer Center	San Antonio	Texas	United States	78229
23	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
24	Virginia Mason	Seattle	Washington	United States	98101
25	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
26	Froedtert Hospital And Medical College	Milwaukee	Wisconsin	United States	53226
27	Samsung Medical Center	Seoul	Gangnam-gu	Korea, Republic of	06351
28	Korea University Guro Hospital	Seoul	Guro-gu	Korea, Republic of	08308
29	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do	Korea, Republic of	13620
30	Seoul National University Hospital	Seoul	Jongno-gu	Korea, Republic of	03080
31	The Catholic University of Korea Seoul St. Mary's Hospital	Seoul	Seocho-gu	Korea, Republic of	06591
32	Severance Hospital, Yonsei University Health System	Seoul	Seodaemun-Gu	Korea, Republic of	03722
33	Asan Medical Center	Seoul	Songpa-gu	Korea, Republic of	05505
34	Maharaj Nakorn Chiang Mai Hospital	Chiang mai	Muang	Thailand	50200
35	King Chulalongkorn Memorial Hospital	Bangkok	Patumwan	Thailand	10330
36	Prince of Songkla University	Hat Yai	Songkla	Thailand	90110

Sponsors and Collaborators

Halozyme Therapeutics

Investigators

Study Director: VP, Medical, Regulatory and Drug Safety, Halozyme Therapeutics

Study Documents (Full-Text)

Study Protocol - Apr 9, 2019

More Information

Publications

None provided.

Responsible Party:

Halozyme Therapeutics

ClinicalTrials.gov Identifier:

NCT03267940

Other Study ID Numbers:

Halo-110-101

First Posted:

Aug 31, 2017

Last Update Posted:

Feb 7, 2020

Last Verified:

Jan 1, 2020

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Halozyme Therapeutics

Extrahepatic Cholangiocarcinoma

Intrahepatic Cholangiocarcinoma

Gallbladder Adenocarcinoma

PEGylated Recombinant Human Hyaluronidase

PEGylated Recombinant Human Hyaluronidase with atezolizumab

Additional relevant MeSH terms:

Adenocarcinoma

Cholangiocarcinoma

Atezolizumab

Study Results

Participant Flow

Recruitment Details	The study was conducted in 2 portions: Run-in portion and Expansion portion.
Pre-assignment Detail	The study was terminated prematurely by the Sponsor due to stopping the clinical development of PEGPH20 in all indications based on negative pivotal data in metastatic pancreatic cancer.

Arm/Group Title	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/Group Description	Participants received 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 cisplatin (CIS) plus 1000 mg/m^2 of gemcitabine (GEM) administered on Days 2 and 9 of each 21-day cycle by intravenous (IV) infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 1200 mg atezolizumab (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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Period Title: Run-in Portion (Max. Exposure: 508 Days)
STARTED	9	9	0	0	0	0
Received at Least 1 Dose of Study Drug	9	9	0	0	0	0
COMPLETED	1	2	0	0	0	0
NOT COMPLETED	8	7	0	0	0	0
Period Title: Run-in Portion (Max. Exposure: 508 Days)
STARTED	0	0	24	22	11	10
Received at Least 1 Dose of Study Drug	0	0	24	22	11	10
COMPLETED	0	0	3	0	1	0
NOT COMPLETED	0	0	21	22	10	10

Baseline Characteristics

Arm/Group Title	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	Total
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).	Total of all reporting groups
Overall Participants	9	9	24	22	11	10	85
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	7 77.8%	3 33.3%	15 62.5%	10 45.5%	4 36.4%	6 60%	45 52.9%
>=65 years	2 22.2%	6 66.7%	9 37.5%	12 54.5%	7 63.6%	4 40%	40 47.1%
Sex: Female, Male (Count of Participants)
Female	6 66.7%	2 22.2%	13 54.2%	8 36.4%	6 54.5%	8 80%	43 50.6%
Male	3 33.3%	7 77.8%	11 45.8%	14 63.6%	5 45.5%	2 20%	42 49.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	1 4.5%	0 0%	1 10%	2 2.4%
Not Hispanic or Latino	9 100%	8 88.9%	24 100%	21 95.5%	11 100%	8 80%	81 95.3%
Unknown or Not Reported	0 0%	1 11.1%	0 0%	0 0%	0 0%	1 10%	2 2.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	4 44.4%	4 44.4%	9 37.5%	7 31.8%	3 27.3%	4 40%	31 36.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 11.1%	0 0%	0 0%	0 0%	0 0%	1 1.2%
White	5 55.6%	4 44.4%	14 58.3%	14 63.6%	7 63.6%	6 60%	50 58.8%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 4.2%	1 4.5%	1 9.1%	0 0%	3 3.5%

Outcome Measures

1. Primary Outcome

Title	Run-in Portion: Number of Participants With Adverse Events (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. 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'.
Time Frame	From first exposure to study drug through 30 days after the end of treatment visit (maximum exposure: 508 days)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received any study medication.

Arm/Group Title	Run-in Portion: PEGCISGEM	Run-in Portion: PEGCISGEMATEZO
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)
Measure Participants	9	9
Count of Participants [Participants]	9 100%	9 100%

2. Primary Outcome

Title	Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters (Hematology and Blood Chemistry)
Description	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'.
Time Frame	From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received any study medication.

Arm/Group Title	Run-in Portion: PEGCISGEM	Run-in Portion: PEGCISGEMATEZO
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)
Measure Participants	9	9
Count of Participants [Participants]	0 0%	0 0%

3. Primary Outcome

Title	Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) and Vital Signs
Description	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'.
Time Frame	From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Run-in Portion: PEGCISGEM	Run-in Portion: PEGCISGEMATEZO
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)
Measure Participants	0	0

4. Primary Outcome

Title	Run-in Portion: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication
Description	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'.
Time Frame	From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received any study medication.

Arm/Group Title	Run-in Portion: PEGCISGEM	Run-in Portion: PEGCISGEMATEZO
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)
Measure Participants	9	9
Count of Participants [Participants]	6 66.7%	7 77.8%

5. Primary Outcome

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	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.
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)

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Portion: PEGCISGEM	Expansion Portion: PEGCISGEMATEZO Twice Weekly	Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly	Expansion Portion: CISGEM
Arm/Group Description	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not Collected due to early termination of study.

Arm/Group Title	Run-in Portion: PEGCISGEM	Run-in Portion: PEGCISGEMATEZO
Arm/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)
Measure Participants	0	0

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Portion: PEGCISGEM	Expansion Portion: PEGCISGEMATEZO Twice Weekly	Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly	Expansion Portion: CISGEM
Arm/Group Description	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0

8. Secondary Outcome

Title	Expansion Portion: Progression-Free Survival (PFS) Based on RECIST v1.1
Description	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.
Time Frame	From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days)

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Portion: PEGCISGEM	Expansion Portion: PEGCISGEMATEZO Twice Weekly	Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly	Expansion Portion: CISGEM
Arm/Group Description	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0

9. Secondary Outcome

Title	Expansion Portion: Disease Control Rate (DCR) Based on RECIST v1.1: Percentage of Participants With CR, PR or Stable Disease (SD)
Description	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.
Time Frame	From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days)

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Portion: PEGCISGEM	Expansion Portion: PEGCISGEMATEZO Twice Weekly	Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly	Expansion Portion: CISGEM
Arm/Group Description	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0

10. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description
This data was not collected as an endpoint but all deaths due to any cause are reported in the AE module.

Arm/Group Title	Expansion Portion: PEGCISGEM	Expansion Portion: PEGCISGEMATEZO Twice Weekly	Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly	Expansion Portion: CISGEM
Arm/Group Description	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0

11. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description
This data was not collected as an endpoint but all deaths due to any cause are reported in the AE module.

Arm/Group Title	Expansion Portion: PEGCISGEM	Expansion Portion: PEGCISGEMATEZO Twice Weekly	Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly	Expansion Portion: CISGEM
Arm/Group Description	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0

12. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received any study medication.

Arm/Group Title	Expansion Portion: PEGCISGEM	Expansion Portion: PEGCISGEMATEZO Twice Weekly	Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly	Expansion Portion: CISGEM
Arm/Group Description	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	24	22	11	10
Count of Participants [Participants]	24 266.7%	22 244.4%	10 41.7%	10 45.5%

13. Secondary Outcome

Title	Expansion Portion: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters (Hematology and Blood Chemistry)
Description	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'.
Time Frame	From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received any study medication.

