Clinical trial NCT03267940: Study of PEGPH20 With Cisplatin (CIS) and Gemcitabine (GEM); PEGPH20 With Atezolizumab (ATEZO), CIS, and GEM; and CIS and GEM Alone in Participants With Previously Untreated, Unresectable, Locally Advanced, or Metastatic Intrahepatic and Extrahepatic Cholangiocarcinoma and Gallbladder Adenocarcinoma
Official title: A Phase 1B, Randomized, Open-Label Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) in Combination With Cisplatin Plus Gemcitabine and PEGPH20 in Combination With Atezolizumab and Cisplatin Plus Gemcitabine Compared With Cisplatin Plus Gemcitabine in Subjects With Previously Untreated, Unresectable, Locally Advanced, or Metastatic Intrahepatic and Extrahepatic Cholangiocarcinoma and Gallbladder Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Cholangiocarcinoma Non-resectable
Cholangiocarcinoma, Intrahepatic
Cholangiocarcinoma, Extrahepatic
Gallbladder Adenocarcinoma
Keywords: Extrahepatic Cholangiocarcinoma
Intrahepatic Cholangiocarcinoma
Gallbladder Adenocarcinoma
PEGylated Recombinant Human Hyaluronidase
PEGylated Recombinant Human Hyaluronidase with atezolizumab
Lead sponsor: Halozyme Therapeutics
Sponsor class: INDUSTRY
First posted: 2017-08-31
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

For both portions of the study, participants must satisfy all of the following inclusion criteria to be enrolled in the study:

* Written Institutional Review Board/Ethics Committee-approved informed consent form (ICF), signed by participant or legally authorized representative.
* Participants must be determined to have histologically confirmed unresectable, locally advanced or metastatic adenocarcinoma of the intra- and/or extra-hepatic bile ducts and/or gallbladder. Participants must have sufficient tissue with architectural integrity, including tumor and associated stroma, available for retrospective biomarker testing.
* One or more lesions measurable on computed tomography (CT) scan/magnetic resonance imaging (MRI) scan per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1).
* Participants having Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
* Life expectancy ≥3 months.
* Males and females aged ≥18 years.
* Screening clinical laboratory values within pre-determined parameters
* Female participants of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 7 days before Day 1 (first dose of study medication).
* For WOCBP and for men, agreement to use a highly effective contraceptive method from the time of screening throughout the study until 5 months (WOCBP) or 6 months (men) after administration of the last dose of any study medication. Highly effective contraceptive methods consist of prior sterilization, intrauterine device (IUD), intrauterine hormone releasing system (IUS), oral or injectable contraceptives, barrier methods, and/or true sexual abstinence.

Exclusion Criteria:

Participants are ineligible for enrollment if they meet any of the following exclusion criteria:

* Clinical evidence of deep vein thrombosis or pulmonary embolism present during the screening period
* New York Heart Association Class III or IV cardiac disease, atrial fibrillation, unstable angina, or myocardial infarction within the past 12 months before screening.
* Participants with known brain metastases
* History of cerebrovascular accident or transient ischemic attack
* History of active bleeding within the last 3 months prior to screening requiring transfusion.
* Participants must have received no previous radiotherapy, surgery, chemotherapy or investigational therapy for treatment of metastatic or locally advanced disease.
* Intolerance to non-steroidal anti-inflammatory drugs (NSAIDs).
* Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen (HBsAg) test at screening
* Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at screening
* History of:

  1. Idiopathic pulmonary fibrosis, organizing pneumonia (for example, bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
  2. Or known cases of hepatobiliary diseases (for example, primary biliary cholangitis, primary sclerosing cholangitis, history of immune-mediated cholangitis);

     Participants with cholangitis attributed to infectious etiology (for example, ascending cholangitis, bacterial cholangitis) are eligible if the infection has been fully resolved prior to the screening visit.
  3. Or known cases of drug-induced hepatobiliary toxicities.
* Active or history of autoimmune diseases
* Uncontrolled hypercalcemia

