Cholangiocarcinoma Non-resectable, Cholangiocarcinoma, Intrahepatic, Cholangiocarcinoma, Extrahepatic, Gallbladder Adenocarcinoma
Conditions
Keywords
Extrahepatic Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Gallbladder Adenocarcinoma, PEGylated Recombinant Human Hyaluronidase, PEGylated Recombinant Human Hyaluronidase with atezolizumab
Brief summary
The study is being conducted to assess the safety and tolerability of (1) PEGPH20 in combination with CIS and GEM (PEGCISGEM), and (2) PEGPH20 in combination with CIS, GEM, and atezolizumab (PEGCISGEMATEZO) compared with (3) cisplatin and gemcitabine (CISGEM).
Detailed description
The study will have a Run-in portion and an Expansion portion. The Run-in portion will be used to evaluate the safety profile of the PEGCISGEM and PEGCISGEMATEZO treatments prior to evaluating the efficacy and safety of PEGCISGEM and PEGCISGEMATEZO treatments compared with CISGEM treatment in the Expansion portion of the study. Treatment in both portions of the study will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity.
Interventions
DRUGPEGPH20
PEGPH20 will be administered as per the schedule specified in the respective arms.
DRUGCIS
CIS will be administered as per the schedule specified in the respective arms.
DRUGGEM
GEM will be administered as per the schedule specified in the respective arms.
DRUGAtezolizumab
Atezolizumab will be administered as per the schedule specified in the respective arms.
Sponsors
Halozyme Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
| 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. |
| 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. |
Countries
South Korea, Thailand, United States
Participant flow
Recruitment details
The study was conducted in 2 portions: Run-in portion and Expansion portion.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Run-in Portion: PEGCISGEM 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) | 9 |
| Run-in Portion: PEGCISGEMATEZO 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) | 9 |
| Expansion Portion: PEGCISGEM 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). | 24 |
| Expansion Portion: PEGCISGEMATEZO Twice Weekly 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). | 22 |
| Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly 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). | 11 |
| Expansion Portion: CISGEM 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). | 10 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Expansion (Maximum Exposure: 421 Days) | Death | 0 | 0 | 10 | 13 | 0 | 6 |
| Expansion (Maximum Exposure: 421 Days) | Investigator or Sponsor Decision | 0 | 0 | 2 | 1 | 2 | 0 |
| Expansion (Maximum Exposure: 421 Days) | Other than specified | 0 | 0 | 0 | 3 | 2 | 0 |
| Expansion (Maximum Exposure: 421 Days) | Sponsor Terminated Study | 0 | 0 | 7 | 4 | 5 | 3 |
| Expansion (Maximum Exposure: 421 Days) | Withdrawal by Subject | 0 | 0 | 2 | 1 | 1 | 1 |
| Run-in Portion (Max. Exposure: 508 Days) | Death | 7 | 3 | 0 | 0 | 0 | 0 |
| Run-in Portion (Max. Exposure: 508 Days) | Investigator or Sponsor Decision | 1 | 2 | 0 | 0 | 0 | 0 |
| Run-in Portion (Max. Exposure: 508 Days) | Sponsor Terminated Study | 0 | 1 | 0 | 0 | 0 | 0 |
| Run-in Portion (Max. Exposure: 508 Days) | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 6 Participants | 9 Participants | 12 Participants | 7 Participants | 4 Participants | 40 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 3 Participants | 15 Participants | 10 Participants | 4 Participants | 6 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 8 Participants | 24 Participants | 21 Participants | 11 Participants | 8 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 4 Participants | 9 Participants | 7 Participants | 3 Participants | 4 Participants | 31 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 5 Participants | 4 Participants | 14 Participants | 14 Participants | 7 Participants | 6 Participants | 50 Participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 13 Participants | 8 Participants | 6 Participants | 8 Participants | 43 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 11 Participants | 14 Participants | 5 Participants | 2 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 9 | 3 / 9 | 10 / 24 | 13 / 22 | 0 / 11 | 6 / 10 |
| other Total, other adverse events | 9 / 9 | 9 / 9 | 24 / 24 | 22 / 22 | 10 / 11 | 10 / 10 |
| serious Total, serious adverse events | 6 / 9 | 2 / 9 | 11 / 24 | 16 / 22 | 7 / 11 | 4 / 10 |
Outcome results
Primary
Expansion Portion: Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: Percentage of Participants With Objective Response
ORR was defined as percentage of participants who achieved either a complete response (CR) or partial response (PR). CR was defined as disappearance of all target and non-target lesions; Any pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
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)
Population: Data for this outcome measure was not collected due to early termination of study.
Primary
Run-in Portion: Number of Participants With Adverse Events (AEs)
An AE is any unfavorable or unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product (for example, study drug), whether or not considered related to the pharmaceutical product. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: From first exposure to study drug through 30 days after the end of treatment visit (maximum exposure: 508 days)
Population: Safety population included all participants who received any study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Run-in Portion: PEGCISGEM | Run-in Portion: Number of Participants With Adverse Events (AEs) | 9 Participants |
| Run-in Portion: PEGCISGEMATEZO | Run-in Portion: Number of Participants With Adverse Events (AEs) | 9 Participants |
Primary
Run-in Portion: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication
Number of participants with AEs leading to dose reduction or interruption of any study medication (PEGPH20, CIS, GEM, or ATEZO) was reported. An AE is any unfavorable or unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product (for example, study drug), whether or not considered related to the pharmaceutical product. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)
Population: Safety population included all participants who received any study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Run-in Portion: PEGCISGEM | Run-in Portion: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication | 6 Participants |
| Run-in Portion: PEGCISGEMATEZO | Run-in Portion: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication | 7 Participants |
Primary
Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) and Vital Signs
Clinical significance of ECGs was defined as per Investigator's discretion. Assessment of vital signs was to include the measurement of blood pressure (systolic and diastolic), pulse, respiratory rate, and body temperature. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)
Population: Data for this outcome measure was not collected due to early termination of study.
Primary
Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters (Hematology and Blood Chemistry)
Laboratory parameters evaluation included hematology (hemoglobin, hematocrit, red blood cell count, white blood cell \[WBC\] count, neutrophils \[ANC\], lymphocytes, monocytes, eosinophils, basophils, granulocytes, mean corpuscular hemoglobin, mean corpuscular volume, and platelet count) and blood chemistry (glucose, blood urea nitrogen \[BUN\], albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], electrolytes \[including sodium, potassium, calcium, magnesium, chloride, and bicarbonate\], and creatinine) evaluation. Clinical significance was defined as per Investigator's discretion. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)
Population: Safety population included all participants who received any study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Run-in Portion: PEGCISGEM | Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters (Hematology and Blood Chemistry) | 0 Participants |
| Run-in Portion: PEGCISGEMATEZO | Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters (Hematology and Blood Chemistry) | 0 Participants |
Secondary
Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication
Number of participants with AEs leading to dose reduction or interruption of any study medication (PEGPH20, CIS, GEM, or ATEZO) was reported. An AE is any unfavorable or unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product (for example, study drug), whether or not considered related to the pharmaceutical product. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: From first exposure to study drug through 30 days after the end of treatment visit (maximum exposure: 421 days)
Population: Safety population included all participants who received any study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Run-in Portion: PEGCISGEM | Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication | 16 Participants |
| Run-in Portion: PEGCISGEMATEZO | Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication | 21 Participants |
| Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly | Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication | 4 Participants |
| Expansion Portion: CISGEM | Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication | 7 Participants |
Secondary
Expansion Portion: Disease Control Rate (DCR) Based on RECIST v1.1: Percentage of Participants With CR, PR or Stable Disease (SD)
DCR was defined as the percentage of participants with CR, PR, or SD based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review. CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.
Time frame: From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days)
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Expansion Portion: Duration of Response (DOR) Based on RECIST v1.1
DOR was considered the time from date of the first CR or PR until the date of first documentation of disease progression or date of death based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review. CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.
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)
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Expansion Portion: Number of Participants With AEs
An AE is any unfavorable or unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product (for example, study drug), whether or not considered related to the pharmaceutical product. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)
Population: Safety population included all participants who received any study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Run-in Portion: PEGCISGEM | Expansion Portion: Number of Participants With AEs | 24 Participants |
| Run-in Portion: PEGCISGEMATEZO | Expansion Portion: Number of Participants With AEs | 22 Participants |
| Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly | Expansion Portion: Number of Participants With AEs | 10 Participants |
| Expansion Portion: CISGEM | Expansion Portion: Number of Participants With AEs | 10 Participants |
Secondary
Expansion Portion: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters (Hematology and Blood Chemistry)
Laboratory parameters evaluation included hematology (hemoglobin, hematocrit, red blood cell count, WBC count, neutrophils \[ANC\], lymphocytes, monocytes, eosinophils, basophils, granulocytes, mean corpuscular hemoglobin, mean corpuscular volume, and platelet count) and blood chemistry (glucose, BUN, albumin, total bilirubin, alkaline phosphatase, AST, ALT, electrolytes \[including sodium, potassium, calcium, magnesium, chloride, and bicarbonate\], and creatinine) evaluation. Clinical significance was defined as per Investigator's discretion. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)
Population: Safety population included all participants who received any study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Run-in Portion: PEGCISGEM | Expansion Portion: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters (Hematology and Blood Chemistry) | 0 Participants |
| Run-in Portion: PEGCISGEMATEZO | Expansion Portion: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters (Hematology and Blood Chemistry) | 0 Participants |
| Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly | Expansion Portion: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters (Hematology and Blood Chemistry) | 0 Participants |
| Expansion Portion: CISGEM | Expansion Portion: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters (Hematology and Blood Chemistry) | 0 Participants |
Secondary
Expansion Portion: Number of Participants With Clinically Significant Abnormalities in ECG and Vital Signs
Clinical significance of ECGs was defined as per Investigator's discretion. Assessment of vital signs was to include the measurement of blood pressure (systolic and diastolic), pulse, respiratory rate, and body temperature. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Expansion Portion: OS by PD-L1 Expression Levels
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)
Population: This data was not collected as an endpoint but all deaths due to any cause are reported in the AE module.
Secondary
Expansion Portion: Overall Survival (OS)
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)
Population: This data was not collected as an endpoint but all deaths due to any cause are reported in the AE module.
Secondary
Expansion Portion: Progression-Free Survival (PFS) Based on RECIST v1.1
PFS was based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review and was defined as the time from randomization to radiological disease progression or death. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on or prior to the current assessment (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of greater than or equal to (≥) 5 mm.
Time frame: From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days)
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Run-in and Expansion Portion: Area Under the Concentration Time Curve (AUC) of PEGPH20, ATEZO, GEM, and CIS
PK data were planned to be analyzed using a noncompartmental analysis approach.
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
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Run-in and Expansion Portion : Clearance (CL) of PEGPH20, ATEZO, GEM, and CIS
PK data were planned to be analyzed using a noncompartmental analysis approach.
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
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Run-in and Expansion Portion : Elimination Rate Constant (Kel) of PEGPH20
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
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Run-in and Expansion Portion : Maximum Observed Plasma Concentration (Cmax) of PEGPH20, ATEZO, GEM, and CIS
Plasma pharmacokinetic (PK) data were planned to be analyzed using a noncompartmental analysis approach.
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
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Run-in and Expansion Portion : Minimum Observed Plasma Concentration (Cmin) of PEGPH20 and ATEZO
PK data were planned to be analyzed using a noncompartmental analysis approach.
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)
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Run-in and Expansion Portion : Terminal Elimination Plasma Half-life (t1/2) of PEGPH20, ATEZO, GEM, and CIS
PK data were planned to be analyzed using a noncompartmental analysis approach.
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
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Run-in and Expansion Portion : Volume of Distribution (Vd) of PEGPH20, ATEZO, GEM, and CIS
PK data were planned to be analyzed using a noncompartmental analysis approach.
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
Population: Data for this outcome measure was not collected due to early termination of study.
Secondary
Run-in Portion: ORR Based on RECIST v1.1: Percentage of Participants With Objective Response
ORR was defined as percentage of participants who achieved either a CR or PR. CR was defined as disappearance of all target and non-target lesions; Any pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
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)
Population: Data for this outcome measure was not Collected due to early termination of study.