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Open-Label Study of PEGPH20 With CIS and GEM; PEGPH20 With Atezolizumab, CIS and GEM; and Compared With CIS and GEM Alone in HA-high 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 : March 7, 2018
Sponsor:
Information provided by (Responsible Party):
Halozyme Therapeutics

Brief Summary:
The study was conducted to assess the safety and tolerability of (1) polyethylene glycol (PEG) 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).

Condition or disease Intervention/treatment Phase
Cholangiocarcinoma Non-resectable Cholangiocarcinoma, Intrahepatic Cholangiocarcinoma, Extrahepatic Gallbladder Adenocarcinoma Drug: PEGylated Recombinant Human Hyaluronidase Drug: Cisplatin Drug: Gemcitabine Drug: Atezolizumab Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b, Randomized, Open-Label Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) in Combination With Cisplatin Plus Gemcitabine and PEGPH20 in Combination With Atezolizumab and Cisplatin Plus Gemcitabine Compared With Cisplatin Plus Gemcitabine in Hyaluronan-High (HA-high) Subjects With Previously Untreated, Unresectable, Locally Advanced, or Metastatic Intrahepatic and Extrahepatic Cholangiocarcinoma and Gallbladder Adenocarcinoma
Actual Study Start Date : September 12, 2017
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
Experimental: Run-in Portion Arm 1: PEGCISGEM
Approximately 6 hyaluronan (HA)-high 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. PEGPH20 plus CIS and GEM (PEGCISGEM) by intravenous (IV) infusion.
Drug: PEGylated Recombinant Human Hyaluronidase
3.0 µg/kg PEGylated Recombinant Human Hyaluronidase (PEGPH20) will be administered by IV infusion on Days 1, 8, and 15 of each 21-day cycle in both the Run-in Portion and Expansion Portion.
Other Name: PEGPH20
Drug: Cisplatin
25 mg/m^2 of CIS will be administered by IV infusion on Days 2 and 9 of each 21-day cycle in the Run-in Portion, and Days 1 and 8 of each 21-day cycle in the Expansion Portion.
Other Names:
  • CIS
  • Platinol
  • Platinol-AQ
Drug: Gemcitabine
1000 mg/m^2 GEM will be administered by IV infusion on Days 2 and 9 of each 21-day cycle in the Run-in Portion, and Days 1 and 8 of each 21-day cycle in the Expansion Portion.
Other Names:
  • GEM
  • Gemzar
Experimental: Run-in Portion Arm 2: PEGCISGEMATEZO
After the 6 HA-high 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. PEGPH20 plus ATEZO, CIS, and GEM (PEGCISGEMATEZO)
Drug: PEGylated Recombinant Human Hyaluronidase
3.0 µg/kg PEGylated Recombinant Human Hyaluronidase (PEGPH20) will be administered by IV infusion on Days 1, 8, and 15 of each 21-day cycle in both the Run-in Portion and Expansion Portion.
Other Name: PEGPH20
Drug: Cisplatin
25 mg/m^2 of CIS will be administered by IV infusion on Days 2 and 9 of each 21-day cycle in the Run-in Portion, and Days 1 and 8 of each 21-day cycle in the Expansion Portion.
Other Names:
  • CIS
  • Platinol
  • Platinol-AQ
Drug: Gemcitabine
1000 mg/m^2 GEM will be administered by IV infusion on Days 2 and 9 of each 21-day cycle in the Run-in Portion, and Days 1 and 8 of each 21-day cycle in the Expansion Portion.
Other Names:
  • GEM
  • Gemzar
Drug: Atezolizumab
1200 mg atezolizumab will be administered by IV infusion 1 to 3 hours after PEGPH20 on Day 1 of each 21-day cycle in both the Run-in Portion and Expansion Portion.
Other Names:
  • Tecentriq
  • ATEZO
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 administered by IV infusion on Days 2 and 9 of each 21-day cycle.
Drug: PEGylated Recombinant Human Hyaluronidase
3.0 µg/kg PEGylated Recombinant Human Hyaluronidase (PEGPH20) will be administered by IV infusion on Days 1, 8, and 15 of each 21-day cycle in both the Run-in Portion and Expansion Portion.
Other Name: PEGPH20
Drug: Cisplatin
25 mg/m^2 of CIS will be administered by IV infusion on Days 2 and 9 of each 21-day cycle in the Run-in Portion, and Days 1 and 8 of each 21-day cycle in the Expansion Portion.
Other Names:
  • CIS
  • Platinol
  • Platinol-AQ
Drug: Gemcitabine
1000 mg/m^2 GEM will be administered by IV infusion on Days 2 and 9 of each 21-day cycle in the Run-in Portion, and Days 1 and 8 of each 21-day cycle in the Expansion Portion.
Other Names:
  • GEM
  • Gemzar
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.
Drug: PEGylated Recombinant Human Hyaluronidase
3.0 µg/kg PEGylated Recombinant Human Hyaluronidase (PEGPH20) will be administered by IV infusion on Days 1, 8, and 15 of each 21-day cycle in both the Run-in Portion and Expansion Portion.
Other Name: PEGPH20
Drug: Cisplatin
25 mg/m^2 of CIS will be administered by IV infusion on Days 2 and 9 of each 21-day cycle in the Run-in Portion, and Days 1 and 8 of each 21-day cycle in the Expansion Portion.
Other Names:
  • CIS
  • Platinol
  • Platinol-AQ
Drug: Gemcitabine
1000 mg/m^2 GEM will be administered by IV infusion on Days 2 and 9 of each 21-day cycle in the Run-in Portion, and Days 1 and 8 of each 21-day cycle in the Expansion Portion.
Other Names:
  • GEM
  • Gemzar
Drug: Atezolizumab
1200 mg atezolizumab will be administered by IV infusion 1 to 3 hours after PEGPH20 on Day 1 of each 21-day cycle in both the Run-in Portion and Expansion Portion.
Other Names:
  • Tecentriq
  • ATEZO
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. Cisplatin plus gemcitabine (CISGEM) by IV infusion.
Drug: Cisplatin
25 mg/m^2 of CIS will be administered by IV infusion on Days 2 and 9 of each 21-day cycle in the Run-in Portion, and Days 1 and 8 of each 21-day cycle in the Expansion Portion.
Other Names:
  • CIS
  • Platinol
  • Platinol-AQ
Drug: Gemcitabine
1000 mg/m^2 GEM will be administered by IV infusion on Days 2 and 9 of each 21-day cycle in the Run-in Portion, and Days 1 and 8 of each 21-day cycle in the Expansion Portion.
Other Names:
  • GEM
  • Gemzar



Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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).

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

  1. Written Institutional Review Board/Ethics Committee-approved informed consent form (ICF), signed by participant or legally authorized representative.
  2. 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.
  3. Participants (intrahepatic cholangiocarcinoma (CCA), extrahepatic CCA, or gallbladder adenocarcinoma participants) must be determined to have hyaluronan (HA-) high tumor biopsies based on a co-developed investigational assay. Tumor tissue, from the primary lesion or a metastatic lesion are required.

    Note: Fine needle aspirates or brushing biopsies will not be acceptable. Archived resection specimens from the primary tumor without evidence of locally advanced disease or without radiologic evidence of metastasis at the time of resection are not suitable to determine HA-status and require new tumor tissue of a metastatic site.

  4. CCA and gallbladder adenocarcinoma cancer participants must have tissue available for PD-L1 testing. Tumor samples must meet the requirements noted in the Inclusion Criterion #3.
  5. 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).
  6. Participants having Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
  7. Life expectancy ≥3 months.
  8. Males and females aged ≥18 years.
  9. Screening clinical laboratory values as follows:

    • Total bilirubin ≤1.5 × upper limit of normal (ULN), except for Gilbert's syndrome
    • Aspartate aminotransferase and alanine aminotransferase ≤2.5 × ULN (<5 × ULN is allowed if liver metastases are present)
    • Serum creatinine ≤1.5 milligrams/deciliter (mg/dL)
    • Serum albumin ≥2.5 grams/deciliter (g/dL)
    • Hemoglobin ≥9 g/dL (transfusion and erythropoietic agents allowed)
    • Absolute neutrophil count ≥1500 cells/millimeter squared (mm^3)
    • Platelet count ≥100,000/mm^3
  10. 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).
  11. For WOCBP and for men, agreement to use an 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, and/or barrier methods. Abstinence alone is not considered an adequate contraceptive measure for the purposes of this study.

Exclusion Criteria:

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

  1. Clinical evidence of deep vein thrombosis or pulmonary embolism present during the screening period.

    • Participant with superficial vein thrombosis are eligible.
    • Participant with visceral/splanchnic vein thrombosis, that in the opinion of the Principal investigator are primarily associated with the anatomic location of the underlying disease of metastatic biliary tract cancer, are eligible.
  2. New York Heart Association Class III or IV cardiac disease, atrial fibrillation, unstable angina, or myocardial infarction within the past 12 months before screening.
  3. Participants with known brain metastases
  4. History of cerebrovascular accident or transient ischemic attack
  5. History of active bleeding within the last 3 months prior to screening requiring transfusion.
  6. Contraindication to heparin as per institutional guidelines.
  7. Participants must have received no previous radiotherapy, surgery, chemotherapy or investigational therapy for treatment of metastatic or locally advanced disease.
  8. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (anti-PD-1), and anti-PD-L1 therapeutic antibodies
  9. Prior treatment with 5-fluorouracil (FU) or gemcitabine (GEM) administered as a radiation sensitizer in the neoadjuvant and adjuvant settings surrounding surgery, during and up to 4 weeks after radiation therapy, is allowed if all toxicities have returned to baseline or ≤ Grade 1.
  10. If a participant received therapy in the adjuvant setting, tumor recurrence or disease progression must have occurred no sooner than 6 months after completing the last dose of the adjuvant therapy.
  11. Clinically significant pre-existing carotid artery disease.
  12. Active, uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
  13. Known allergy to hyaluronidase.
  14. Intolerance to piroxicam.
  15. Current use of megestrol acetate or megestrol acetate-containing drugs (within 10 days of Day 1).
  16. Women currently pregnant or breastfeeding.
  17. Positive human immunodeficiency virus (HIV) test
  18. Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen (HBsAg) test at screening

    • Participants with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study if active HBV infection is ruled out on the basis of HBV ribonucleic acid (RNA)/deoxyribonucleic acid (DNA) viral load per local guidelines.

  19. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at screening

    • Participants who have a positive HCV antibody test are eligible for the study if a polymerase chain reaction assay is negative for HCV RNA.

  20. Active tuberculosis.
  21. History of 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.
  22. Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease.
  23. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells.
  24. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
  25. Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study treatment

    • Participants receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.

  26. Signs or symptoms of infection within 2 weeks prior to initiation of study treatment.
  27. Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study

    • Placement of central venous access catheter(s) (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted.

  28. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study

    • Influenza vaccination should be given during influenza season only (approximately October to March in the Northern Hemisphere and approximately April through September in the Southern Hemisphere). Participants must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to the start of study treatment, during treatment, or within 90 days after the last dose of atezolizumab.

  29. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2) within 6 weeks or 5 half-lives of the drug, whichever is longer, prior to initiation of study treatment.
  30. Treatment with systemic immunosuppressive medication (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor alpha [anti-TNF-α] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study

    • Participants who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the Medical Monitor.
    • The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for participants with orthostatic hypotension, chronic obstructive pulmonary disease, or adrenocortical insufficiency is allowed.
    • Participants with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments performed using MRI.
  31. Active or history of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

    • Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible for this study after discussion with and approval by the Medical Monitor.
    • Participants with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study after discussion with and approval by the Medical Monitor.
  32. Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis) are permitted provided that they meet the following conditions:

    • Participants with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
    • Rash must cover less than 10% of body surface area (BSA)
    • Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
    • No acute exacerbations of underlying condition within the last 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids)
  33. Uncontrolled tumor-related pain

    • Participants requiring narcotic pain medication must be on a stable regimen at study entry.
    • Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to start of study treatment. Participants should be recovered from the effects of radiation. There is no required minimum recovery period.
    • Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to the start of study treatment.
  34. Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy

    • Participants who are receiving denosumab must discontinue denosumab use and replace it with a bisphosphonate instead while in the study. There is no required minimum washout period for denosumab.
    • Participants who are receiving bisphosphonate therapy specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible.
  35. Prior allogeneic stem cell or solid organ transplantation.
  36. History of another primary cancer within the last 3 years that required treatment, with the exception of non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical carcinoma in situ.
  37. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that lead to reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk for treatment complications.
  38. Participant inability to comply with study and follow-up procedures, as judged by the Investigator.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03267940


Contacts
Contact: Halozyme Study Information 844-855 HALO (4256) Medinfo@halozyme.com

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Sponsors and Collaborators
Halozyme Therapeutics

Responsible Party: Halozyme Therapeutics
ClinicalTrials.gov Identifier: NCT03267940     History of Changes
Other Study ID Numbers: Halo-110-101
First Posted: August 31, 2017    Key Record Dates
Last Update Posted: March 7, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Halozyme Therapeutics:
Extrahepatic Cholangiocarcinoma
Intrahepatic Cholangiocarcinoma
Gallbladder Adenocarcinoma
PEGylated Recombinant Human Hyaluronidase
PEGylated Recombinant Human Hyaluronidase with atezolizumab

Additional relevant MeSH terms:
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Cholangiocarcinoma
Carcinoma
Gemcitabine
Atezolizumab
Cisplatin
Antibodies, Monoclonal
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs