Neoplasms

All Conditions

Rare Diseases

Adenocarcinoma

Cholangiocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Bile Duct Cancer

Intrahepatic Cholangiocarcinoma

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Cisplatin

Atezolizumab

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Participants will receive 3.0 micrograms per kilogram (mcg/kg) PEGPH20 on Days 1, 8, and 15 in combination with 25 milligrams per meter square (mg/m\^2) of CIS plus 1000 mg/m\^2 of GEM administered on Days 2 and 9 of each 21-day cycle by intravenous (IV) infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity.

After 6 participants from the PEGCISGEM arm are treated for at least 1 cycle without significant toxicities, new participants will be enrolled in this arm to receive 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 1200 mg ATEZO (administered 1 to 3 hours after PEGPH20 on Day 1 of each 21-day cycle) plus 25 mg/m\^2 of CIS and 1000 mg/m\^2 GEM on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity.

After the Investigators and the Sponsor considers the study treatment with PEGCISGEM during the Run-in portion safe and tolerable, new participants will be enrolled to receive 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 25 mg/m\^2 CIS and 1000 mg/m\^2 GEM on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity.

After the Investigators and the Sponsor considers the study treatment with PEGCISGEM during the Run-in portion safe and tolerable, new participants will be enrolled to receive 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 1200 mg ATEZO (administered 1 to 3 hours after PEGPH20 on Day 1 of each 21-day cycle) plus 25 mg/m\^2 of CIS and 1000 mg/m\^2 GEM on Days 2 and 9 of each 21-day cycle by IV infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity.

After the implementation of Protocol Amendment #3 and as communicated to the Investigators via a letter dated 22 March 2019, participants will receive 3.0 mcg/kg PEGPH20 on Days 1, 4, 8, 11, 15 and 18 in combination with 1200 mg ATEZO (administered 1 to 3 hours after PEGPH20 on Day 1 Cycle 1) plus 25 mg/m\^2 of CIS and 1000 mg/m\^2 GEM on Days 2 and 9 of Cycle 1 (cycle length = 21 days) by IV infusion. Participants will receive 3.0 mcg/kg PEGPH20 on Days 1, 8, and 15 in combination with 1200 mg ATEZO (administered 1 to 3 hours after PEGPH20 on Day 1 of each 21-day cycle) plus 25 mg/m\^2 of CIS and 1000 mg/m\^2 GEM on Days 2 and 9 of each 21-day cycle from Cycle 2 and beyond by IV infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity.

After the Investigators and the Sponsor considers the study treatment with PEGCISGEM during the run-in portion safe and tolerable, new participants will be enrolled to receive 25 mg/m\^2 CIS and 1000 mg/m\^2 GEM on Days 1 and 8 of each 21-day cycle by IV infusion. Treatment will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity.

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

PEGPH20

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

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

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

VP, Medical, Regulatory and Drug Safety

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).

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 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

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

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'.

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'.

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'.

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'.

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.

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.

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.

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.

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.

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

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'.

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'.

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

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

Halozyme Therapeutics

Safety population included all participants who received any study medication.

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)

Run-in Portion: PEGCISGEM

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)

Run-in Portion: PEGCISGEMATEZO

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).

Expansion Portion: PEGCISGEM

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).

Expansion Portion: PEGCISGEMATEZO 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).

Expansion Portion: PEGCISGEMATEZO Once Weekly/Twice Weekly

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).

Expansion Portion: CISGEM

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Enrolled population included all participants enrolled in the Run-in portion and the Expansion portion of the study.

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.

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

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

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

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

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

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

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

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

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

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

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

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

Expansion Portion: Overall Survival (OS)

Expansion Portion: OS by PD-L1 Expression Levels

Expansion Portion: Number of Participants With AEs

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

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

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

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

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

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

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

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

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

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

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)

Run-in Portion (Max. Exposure: 508 Days)

Expansion (Maximum Exposure: 421 Days)

PEGylated recombinant human hyaluronidase

Joy Zhu, M.D.

Open-label, multicenter, dose-escalation, safety, pharmacodynamic, and pharmacokinetic study.

This is a study of PEGPH20 in human subjects and is designed to evaluate the safety of PEGPH20 and to determine the maximum tolerated dose of PEGPH20. All patients will receive PEGPH20. Each group of patients will receive a higher dose than the previous group. This will continue until the group with the highest planned dose completes the study or until a group has major side effects from their assigned dose.

Safety Study of PEGPH20 Given to Patients With Advanced Solid Tumors

Phase 1, Multicenter, Open-Label, Dose-Escalation, Safety, Pharmacodynamic, and Pharmacokinetic Study of PEGPH20 (PEGylated Recombinant Human Hyaluronidase) Given Intravenously to Patients With Advanced Solid Tumors

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Dexamethasone

Dexamethasone acetate

To identify the maximally tolerated dose (MTD) of PEGPH20.

PEGylated Recombinant Human Hyaluronidase

This is an open-label, multicenter, dose-escalation, safety, tolerability, pharmacokinetic and pharmacodynamic study in patients with advanced solid tumors.

A study of PEGylated recombinant human hyaluronidase (PEGPH20) administered on a twice weekly schedule for 28 days followed by a weekly dosing schedule in patients with advanced solid tumors who have either failed to respond to standard therapy or for whom no standard therapy exists.

Study of PEGPH20 With Initial Dexamethasone Premedication Given Intravenously to Patients With Advanced Solid Tumors

A Phase 1, Multicenter, Open-Label, Dose-Escalation, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of PEGPH20 With Initial Dexamethasone Premedication Given Intravenously to Patients With Advanced Solid Tumors

The PEGPH20 monotherapy MTD is the highest dose at which no more than one of six evaluable patients experience Dose-Limiting Toxicity (DLT)

All safety data will be evaluated using the NCI CTCAE scoring system (version 4.0)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT03267940	Cholangiocarcin... Cholangiocarcin... Cholangiocarcin... Gallbladder Ade...	PEGPH20 CIS GEM Atezolizumab	18 Years -	Halozyme Therapeutics
Safety Study of PEGPH20 Given to Patients With Advanced Solid Tumors	NCT00834704	Solid Tumor	PEGPH20	18 Years -	Halozyme Therapeutics
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	NCT03267940	Cholangiocarcin... Cholangiocarcin... Cholangiocarcin... Gallbladder Ade...	PEGPH20 CIS GEM Atezolizumab	18 Years -	Halozyme Therapeutics
Safety Study of PEGPH20 Given to Patients With Advanced Solid Tumors	NCT00834704	Solid Tumor	PEGPH20	18 Years -	Halozyme Therapeutics
Study of PEGPH20 With Initial Dexamethasone Premedication Given Intravenously to Patients With Advanced Solid Tumors	NCT01170897	Solid Tumor	PEGPH20	18 Years -	Halozyme Therapeutics
Safety Study of PEGPH20 Given to Patients With Advanced Solid Tumors	NCT00834704	Solid Tumor	PEGPH20	18 Years -	Halozyme Therapeutics

Spots Global Cancer Trial Database for pegylated recombinant human hyaluronidase