Arm/Group Title	Expansion Portion: PEGCISGEM	Expansion Portion: PEGCISGEMATEZO Twice Weekly	Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly	Expansion Portion: CISGEM
Arm/Group Description	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	24	22	11	10
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

14. Secondary Outcome

Title	Expansion Portion: Number of Participants With Clinically Significant Abnormalities in ECG and Vital Signs
Description	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'.
Time Frame	From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	Expansion Portion: PEGCISGEM	Expansion Portion: PEGCISGEMATEZO Twice Weekly	Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly	Expansion Portion: CISGEM
Arm/Group Description	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0

15. Secondary Outcome

Title	Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication
Description	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'.
Time Frame	From first exposure to study drug through 30 days after the end of treatment visit (maximum exposure: 421 days)

Outcome Measure Data

Analysis Population Description
Safety population included all participants who received any study medication.

Arm/Group Title	Expansion Portion: PEGCISGEM	Expansion Portion: PEGCISGEMATEZO Twice Weekly	Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly	Expansion Portion: CISGEM
Arm/Group Description	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	24	22	11	10
Count of Participants [Participants]	16 177.8%	21 233.3%	4 16.7%	7 31.8%

16. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	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/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0	0	0

17. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	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/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0	0	0

18. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	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/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0	0	0

19. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	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/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0	0	0

20. Secondary Outcome

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	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

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	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/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0	0	0

21. Secondary Outcome

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	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

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	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/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0	0	0

22. Secondary Outcome

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	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

Outcome Measure Data

Analysis Population Description
Data for this outcome measure was not collected due to early termination of study.

Arm/Group Title	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/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).	Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).	Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
Measure Participants	0	0	0	0	0	0

Adverse Events

	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
Time Frame	From first exposure to study drug through 30 days after end of treatment visit (maximum exposure: 508 days for run-in portion and 421 days for expansion portion)
Adverse Event Reporting Description	Safety population included all participants who received any study medication.

Arm/Group Title	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/Group Description	Participants received 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m^2 of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 190 days)		Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity. (Maximum exposure: 508 days)		Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 421 days).		Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 416 days).		Participants received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 59 days).		Participants received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (Maximum exposure: 218 days).
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/9 (77.8%)		3/9 (33.3%)		10/24 (41.7%)		13/22 (59.1%)		0/11 (0%)		6/10 (60%)
Serious Adverse Events
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/9 (66.7%)		2/9 (22.2%)		11/24 (45.8%)		16/22 (72.7%)		7/11 (63.6%)		4/10 (40%)
Blood and lymphatic system disorders
Anaemia	0/9 (0%)		2/9 (22.2%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Febrile neutropenia	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Leukopenia	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Neutropenia	0/9 (0%)		1/9 (11.1%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Thrombocytopenia	1/9 (11.1%)		2/9 (22.2%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Cardiac disorders
Cardiac failure congestive	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Palpitations	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Gastrointestinal disorders
Abdominal pain	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Ascites	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Autoimmune colitis	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Diarrhoea	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Ileus	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Large intestinal haemorrhage	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Large intestinal obstruction	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Melaena	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Nausea	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Upper gastrointestinal haemorrhage	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Vomiting	2/9 (22.2%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		1/10 (10%)
General disorders
Asthenia	0/9 (0%)		0/9 (0%)		0/24 (0%)		3/22 (13.6%)		0/11 (0%)		0/10 (0%)
Chills	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		1/11 (9.1%)		0/10 (0%)
Oedema peripheral	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Pyrexia	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		5/22 (22.7%)		2/11 (18.2%)		1/10 (10%)
Hepatobiliary disorders
Bile duct obstruction	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Cholangitis	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		4/22 (18.2%)		0/11 (0%)		0/10 (0%)
Cholecystitis	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Hyperbilirubinaemia	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Portal hypertension	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Immune system disorders
Systemic immune activation	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Infections and infestations
Bacteraemia	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Biliary tract infection	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Cellulitis	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Cholangitis infective	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Pneumonia	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		1/11 (9.1%)		0/10 (0%)
Sepsis	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Septic shock	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Injury, poisoning and procedural complications
Clavicle fracture	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Infusion related reaction	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		1/11 (9.1%)		0/10 (0%)
Subdural haematoma	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Transfusion reaction	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Investigations
Blood bilirubin increased	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		2/11 (18.2%)		0/10 (0%)
Platelet count decreased	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Metabolism and nutrition disorders
Dehydration	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Failure to thrive	0/9 (0%)		1/9 (11.1%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Hypokalaemia	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Hyponatraemia	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Musculoskeletal and connective tissue disorders
Muscular weakness	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Myalgia	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Nervous system disorders
Dizziness	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Haemorrhage intracranial	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Renal and urinary disorders
Renal failure	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Renal vein thrombosis	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Reproductive system and breast disorders
Ovarian necrosis	0/6 (0%)		0/2 (0%)		1/13 (7.7%)		0/8 (0%)		0/6 (0%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Haemoptysis	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Pleural effusion	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Pulmonary embolism	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Rash	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Vascular disorders
Embolism	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Hypotension	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		9/9 (100%)		24/24 (100%)		22/22 (100%)		10/11 (90.9%)		10/10 (100%)
Blood and lymphatic system disorders
Anaemia	4/9 (44.4%)		6/9 (66.7%)		12/24 (50%)		15/22 (68.2%)		3/11 (27.3%)		8/10 (80%)
Haemorrhagic anaemia	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Leukocytosis	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Leukopenia	2/9 (22.2%)		1/9 (11.1%)		2/24 (8.3%)		3/22 (13.6%)		0/11 (0%)		1/10 (10%)
Lymphopenia	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Neutropenia	2/9 (22.2%)		2/9 (22.2%)		5/24 (20.8%)		5/22 (22.7%)		0/11 (0%)		1/10 (10%)
Pancytopenia	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Thrombocytopenia	4/9 (44.4%)		2/9 (22.2%)		2/24 (8.3%)		5/22 (22.7%)		0/11 (0%)		1/10 (10%)
Thrombocytosis	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Cardiac disorders
Atrial fibrillation	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Palpitations	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Sinus tachycardia	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Supraventricular tachycardia	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Tachycardia	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Ear and labyrinth disorders
Cerumen impaction	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Ear discomfort	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Ear pain	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Eustachian tube dysfunction	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Hypoacusis	1/9 (11.1%)		1/9 (11.1%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Tinnitus	1/9 (11.1%)		1/9 (11.1%)		1/24 (4.2%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Vertigo	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Endocrine disorders
Hyperthyroidism	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Eye disorders
Eye discharge	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Eye swelling	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Photopsia	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Vision blurred	0/9 (0%)		1/9 (11.1%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Visual impairment	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		1/10 (10%)
Gastrointestinal disorders
Abdominal distension	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		3/22 (13.6%)		0/11 (0%)		0/10 (0%)
Abdominal pain	2/9 (22.2%)		2/9 (22.2%)		10/24 (41.7%)		5/22 (22.7%)		2/11 (18.2%)		2/10 (20%)
Abdominal pain lower	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Abdominal pain upper	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Abdominal tenderness	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Ascites	2/9 (22.2%)		0/9 (0%)		1/24 (4.2%)		2/22 (9.1%)		0/11 (0%)		1/10 (10%)
Constipation	4/9 (44.4%)		4/9 (44.4%)		10/24 (41.7%)		8/22 (36.4%)		3/11 (27.3%)		5/10 (50%)
Dental caries	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Diarrhoea	1/9 (11.1%)		2/9 (22.2%)		9/24 (37.5%)		9/22 (40.9%)		1/11 (9.1%)		1/10 (10%)
Dry mouth	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		1/11 (9.1%)		0/10 (0%)
Duodenal obstruction	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Dyspepsia	1/9 (11.1%)		2/9 (22.2%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		2/10 (20%)
Dysphagia	0/9 (0%)		0/9 (0%)		3/24 (12.5%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Enteritis	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Eructation	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Flatulence	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Gastrooesophageal reflux disease	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Glossodynia	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Inguinal hernia	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Nausea	5/9 (55.6%)		4/9 (44.4%)		18/24 (75%)		11/22 (50%)		3/11 (27.3%)		9/10 (90%)
Salivary hypersecretion	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Sensitivity of teeth	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Stomatitis	0/9 (0%)		1/9 (11.1%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		2/10 (20%)
Vomiting	3/9 (33.3%)		3/9 (33.3%)		12/24 (50%)		7/22 (31.8%)		1/11 (9.1%)		5/10 (50%)
Oral pain	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
General disorders
Asthenia	2/9 (22.2%)		1/9 (11.1%)		2/24 (8.3%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Catheter site inflammation	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Catheter site pain	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Chest discomfort	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		1/11 (9.1%)		0/10 (0%)
Chest pain	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Chills	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		4/22 (18.2%)		0/11 (0%)		1/10 (10%)
Fatigue	5/9 (55.6%)		8/9 (88.9%)		15/24 (62.5%)		13/22 (59.1%)		2/11 (18.2%)		6/10 (60%)
Feeling cold	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Generalised oedema	0/9 (0%)		0/9 (0%)		0/24 (0%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Influenza like illness	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Injection site bruising	0/9 (0%)		2/9 (22.2%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Injection site pain	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Localised oedema	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Non-cardiac chest pain	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Oedema peripheral	3/9 (33.3%)		5/9 (55.6%)		10/24 (41.7%)		10/22 (45.5%)		3/11 (27.3%)		3/10 (30%)
Peripheral swelling	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Pyrexia	1/9 (11.1%)		1/9 (11.1%)		6/24 (25%)		11/22 (50%)		3/11 (27.3%)		5/10 (50%)
Vessel puncture site bruise	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Hepatobiliary disorders
Cholangitis	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Jaundice	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Portal vein thrombosis	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Immune system disorders
Hypersensitivity	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Infections and infestations
Acute sinusitis	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Bacteraemia	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Catheter site cellulitis	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Cystitis	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Epididymitis	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Folliculitis	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Infected dermal cyst	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Influenza	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Lung infection	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Nasopharyngitis	0/9 (0%)		0/9 (0%)		0/24 (0%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Oesophageal candidiasis	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Pharyngitis	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Rhinitis	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Candida infection	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Sinusitis	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Upper respiratory tract infection	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Urinary tract infection	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		4/22 (18.2%)		0/11 (0%)		0/10 (0%)
Injury, poisoning and procedural complications
Animal bite	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Contusion	0/9 (0%)		1/9 (11.1%)		3/24 (12.5%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Fall	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Febrile nonhaemolytic transfusion reaction	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Infusion related reaction	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		1/11 (9.1%)		0/10 (0%)
Mouth injury	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Nail injury	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Procedural pain	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Skin abrasion	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Investigations
Alanine aminotransferase increased	1/9 (11.1%)		2/9 (22.2%)		4/24 (16.7%)		6/22 (27.3%)		2/11 (18.2%)		1/10 (10%)
Aspartate aminotransferase increased	4/9 (44.4%)		2/9 (22.2%)		6/24 (25%)		8/22 (36.4%)		3/11 (27.3%)		2/10 (20%)
Blood albumin decreased	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Blood alkaline phosphatase increased	2/9 (22.2%)		0/9 (0%)		1/24 (4.2%)		3/22 (13.6%)		1/11 (9.1%)		1/10 (10%)
Blood bilirubin increased	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		4/22 (18.2%)		2/11 (18.2%)		1/10 (10%)
Blood creatinine increased	1/9 (11.1%)		1/9 (11.1%)		0/24 (0%)		3/22 (13.6%)		0/11 (0%)		0/10 (0%)
Blood fibrinogen decreased	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Blood magnesium decreased	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Blood phosphorus decreased	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Blood pressure increased	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Blood sodium increased	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Creatinine renal clearance decreased	0/9 (0%)		1/9 (11.1%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Glomerular filtration rate decreased	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Granulocyte count decreased	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Grip strength decreased	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Haematocrit decreased	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Hepatic enzyme increased	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Liver function test increased	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Lymphocyte count decreased	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		2/11 (18.2%)		0/10 (0%)
Monocyte count increased	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Neutrophil count decreased	0/9 (0%)		4/9 (44.4%)		7/24 (29.2%)		8/22 (36.4%)		2/11 (18.2%)		2/10 (20%)
Platelet count decreased	1/9 (11.1%)		3/9 (33.3%)		5/24 (20.8%)		8/22 (36.4%)		2/11 (18.2%)		5/10 (50%)
Red blood cell count decreased	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Transaminases increased	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Troponin I increased	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Weight decreased	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		4/22 (18.2%)		0/11 (0%)		0/10 (0%)
Weight increased	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
White blood cell count decreased	0/9 (0%)		0/9 (0%)		5/24 (20.8%)		9/22 (40.9%)		2/11 (18.2%)		1/10 (10%)
White blood cell count increased	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Metabolism and nutrition disorders
Decreased appetite	4/9 (44.4%)		4/9 (44.4%)		6/24 (25%)		5/22 (22.7%)		1/11 (9.1%)		4/10 (40%)
Dehydration	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Failure to thrive	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Gout	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Hypercalcaemia	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		1/10 (10%)
Hyperglycaemia	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Hyperkalaemia	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		2/22 (9.1%)		0/11 (0%)		1/10 (10%)
Hypermagnesaemia	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Hyperuricaemia	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Hypoalbuminaemia	1/9 (11.1%)		1/9 (11.1%)		1/24 (4.2%)		2/22 (9.1%)		2/11 (18.2%)		1/10 (10%)
Hypocalcaemia	0/9 (0%)		1/9 (11.1%)		1/24 (4.2%)		1/22 (4.5%)		1/11 (9.1%)		0/10 (0%)
Hypokalaemia	0/9 (0%)		0/9 (0%)		3/24 (12.5%)		2/22 (9.1%)		1/11 (9.1%)		3/10 (30%)
Hypomagnesaemia	0/9 (0%)		2/9 (22.2%)		9/24 (37.5%)		7/22 (31.8%)		2/11 (18.2%)		1/10 (10%)
Hyponatraemia	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		2/22 (9.1%)		2/11 (18.2%)		2/10 (20%)
Hypophosphataemia	0/9 (0%)		1/9 (11.1%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/9 (11.1%)		1/9 (11.1%)		5/24 (20.8%)		5/22 (22.7%)		2/11 (18.2%)		1/10 (10%)
Arthritis	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Back pain	0/9 (0%)		2/9 (22.2%)		2/24 (8.3%)		1/22 (4.5%)		1/11 (9.1%)		3/10 (30%)
Bone pain	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Bursitis	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Extremity contracture	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Flank pain	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		1/10 (10%)
Muscle spasms	3/9 (33.3%)		2/9 (22.2%)		11/24 (45.8%)		8/22 (36.4%)		2/11 (18.2%)		2/10 (20%)
Muscular weakness	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		1/11 (9.1%)		0/10 (0%)
Musculoskeletal chest pain	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Musculoskeletal pain	1/9 (11.1%)		1/9 (11.1%)		2/24 (8.3%)		0/22 (0%)		1/11 (9.1%)		1/10 (10%)
Myalgia	3/9 (33.3%)		3/9 (33.3%)		8/24 (33.3%)		7/22 (31.8%)		2/11 (18.2%)		2/10 (20%)
Neck pain	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		2/10 (20%)
Pain in extremity	1/9 (11.1%)		2/9 (22.2%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		2/10 (20%)
Periarthritis	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Trismus	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Pain in jaw	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm of skin	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Seborrhoeic keratosis	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Nervous system disorders
Balance disorder	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Dizziness	0/9 (0%)		3/9 (33.3%)		3/24 (12.5%)		5/22 (22.7%)		1/11 (9.1%)		0/10 (0%)
Dysarthria	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Dysgeusia	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		2/22 (9.1%)		1/11 (9.1%)		0/10 (0%)
Encephalopathy	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Facial paralysis	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Headache	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		3/22 (13.6%)		2/11 (18.2%)		1/10 (10%)
Lethargy	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Migraine	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Neuropathy peripheral	1/9 (11.1%)		1/9 (11.1%)		2/24 (8.3%)		4/22 (18.2%)		0/11 (0%)		0/10 (0%)
Paraesthesia	1/9 (11.1%)		1/9 (11.1%)		2/24 (8.3%)		2/22 (9.1%)		0/11 (0%)		1/10 (10%)
Peripheral sensory neuropathy	1/9 (11.1%)		1/9 (11.1%)		5/24 (20.8%)		1/22 (4.5%)		0/11 (0%)		1/10 (10%)
Polyneuropathy	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Restless legs syndrome	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Tremor	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		2/11 (18.2%)		0/10 (0%)
Psychiatric disorders
Anxiety	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		2/22 (9.1%)		0/11 (0%)		1/10 (10%)
Confusional state	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Delirium	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Depression	1/9 (11.1%)		0/9 (0%)		4/24 (16.7%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Emotional distress	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Insomnia	1/9 (11.1%)		3/9 (33.3%)		5/24 (20.8%)		7/22 (31.8%)		0/11 (0%)		2/10 (20%)
Panic attack	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Renal and urinary disorders
Acute kidney injury	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Dysuria	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Pollakiuria	0/9 (0%)		0/9 (0%)		0/24 (0%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Proteinuria	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Renal impairment	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Reproductive system and breast disorders
Breast pain	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Gynaecomastia	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Vulvovaginal pruritus	0/6 (0%)		0/2 (0%)		1/13 (7.7%)		0/8 (0%)		0/6 (0%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/9 (0%)		1/9 (11.1%)		6/24 (25%)		4/22 (18.2%)		1/11 (9.1%)		0/10 (0%)
Dysphonia	0/9 (0%)		0/9 (0%)		4/24 (16.7%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Dyspnoea	2/9 (22.2%)		2/9 (22.2%)		4/24 (16.7%)		3/22 (13.6%)		1/11 (9.1%)		3/10 (30%)
Dyspnoea exertional	1/9 (11.1%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Epistaxis	0/9 (0%)		0/9 (0%)		0/24 (0%)		2/22 (9.1%)		1/11 (9.1%)		1/10 (10%)
Hiccups	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Hypoxia	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		1/10 (10%)
Increased upper airway secretion	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Nasal congestion	0/9 (0%)		0/9 (0%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Nasal dryness	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Oropharyngeal pain	0/9 (0%)		1/9 (11.1%)		1/24 (4.2%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Pleural effusion	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Rhinorrhoea	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		2/10 (20%)
Throat irritation	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Upper-airway cough syndrome	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Acne	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Alopecia	0/9 (0%)		1/9 (11.1%)		1/24 (4.2%)		3/22 (13.6%)		0/11 (0%)		0/10 (0%)
Dermatitis acneiform	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Erythema	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Erythema multiforme	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Hyperhidrosis	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Night sweats	1/9 (11.1%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Pain of skin	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Prurit	0/9 (0%)		2/9 (22.2%)		1/24 (4.2%)		3/22 (13.6%)		1/11 (9.1%)		1/10 (10%)
Rash	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		2/22 (9.1%)		1/11 (9.1%)		2/10 (20%)
Rash macular	0/9 (0%)		0/9 (0%)		0/24 (0%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Rash maculo-papular	0/9 (0%)		0/9 (0%)		2/24 (8.3%)		1/22 (4.5%)		0/11 (0%)		1/10 (10%)
Rash pruritic	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		0/10 (0%)
Skin hyperpigmentation	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Urticaria	0/9 (0%)		1/9 (11.1%)		0/24 (0%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Vascular disorders
Embolism	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		1/10 (10%)
Flushing	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		0/10 (0%)
Haematoma	0/9 (0%)		0/9 (0%)		0/24 (0%)		1/22 (4.5%)		0/11 (0%)		0/10 (0%)
Hot flush	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		1/11 (9.1%)		2/10 (20%)
Hypertension	0/9 (0%)		1/9 (11.1%)		1/24 (4.2%)		0/22 (0%)		0/11 (0%)		1/10 (10%)
Hypotension	1/9 (11.1%)		1/9 (11.1%)		3/24 (12.5%)		2/22 (9.1%)		0/11 (0%)		0/10 (0%)
Thrombophlebitis superficial	0/9 (0%)		0/9 (0%)		0/24 (0%)		0/22 (0%)		0/11 (0%)		1/10 (10%)

Limitations/Caveats

The study was terminated prematurely by the Sponsor due to stopping the clinical development of PEGPH20 in all indications based on negative pivotal data in metastatic pancreatic cancer.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Results Point of Contact

Name/Title	VP, Medical, Regulatory and Drug Safety
Organization	Halozyme Therapeutics
Phone	858-794-8889
Email	medinfo@halozyme.com

Responsible Party:

Halozyme Therapeutics

ClinicalTrials.gov Identifier:

NCT03267940

Other Study ID Numbers:

Halo-110-101

First Posted:

Aug 31, 2017

Last Update Posted:

Feb 7, 2020

Last Verified:

Jan 1, 2020

Study Details

Study Description

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Detailed Description

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

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Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

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Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

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Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

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Results Point of Contact