Primary outcomes:
measure: Run-in Portion: Number of Participants With Adverse Events (AEs)
timeFrame: From first exposure to study drug through 30 days after the end of treatment visit (maximum exposure: 508 days)
measure: Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters (Hematology and Blood Chemistry)
timeFrame: From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)
measure: Run-in Portion: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) and Vital Signs
timeFrame: From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)
measure: Run-in Portion: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication
timeFrame: From first exposure to study drug through the end of treatment visit (maximum exposure: 508 days)
measure: Expansion Portion: Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: Percentage of Participants With Objective Response
timeFrame: From date of randomization until the date of first documented progression of disease or date of death from any cause, whichever came first (maximum exposure: 421 days)
Secondary outcomes:
measure: Run-in Portion: ORR Based on RECIST v1.1: Percentage of Participants With Objective Response
timeFrame: 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)
measure: Expansion Portion: Duration of Response (DOR) Based on RECIST v1.1
timeFrame: 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)
measure: Expansion Portion: Progression-Free Survival (PFS) Based on RECIST v1.1
timeFrame: From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days)
measure: Expansion Portion: Disease Control Rate (DCR) Based on RECIST v1.1: Percentage of Participants With CR, PR or Stable Disease (SD)
timeFrame: From date of randomization until date of progressive disease or death from any cause, whichever came first (maximum exposure: 421 days)
measure: Expansion Portion: Overall Survival (OS)
timeFrame: From randomization until death from any cause (maximum exposure: 421 days)
measure: Expansion Portion: OS by PD-L1 Expression Levels
timeFrame: From randomization until death from any cause (maximum exposure: 421 days)
measure: Expansion Portion: Number of Participants With AEs
timeFrame: From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)
measure: Expansion Portion: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters (Hematology and Blood Chemistry)
timeFrame: From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)
measure: Expansion Portion: Number of Participants With Clinically Significant Abnormalities in ECG and Vital Signs
timeFrame: From first exposure to study drug through the end of treatment visit (maximum exposure: 421 days)
measure: Expansion Period: Number of Participants With AEs Leading to Dose Reduction or Interruption of Any Study Medication
timeFrame: From first exposure to study drug through 30 days after the end of treatment visit (maximum exposure: 421 days)
measure: Run-in and Expansion Portion : Maximum Observed Plasma Concentration (Cmax) of PEGPH20, ATEZO, GEM, and CIS
timeFrame: 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
measure: Run-in and Expansion Portion : Minimum Observed Plasma Concentration (Cmin) of PEGPH20 and ATEZO
timeFrame: 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)
measure: Run-in and Expansion Portion : Elimination Rate Constant (Kel) of PEGPH20
timeFrame: Cycle 1: multiple timepoints on Days 1, 2, 8, 9, and 15
measure: Run-in and Expansion Portion : Terminal Elimination Plasma Half-life (t1/2) of PEGPH20, ATEZO, GEM, and CIS
timeFrame: 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
measure: Run-in and Expansion Portion : Clearance (CL) of PEGPH20, ATEZO, GEM, and CIS
timeFrame: 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
measure: Run-in and Expansion Portion : Volume of Distribution (Vd) of PEGPH20, ATEZO, GEM, and CIS
timeFrame: 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
measure: Run-in and Expansion Portion: Area Under the Concentration Time Curve (AUC) of PEGPH20, ATEZO, GEM, and CIS
timeFrame: 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
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic of Arizona
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: La Jolla
country: United States
facility: Scripps
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Orange
country: United States
facility: University of California Irvine Division of Hematology-Oncology, Department of Medicine UC Irvine Health
state: California
city: Sacramento
country: United States
facility: UC Davis
state: California
city: Santa Monica
country: United States
facility: UCLA - David Geffen School of Medicine
state: California
city: Whittier
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Washington
country: United States
facility: Lombardi Cancer Center, Georgetown University
state: District of Columbia
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Mount Sinai
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: UT Health Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Virginia Mason
state: Washington
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Milwaukee
country: United States
facility: Froedtert Hospital And Medical College
state: Wisconsin
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
state: Gangnam-gu
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
state: Guro-gu
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Jongno-gu
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Seoul St. Mary's Hospital
state: Seocho-gu
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
state: Seodaemun-Gu
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Songpa-gu
city: Chiang mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital
state: Muang
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
state: Patumwan
city: Hat Yai
country: Thailand
facility: Prince of Songkla University
state: Songkla
Study officials:
affiliation: Halozyme Therapeutics
name: VP, Medical, Regulatory and Drug Safety
role: STUDY_DIRECTOR
References: