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Study of PEGPH20 With CIS and GEM; PEGPH20 With Atezolizumab, CIS, and GEM; and CIS and GEM Alone in Subjects With Previously Untreated, Unresectable, Locally Advanced, or Metastatic Intrahepatic and Extrahepatic Cholangiocarcinoma and Gallbladder Adenocarcinoma

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ClinicalTrials.gov Identifier: NCT03267940
Recruitment Status : Recruiting
First Posted : August 31, 2017
Last Update Posted : September 13, 2018
Sponsor:
Information provided by (Responsible Party):
Halozyme Therapeutics

July 25, 2017
August 31, 2017
September 13, 2018
September 12, 2017
October 2019   (Final data collection date for primary outcome measure)
  • Run-in Portion: Number of Participants with Adverse Events (AEs) [ Time Frame: From date of randomization up to 30 days after the last dose of study treatment (up to approximately 2 years 5 months) ]
  • Expansion Portion: Objective Response Rate (ORR) as determined by the investigator, based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) [ 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 (up to approximately 2 years 5 months) ]
  • Run-in Portion: Number of Participants with Adverse Events (AEs) [ Time Frame: From date of randomization up to 30 days after the last dose of study treatment, (up to approximately 2 years 8 months) ]
    Safety will be assessed by monitoring and recording all AEs, changes in clinical safety laboratory values (hematology, blood chemistry, coagulation, thyroid hormone levels, urinalysis results, viral serology, and PEGPH20 and ATEZO immunogenicity), 12-lead electrocardiogram (ECG) results, vital signs, physical examinations, medical history, concomitant medications, dose modifications (e.g. dose interruptions and delays) and Eastern Cooperative Oncology Group (ECOG) Performance Status. Severity of AEs will be graded by Investigators using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
  • Expansion Portion: Objective Response Rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) [ 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, (assessed up to approximately 2 years 8 months) ]
    ORR (ORR=CR+PR) will be calculated as the number of participants with a complete response (CR) or partial response (PR) divided by the number of participants in the analysis population. Disease progression will be documented by magnetic resonance imaging/computed tomography (MRI/CT) scans of target lesions, and based on the Investigator's radiology reviewer's assessment. CR is defined as the disappearance of all lesions. PR is 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. Treatment differences between the investigational and control arm will be tested using 1-sided Fisher's Exact test.
Complete list of historical versions of study NCT03267940 on ClinicalTrials.gov Archive Site
  • Run-in Portion : Maximum Plasma Concentration (Cmax) of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20 and ATEZO: Treatment Cycle 1 (TC1) multiple time points (tpts) on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and end of treatment (EOT) visit (after last 21-day TC); CIS and GEM: TC1, multiple tpts on Days 2 and 9 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS (total and unbound) in plasma using a standardized procedure. Plasma pharmacokinetic (PK) data will be analyzed using a noncompartmental analysis approach to obtain individual participant estimates of Cmax, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion : Minimum Plasma Concentration (Cmin) of PEGPH20 and ATEZO [ Time Frame: PEGPH20 and ATEZO: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and EOT visit (after last 21-day TC) ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 and ATEZO in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Cmin which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion: Elimination Rate Constant (Kel) of PEGPH20 [ Time Frame: TC1 multiple tpts on Days 1, 2, 8, 9, and 15 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Kel, which will then be summarized for all participants.
  • Run-in Portion: Terminal Elimination Plasma Half-life (t1/2) of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20 and ATEZO: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and EOT visit (after last 21-day TC); CIS and GEM: TC1, multiple tpts on Days 2 and 9 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using a noncompartmental analysis approach to obtain individual participant estimates of t1/2, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion: Clearance (CL) of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20 and ATEZO: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and EOT visit (after last 21-day TC); CIS and GEM: TC1, multiple tpts on Days 2 and 9 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of CL, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion: Volume of Distribution (Vd) of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20 and ATEZO: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and EOT visit (after last 21-day TC); CIS and GEM: TC1, multiple tpts on Days 2 and 9 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Vd, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion: Intercompartmental Rate of Distribution (K12 and K21) of PEGPH20 [ Time Frame: TC1 multiple tpts on Days 1, 2, 8, 9, and 15 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of K12 and K21, which will then be summarized for all participants.
  • Run-in Portion: Area Under the Concentration Time Curve (AUC) of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20 and ATEZO: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and EOT visit (after last 21-day TC); CIS and GEM: TC1, multiple tpts on Days 2 and 9 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using a noncompartmental analysis approach to obtain individual participant estimates of AUC, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion: ORR based on RECIST v1.1 [ 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, (assessed up to approximately 2 years 8 months) ]
    ORR (ORR=CR+PR) will be calculated as the number of participants with a CR or PR divided by the number of participants in the analysis population. Disease progression will be documented by MRI/CT scans of target lesions, and based on the Investigator's radiology reviewer's assessment. CR is defined as the disappearance of all lesions. PR is 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. OS is defined as time from randomization to death at any time. Participant's tumor samples will be tested retrospectively for PD-L1 expression levels. Treatment differences between the investigational and control arm will be tested using 1-sided Fisher's Exact test.
  • Expansion Portion: Cmax of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC); CIS and GEM: multiple tpts on Days 1 and 8 of TC1 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS (total and unbound) in plasma using a standardized procedure. Plasma PK data will be analyzed using a noncompartmental analysis approach to obtain individual participant estimates of Cmax, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: Cmin of PEGPH20 and ATEZO [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC) ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 and ATEZO in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Cmin which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: Kel of PEGPH20 [ Time Frame: TC1 multiple tpts on Days 1, 2, 8, 9, and 15 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Kel which will then be summarized for all participants.
  • Expansion Portion: Terminal Elimination Plasma t1/2 of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC); CIS and GEM: multiple tpts on Days 1 and 8 of TC1 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using a noncompartmental analysis approach to obtain individual participant estimates of t1/2, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: CL of PEGPH20, ATEZO, GEM, and CIS from Plasma [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC); CIS and GEM: multiple tpts on Days 1 and 8 of TC1 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of CL which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: Vd of PEGPH20, ATEZO, GEM, and CIS in Plasma [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC); CIS and GEM: multiple tpts on Days 1 and 8 of TC1 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standard procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Vd which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: K12 and K21 of PEGPH20 [ Time Frame: TC1 multiple tpts on Days 1, 2, 8, 9, and 15 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of K12 and K21 which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: AUC of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC); CIS and GEM: multiple tpts on Days 1 and 8 of TC1 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using a noncompartmental analysis approach to obtain individual participant of AUC, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: Duration of Response (DOR) based on RECIST v1.1 and Overall Survival (OS) [ 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, (assessed up to approximately 2 years 8 months) ]
    DOR is 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 is defined as the disappearance of all target lesions. PR is 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. OS is defined as time from randomization to death at any time. Median DOR will be estimated by treatment arm using Kaplan-Meier method.
  • Expansion Portion: Progression Free Survival (PFS) based on RECIST v1.1 and OS [ Time Frame: From date of randomization until date of progressive disease or death from any cause, whichever came first, up to approximately 2 years 8 months ]
    PFS is defined as the time from randomization to radiological disease progression or death based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review. Progressive disease (PD) is 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 ≥5 millimeters. OS is defined as time from randomization to death at any time. Kaplan-Meier method will be used to estimate the median PFS and OS, and 80% confidence interval (CI).
  • Expansion Portion: Disease Control Rate (DCR) based on RECIST v1.1 and OS [ Time Frame: From date of randomization until date of progressive disease or death from any cause, whichever came first, (up to approximately 2 years 8 months) ]
    DCR is the percentage of participants who have CR, PR, or stable disease (SD) based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review. CR is defined as the disappearance of all target lesions. PR is 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. Stable disease is defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. OS is defined as time from randomization to death at any time. Treatment differences between the investigational and control arm will be tested using 1-sided Fisher's Exact test.
  • Expansion Portion: ORR based on RECIST v1.1 and OS by Programmed Cell Death Ligand 1 (PD-L1) Expression Levels [ Time Frame: From date of randomization start until death from any cause, whichever came first, (up to approximately 2 years 8 months) ]
    ORR (ORR=CR+PR) will be calculated as the number of participants with a CR or PR divided by the number of participants in the analysis population. Disease progression will be documented by MRI/CT scans of target lesions, and based on the Investigator's radiology reviewer's assessment. CR is defined as the disappearance of all lesions. PR is 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. OS is defined as time from randomization to death at any time. Participant's tumor samples will be tested retrospectively for PD-L1 expression levels. Treatment differences between the investigational and control arm will be tested using 1-sided Fisher's Exact test.
  • Expansion Portion: DOR based on RECIST v1.1 and OS by PD-L1 Expression Levels [ Time Frame: From date of the first CR or PR until the date of first documentation of disease progression or date of death, whichever comes first (up to approximately 2 years 8 months) ]
    DOR based on Immune-Modified RECIST v 1.1 was considered the time from date of the first CT 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. Immune modified RECIST will be done in the PEGCISGEMATEZO Arm only and requires confirmation of disease progression with an additional scan obtained no sooner than 28 days after the initial scan that showed progression. CR is defined as the disappearance of all target lesions. PR is 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. OS is defined as time from randomization to death at any time. Participant's tumor samples will be tested retrospectively for PD-L1 expression levels. Median DOR will be estimated by treatment arm using Kaplan-Meier method.
  • Expansion Portion: Progression-Free Survival based on RECIST v1.1 and OS by PD-L1 Expression Levels [ Time Frame: From date of randomization until date of progressive disease or death from any cause, whichever came first, (up to approximately 2 years 8 months) ]
    PFS is defined as the time from randomization to radiological disease progression or death based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review. PD is 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 ≥5 millimeters. OS is defined as time from randomization to death at any time. Participant's tumor samples will be tested retrospectively for PD-L1 expression levels. Kaplan-Meier method will be used to estimate the median PFS and OS, and 80% CI.
  • Expansion Portion: Number of Participants with AEs [ Time Frame: From date of randomization up to 30 days after the last dose of study treatment, (up to approximately 2 years 8 months) ]
    Safety will be assessed by monitoring and recording all adverse events (AEs), changes in clinical safety laboratory values (hematology, blood chemistry, coagulation, thyroid hormone levels, urinalysis results, viral serology, and PEGPH20 and ATEZO immunogenicity), 12-lead electrocardiogram (ECG) results, vital signs, physical examinations, medical history, concomitant medications, dose modifications (e.g. dose interruptions and delays) and Eastern Cooperative Oncology Group (ECOG) Performance Status. Severity of AEs will be graded by Investigators using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
  • Run-in Portion : Maximum Plasma Concentration (Cmax) of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20 and ATEZO: Treatment Cycle 1 (TC1) multiple time points (tpts) on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and end of treatment (EOT) visit (after last 21-day TC); CIS and GEM: TC1, multiple tpts on Days 2 and 9 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS (total and unbound) in plasma using a standardized procedure. Plasma pharmacokinetic (PK) data will be analyzed using a noncompartmental analysis approach to obtain individual participant estimates of Cmax, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion : Minimum Plasma Concentration (Cmin) of PEGPH20 and ATEZO [ Time Frame: PEGPH20 and ATEZO: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and EOT visit (after last 21-day TC) ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 and ATEZO in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Cmin which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion: Elimination Rate Constant (Kel) of PEGPH20 [ Time Frame: TC1 multiple tpts on Days 1, 2, 8, 9, and 15 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Kel, which will then be summarized for all participants.
  • Run-in Portion: Terminal Elimination Plasma Half-life (t1/2) of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20 and ATEZO: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and EOT visit (after last 21-day TC); CIS and GEM: TC1, multiple tpts on Days 2 and 9 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using a noncompartmental analysis approach to obtain individual participant estimates of t1/2, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion: Clearance (CL) of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20 and ATEZO: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and EOT visit (after last 21-day TC); CIS and GEM: TC1, multiple tpts on Days 2 and 9 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of CL, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion: Volume of Distribution (Vd) of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20 and ATEZO: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and EOT visit (after last 21-day TC); CIS and GEM: TC1, multiple tpts on Days 2 and 9 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Vd, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion: Intercompartmental Rate of Distribution (K12 and K21) of PEGPH20 [ Time Frame: TC1 multiple tpts on Days 1, 2, 8, 9, and 15 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of K12 and K21, which will then be summarized for all participants.
  • Run-in Portion: Area Under the Concentration Time Curve (AUC) of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20 and ATEZO: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent TCs and EOT visit (after last 21-day TC); CIS and GEM: TC1, multiple tpts on Days 2 and 9 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using a noncompartmental analysis approach to obtain individual participant estimates of AUC, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Run-in Portion: ORR based on RECIST v1.1 [ 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, (assessed up to approximately 2 years 8 months) ]
    ORR (ORR=CR+PR) will be calculated as the number of participants with a CR or PR divided by the number of participants in the analysis population. Disease progression will be documented by MRI/CT scans of target lesions, and based on the Investigator's radiology reviewer's assessment. CR is defined as the disappearance of all lesions. PR is 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. OS is defined as time from randomization to death at any time. Participant's tumor samples will be tested retrospectively for PD-L1 expression levels. Treatment differences between the investigational and control arm will be tested using 1-sided Fisher's Exact test.
  • Expansion Portion: Cmax of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC); CIS and GEM: multiple tpts on Days 1 and 8 of TC1 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS (total and unbound) in plasma using a standardized procedure. Plasma PK data will be analyzed using a noncompartmental analysis approach to obtain individual participant estimates of Cmax, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: Cmin of PEGPH20 and ATEZO [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC) ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 and ATEZO in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Cmin which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: Kel of PEGPH20 [ Time Frame: TC1 multiple tpts on Days 1, 2, 8, 9, and 15 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Kel which will then be summarized for all participants.
  • Expansion Portion: Terminal Elimination Plasma t1/2 of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC); CIS and GEM: multiple tpts on Days 1 and 8 of TC1 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using a noncompartmental analysis approach to obtain individual participant estimates of t1/2, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: CL of PEGPH20, ATEZO, GEM, and CIS from Plasma [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC); CIS and GEM: multiple tpts on Days 1 and 8 of TC1 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of CL which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: Vd of PEGPH20, ATEZO, GEM, and CIS in Plasma [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC); CIS and GEM: multiple tpts on Days 1 and 8 of TC1 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standard procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of Vd which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: K12 and K21 of PEGPH20 values, changes in ECG, vital signs, and dose modifications (e.g., dose interruptions and delays) [ Time Frame: TC1 multiple tpts on Days 1, 2, 8, 9, and 15 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20 in plasma using a standardized procedure. Plasma PK data will be analyzed using noncompartmental analysis and compartmental modeling where possible/appropriate to obtain individual estimates of K12 and K21 which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: AUC of PEGPH20, ATEZO, GEM, and CIS [ Time Frame: PEGPH20: TC1 multiple tpts on Days 1, 2, 8, 9, and 15; ATEZO: TC1, multiple tpts on Days 1, 2, 8, 9, and 15; TC2D1 and all subsequent TCs (w/in 2h prior to PEGPH20 SOI); EOT visit (after last 21-day TC); CIS and GEM: multiple tpts on Days 1 and 8 of TC1 ]
    Blood samples will be collected at specific time points then analyzed for the amount of PEGPH20, ATEZO, GEM, and CIS in plasma using a standardized procedure. Plasma PK data will be analyzed using a noncompartmental analysis approach to obtain individual participant of AUC, which will then be summarized for all participants. The EOT visit will occur approximately 7 days after the participant completes their last 21-day treatment cycle.
  • Expansion Portion: Duration of Response (DOR) based on RECIST v1.1 and Overall Survival (OS) [ 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, (assessed up to approximately 2 years 8 months) ]
    DOR is 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 is defined as the disappearance of all target lesions. PR is 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. OS is defined as time from randomization to death at any time. Median DOR will be estimated by treatment arm using Kaplan-Meier method.
  • Expansion Portion: Progression Free Survival (PFS) based on RECIST v1.1 and OS [ Time Frame: From date of randomization until date of progressive disease or death from any cause, whichever came first, up to approximately 2 years 8 months ]
    PFS is defined as the time from randomization to radiological disease progression or death based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review. Progressive disease (PD) is 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 ≥5 millimeters. OS is defined as time from randomization to death at any time. Kaplan-Meier method will be used to estimate the median PFS and OS, and 80% confidence interval (CI).
  • Expansion Portion: Disease Control Rate (DCR) based on RECIST v1.1 and OS [ Time Frame: From date of randomization until date of progressive disease or death from any cause, whichever came first, (up to approximately 2 years 8 months) ]
    DCR is the percentage of participants who have CR, PR, or stable disease (SD) based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review. CR is defined as the disappearance of all target lesions. PR is 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. Stable disease is defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. OS is defined as time from randomization to death at any time. Treatment differences between the investigational and control arm will be tested using 1-sided Fisher's Exact test.
  • Expansion Portion: ORR based on RECIST v1.1 and OS by Programmed Cell Death Ligand 1 (PD-L1) Expression Levels [ Time Frame: From date of randomization start until death from any cause, whichever came first, (up to approximately 2 years 8 months) ]
    ORR (ORR=CR+PR) will be calculated as the number of participants with a CR or PR divided by the number of participants in the analysis population. Disease progression will be documented by MRI/CT scans of target lesions, and based on the Investigator's radiology reviewer's assessment. CR is defined as the disappearance of all lesions. PR is 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. OS is defined as time from randomization to death at any time. Participant's tumor samples will be tested retrospectively for PD-L1 expression levels. Treatment differences between the investigational and control arm will be tested using 1-sided Fisher's Exact test.
  • Expansion Portion: DOR based on RECIST v1.1 and OS by PD-L1 Expression Levels [ Time Frame: From date of the first CR or PR until the date of first documentation of disease progression or date of death, whichever comes first (up to approximately 2 years 8 months) ]
    DOR based on Immune-Modified RECIST v 1.1 was considered the time from date of the first CT 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. Immune modified RECIST will be done in the PEGCISGEMATEZO Arm only and requires confirmation of disease progression with an additional scan obtained no sooner than 28 days after the initial scan that showed progression. CR is defined as the disappearance of all target lesions. PR is 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. OS is defined as time from randomization to death at any time. Participant's tumor samples will be tested retrospectively for PD-L1 expression levels. Median DOR will be estimated by treatment arm using Kaplan-Meier method.
  • Expansion Portion: Progression-Free Survival based on RECIST v1.1 and OS by PD-L1 Expression Levels [ Time Frame: From date of randomization until date of progressive disease or death from any cause, whichever came first, (up to approximately 2 years 8 months) ]
    PFS is defined as the time from randomization to radiological disease progression or death based on RECIST v1.1 for target lesions assessed by MRI/CT scans, as determined by independent radiologic review. PD is 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 ≥5 millimeters. OS is defined as time from randomization to death at any time. Participant's tumor samples will be tested retrospectively for PD-L1 expression levels. Kaplan-Meier method will be used to estimate the median PFS and OS, and 80% CI.
  • Expansion Portion: Non-progression Rate (NPR) at the Second Scheduled Tumor Assessment Scan [ Time Frame: From date of randomization until CR, PR, or SD, (assessed up to approximately 2 years 8 months) ]
    NPR is defined as the percentage of participants with CR, PR, or SD, as assessed by the Investigator according to RECIST v.1.1. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in tumor burden from baseline in the absence of CR. SD is defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. NPR will be assessed at the time of the second scheduled tumor assessment scan.
  • Expansion Portion: Number of Participants with AEs [ Time Frame: From date of randomization up to 30 days after the last dose of study treatment, (up to approximately 2 years 8 months) ]
    Safety will be assessed by monitoring and recording all adverse events (AEs), changes in clinical safety laboratory values (hematology, blood chemistry, coagulation, thyroid hormone levels, urinalysis results, viral serology, and PEGPH20 and ATEZO immunogenicity), 12-lead electrocardiogram (ECG) results, vital signs, physical examinations, medical history, concomitant medications, dose modifications (e.g. dose interruptions and delays) and Eastern Cooperative Oncology Group (ECOG) Performance Status. Severity of AEs will be graded by Investigators using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
Not Provided
Not Provided
 
Study of PEGPH20 With CIS and GEM; PEGPH20 With Atezolizumab, CIS, and GEM; and CIS and GEM Alone in Subjects 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
The study is being conducted to assess the safety and tolerability of (1) PEGylated Recombinant Human Hyaluronidase (PEGPH20) in combination with cisplatin (CIS) and gemcitabine (GEM) (PEGCISGEM), and (2) PEGPH20 in combination with CIS, GEM, and atezolizumab (PEGCISGEMATEZO) compared with (3) cisplatin and gemcitabine (CISGEM).
Not Provided
Interventional
Phase 1
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Cholangiocarcinoma Non-resectable
  • Cholangiocarcinoma, Intrahepatic
  • Cholangiocarcinoma, Extrahepatic
  • Gallbladder Adenocarcinoma
  • Drug: PEGPH20
    IV infusion
  • Drug: CIS
    IV infusion
  • Drug: GEM
    IV infusion
  • Drug: Atezolizumab
    IV infusion
  • Experimental: Run-in Portion Arm 1: PEGCISGEM
    Approximately 6 participants will receive 3.0 micrograms per kilogram (μg/kg) PEGylated Recombinant Human Hyaluronidase (PEGPH20) on Days 1, 8, and 15 in combination with 25 milligrams per meter squared (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.
    Interventions:
    • Drug: PEGPH20
    • Drug: CIS
    • Drug: GEM
  • Experimental: Run-in Portion Arm 2: PEGCISGEMATEZO
    After the 6 participants in Arm 1 are treated for at least 1 cycle without significant toxicities, 6 additional participants will be enrolled into Arm 2 of the Run-in Portion of the study. Participants will receive 3.0 µg/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. PEGPH20 dose reduction to a lower dose of 2.2 µg/kg or 1.6 µg/kg will be performed if necessary.
    Interventions:
    • Drug: PEGPH20
    • Drug: CIS
    • Drug: GEM
    • Drug: Atezolizumab
  • Experimental: Expansion Portion Arm 1: PEGCISGEM
    Participants will receive 3.0 µg/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.
    Interventions:
    • Drug: PEGPH20
    • Drug: CIS
    • Drug: GEM
  • Experimental: Expansion Portion Arm 2: PEGCISGEMATEZO
    Participants will receive 3.0 µg/kg PEGPH20 on Days 1, 8, and 15 in combination with 1200 mg ATEZO (administered 1 to 3 hours after PEGPH20 on Day 1of 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.
    Interventions:
    • Drug: PEGPH20
    • Drug: CIS
    • Drug: GEM
    • Drug: Atezolizumab
  • Active Comparator: Expansion Portion Arm 3: CISGEM
    Participants will 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.
    Interventions:
    • Drug: CIS
    • Drug: GEM
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
70
Same as current
February 2020
October 2019   (Final data collection date for primary outcome measure)

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.
  • 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 (e.g., 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 (e.g., primary biliary cholangitis, primary sclerosing cholangitis, history of immune-mediated cholangitis);

      Participants with cholangitis attributed to infectious etiology (e.g., 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
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact: Halozyme Study Information 844-855 HALO (4256) Medinfo@halozyme.com
Korea, Republic of,   Thailand,   United States
 
 
NCT03267940
Halo-110-101
Not Provided
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Halozyme Therapeutics
Halozyme Therapeutics
Not Provided
Not Provided
Halozyme Therapeutics
September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP