Clinical Trials /

Study of PEGPH20 With Cisplatin (CIS) and Gemcitabine (GEM); PEGPH20 With Atezolizumab (ATEZO), CIS, and GEM; and CIS and GEM Alone in Participants With Previously Untreated, Unresectable, Locally Advanced, or Metastatic Intrahepatic and Extrahepatic Cholangiocarcinoma and Gallbladder Adenocarcinoma

NCT03267940

Description:

The study is being conducted to assess the safety and tolerability of (1) PEGPH20 in combination with CIS and GEM (PEGCISGEM), and (2) PEGPH20 in combination with CIS, GEM, and atezolizumab (PEGCISGEMATEZO) compared with (3) cisplatin and gemcitabine (CISGEM).

Related Conditions:
  • Bile Duct Adenocarcinoma
  • Extrahepatic Bile Duct Adenocarcinoma
  • Extrahepatic Cholangiocarcinoma
  • Gallbladder Adenocarcinoma
  • Intrahepatic Cholangiocarcinoma
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of PEGPH20 With Cisplatin (CIS) and Gemcitabine (GEM); PEGPH20 With Atezolizumab, CIS, and GEM; and CIS and GEM Alone in Participants With Previously Untreated, Unresectable, Locally Advanced, or Metastatic Intrahepatic and Extrahepatic Cholangiocarcinoma and Gallbladder Adenocarcinoma
  • Official Title: A Phase 1b, Randomized, Open-Label Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) in Combination With Cisplatin Plus Gemcitabine and PEGPH20 in Combination With Atezolizumab and Cisplatin Plus Gemcitabine Compared With Cisplatin Plus Gemcitabine in Subjects With Previously Untreated, Unresectable, Locally Advanced, or Metastatic Intrahepatic and Extrahepatic Cholangiocarcinoma and Gallbladder Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: Halo-110-101
  • NCT ID: NCT03267940

Conditions

  • Cholangiocarcinoma Non-resectable
  • Cholangiocarcinoma, Intrahepatic
  • Cholangiocarcinoma, Extrahepatic
  • Gallbladder Adenocarcinoma

Interventions

DrugSynonymsArms
PEGPH20Run-in Portion Arm 1: PEGCISGEM
CISRun-in Portion Arm 1: PEGCISGEM
GEMRun-in Portion Arm 1: PEGCISGEM
AtezolizumabRun-in Portion Arm 2: PEGCISGEMATEZO

Purpose

The study is being conducted to assess the safety and tolerability of (1) PEGPH20 in combination with CIS and GEM (PEGCISGEM), and (2) PEGPH20 in combination with CIS, GEM, and atezolizumab (PEGCISGEMATEZO) compared with (3) cisplatin and gemcitabine (CISGEM).

Detailed Description

      The study will have a Run-in portion and an Expansion portion. The Run-in portion will be
      used to evaluate the safety profile of the PEGCISGEM and PEGCISGEMATEZO treatments prior to
      evaluating the efficacy and safety of PEGCISGEM and PEGCISGEMATEZO treatments compared with
      CISGEM treatment in the Expansion portion of the study. Treatment in both portions of the
      study will continue until death, withdrawal of consent from the study, disease progression,
      or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Run-in Portion Arm 1: PEGCISGEMExperimentalApproximately 6 participants will receive 3.0 micrograms per kilogram (μg/kg) PEGPH20 on Days 1, 8, and 15 in combination with 25 milligrams per meter squared (mg/m^2) of CIS plus 1000 mg/m^2 of GEM administered on Days 2 and 9 of each 21-day cycle by intravenous (IV) infusion.
  • PEGPH20
  • CIS
  • GEM
Run-in Portion Arm 2: PEGCISGEMATEZOExperimentalAfter 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.
  • PEGPH20
  • CIS
  • GEM
  • Atezolizumab
Expansion Portion Arm 1: PEGCISGEMExperimentalParticipants 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.
  • PEGPH20
  • CIS
  • GEM
Expansion Portion Arm 2: PEGCISGEMATEZOExperimentalParticipants 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.
  • PEGPH20
  • CIS
  • GEM
  • Atezolizumab
Expansion Portion Arm 3: PEGCISGEMATEZO ModifiedExperimentalParticipants will receive 3.0 µg/kg PEGPH20 on Days 1, 4, 8, 11, 15 and 18 in Cycle 1 and on Days 1, 8, and 15 from Cycle 2 onwards 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.
  • PEGPH20
  • CIS
  • GEM
  • Atezolizumab
Expansion Portion Arm 4: CISGEMActive ComparatorParticipants 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.
  • CIS
  • GEM

Eligibility Criteria

        Inclusion Criteria:

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

          -  Written Institutional Review Board/Ethics Committee-approved informed consent form
             (ICF), signed by participant or legally authorized representative.

          -  Participants must be determined to have histologically confirmed unresectable, locally
             advanced or metastatic adenocarcinoma of the intra- and/or extra-hepatic bile ducts
             and/or gallbladder. Participants must have sufficient tissue with architectural
             integrity, including tumor and associated stroma, available for retrospective
             biomarker testing.

          -  One or more lesions measurable on computed tomography (CT) scan/magnetic resonance
             imaging (MRI) scan per Response Evaluation Criteria in Solid Tumors (RECIST) version
             1.1 (v1.1).

          -  Participants having Eastern Cooperative Oncology Group (ECOG) Performance Status of 0
             to 1.

          -  Life expectancy ≥3 months.

          -  Males and females aged ≥18 years.

          -  Screening clinical laboratory values within pre-determined parameters

          -  Female participants of childbearing potential (WOCBP) must have a negative urine or
             serum pregnancy test within 7 days before Day 1 (first dose of study medication).

          -  For WOCBP and for men, agreement to use a highly effective contraceptive method from
             the time of screening throughout the study until 5 months (WOCBP) or 6 months (men)
             after administration of the last dose of any study medication. Highly effective
             contraceptive methods consist of prior sterilization, intrauterine device (IUD),
             intrauterine hormone releasing system (IUS), oral or injectable contraceptives,
             barrier methods, and/or true sexual abstinence.

        Exclusion Criteria:

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

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

          -  New York Heart Association Class III or IV cardiac disease, atrial fibrillation,
             unstable angina, or myocardial infarction within the past 12 months before screening.

          -  Participants with known brain metastases

          -  History of cerebrovascular accident or transient ischemic attack

          -  History of active bleeding within the last 3 months prior to screening requiring
             transfusion.

          -  Participants must have received no previous radiotherapy, surgery, chemotherapy or
             investigational therapy for treatment of metastatic or locally advanced disease.

          -  Intolerance to non-steroidal anti-inflammatory drugs (NSAIDs).

          -  Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B
             surface antigen (HBsAg) test at screening

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

          -  History of:

               1. Idiopathic pulmonary fibrosis, organizing pneumonia (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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Run-in Portion: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Considered Related to Study Drug by Investigator
Time Frame:From date of randomization up to 30 days after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to approximately 2 years 5 months)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Run-in Portion: Maximum Observed Plasma Concentration (Cmax) of PEGPH20, ATEZO, GEM, and CIS
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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.
Measure:Run-in Portion: Minimum Observed Plasma Concentration (Cmin) of PEGPH20 and ATEZO
Time Frame:PEGPH20 and ATEZO: Treatment Cycle 1: multiple timepoints on Days 1, 2, 8, 9, and 15; ATEZO: Day 1 of subsequent cycles and EOT visit (after last 21-day cycle) (up to approximately 2 years 5 months)
Safety Issue:
Description: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 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.
Measure:Run-in Portion: Elimination Rate Constant (Kel) of PEGPH20
Time Frame:Cycle 1: multiple timepoints on Days 1, 2, 8, 9, and 15
Safety Issue:
Description: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 where possible/appropriate to obtain individual estimates of Kel, which will then be summarized for all participants.
Measure:Run-in Portion: Terminal Elimination Plasma Half-life (t1/2) of PEGPH20, ATEZO, GEM, and CIS
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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.
Measure:Run-in Portion: Clearance (CL) of PEGPH20, ATEZO, GEM, and CIS
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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 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.
Measure:Run-in Portion: Volume of Distribution (Vd) of PEGPH20, ATEZO, GEM, and CIS
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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 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.
Measure:Run-in Portion: Area Under the Concentration Time Curve (AUC) of PEGPH20, ATEZO, GEM, and CIS
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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.
Measure:Run-in Portion: ORR Based on RECIST v1.1: Percentage of Participants with Objective Response
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 5 months)
Safety Issue:
Description:ORR (ORR=complete response [CR]+partial response [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 magnetic resonance imaging (MRI)/computed topography (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 percent (%) decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.
Measure:Expansion Portion: Duration of Response (DOR) Based on RECIST v1.1
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 5 months)
Safety Issue:
Description: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. Median DOR will be estimated by treatment arm using Kaplan-Meier method.
Measure:Expansion portion: Progression Free Survival (PFS) Based on RECIST v1.1
Time Frame:From date of randomization until date of progressive disease or death from any cause, whichever came first, (up to approximately 2 years 5 months)
Safety Issue:
Description:
Measure:Expansion Portion: Disease Control Rate (DCR) based on RECIST v1.1
Time Frame:From date of randomization until date of progressive disease or death from any cause, whichever came first, (up to approximately 2 years 5 months)
Safety Issue:
Description:DCR is the percentage of participants who have CR, PR, or 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.
Measure:Expansion Portion: Overall Survival (OS)
Time Frame:From randomization to death due to any cause (up to approximately 2 years 5 months)
Safety Issue:
Description:OS is defined as time from randomization to death at any time.
Measure:Expansion Portion: OS by Programmed Cell Death Ligand 1 (PD-L1) Expression Levels
Time Frame:From date of randomization start until death from any cause (up to approximately 2 years 5 months)
Safety Issue:
Description: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.
Measure:Expansion Portion: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) Considered Related to Study Drug by Investigator
Time Frame:From date of randomization up to 30 days after the last dose of study treatment, (up to approximately 2 years 5 months)
Safety Issue:
Description:
Measure:Expansion Portion: Number of Participants with Dose Modifications
Time Frame:From date of randomization up to 30 days after the last dose of study treatment (up to approximately 2 years 5 months)
Safety Issue:
Description:
Measure:Expansion Portion: Cmax of PEGPH20, ATEZO, GEM, and CIS
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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.
Measure:Expansion Portion: Cmin of PEGPH20 and ATEZO
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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 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.
Measure:Expansion Portion: Kel of PEGPH20
Time Frame:Cycle 1: multiple timepoints on Days 1, 2, 8, 9, and 15
Safety Issue:
Description: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 where possible/appropriate to obtain individual estimates of Kel which will then be summarized for all participants.
Measure:Expansion Portion: t1/2 of PEGPH20, ATEZO, GEM, and CIS
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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.
Measure:Expansion Portion: CL of PEGPH20, ATEZO, GEM, and CIS from Plasma
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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 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.
Measure:Expansion Portion: Vd of PEGPH20, ATEZO, GEM, and CIS in Plasma
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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 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.
Measure:Expansion Portion: AUC of PEGPH20, ATEZO, GEM, and CIS
Time Frame:PEGPH20 and ATEZO: Cycle 1: multiple timepoints on Days 1,2,8,9,15; ATEZO: Day 1 of subsequent cycles and end of treatment (EOT) visit (after last 21-day cycle) (up to approximately 2 years 5 months); CIS and GEM: Cycle 1:multiple timepoints on Days 2,9
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Halozyme Therapeutics

Trial Keywords

  • Extrahepatic Cholangiocarcinoma
  • Intrahepatic Cholangiocarcinoma
  • Gallbladder Adenocarcinoma
  • PEGylated Recombinant Human Hyaluronidase
  • PEGylated Recombinant Human Hyaluronidase with atezolizumab

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