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Immunotherapy Combined With Y-90 SIRT Therapy in Advanced Stage Intrahepatic Biliary Tract Cancer (BTC)

Primary Purpose

Intrahepatic Cholangiocarcinoma

Status
Recruiting
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Durvalumab
Tremelimumab
Sponsored by
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Intrahepatic Cholangiocarcinoma focused on measuring Intrahepatic Bile Duct Cancer, Intrahepatic Biliary Tract Carcinoma, Intrahepatic Cholangiocarcinoma, BTC, iBTC, iCCA

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Fully-informed written consent and locally required authorization (European Union [EU]: General Data Privacy Regulation (GDPR)) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
  2. Age ≥ 18 years.
  3. Histologically documented diagnosis of locally-advanced OR limited metasized intrahepatic BTC not amenable to curative treatment (tumor resection or ablation), specified as

    • Tumor being confined to the liver or
    • In case of presence of extrahepatic lesions, metastasis must be stable AND of limited extent* AND patient must have a potential benefit from study participation in comparison to standard of care systemic therapy per local tumor board evaluation.

      *Limited extent is defined in this protocol as presence of

      • EITHER ≤3 malignant extrahepatic lymph nodes (short axis diameter ≥3cm)
      • OR metastatic lesions in one organ other than liver (if only single lesion is present diameter MUST be < 3cm; if up to 3 lesions in one organ each lesion MUST be ≤ 1cm).
      • Presence of peritoneal or brain metastatsis excludes patients from study participation (see exclusion criterion #4)
    • Tumor tissue (block or at least 4 slides) is available for translational research.
  4. Patients with prior chemotherapy can be enrolled if ONE of the following criteria is met:

    • Capecitabin or gemcitabine+cisplatin in the adjuvant setting
    • Experienced progressive disease under gemcitabine+cisplatin therapy in the advanced setting
    • Stable disease after 3 months of gemcitabine+cisplatin treatment
  5. Has been considered candidate for standard-of-care Y-90 SIRT therapy per Investigator decision and after prior consultation with the tumor board if available at site and does not display contraindications against SIRT.

    Contraindications against SIRT would be

    • hepatic tumor load > 50%
    • any Gastrointestinal deposition that cannot be corrected via angiographic techniques
    • irreversibly elevated serum bilirubin
    • renal insufficiency
    • increased pulmonary shunt fraction being able to deliver > 16.5 mCi to the lungs
    • gastrointestinal ulceration
    • hepatic dysfunction
    • biliary complications
    • portal hypertension
    • vascular injury and lymphopenia.
  6. Performance status (PS) ≤ 1 (ECOG scale).
  7. Body weight >30 kg
  8. At least one measurable site of disease as defined by RECIST 1.1 criteria.
  9. Adequate bone marrow and renal function
  10. Adequate hepatic function (with stenting for any obstruction, if required)
  11. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
  12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
  13. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
  14. Must have a life expectancy of at least 12 weeks.
  15. If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection, meets the following criteria:

    • Patients with HBV or HCV infection should be monitored for viral levels during study participation.
    • Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should have HBV DNA < 100 IU/ml and should be managed per local treatment guidelines.

Controlled (treated) hepatitis B subjects will be allowed if they started treatment at the time point of enrollment into the study by the latest and treatment is continued during study participation and for ≥ 6 months after end of study treatment.

- HCV patients with advanced BTC are mostly not treated for their HCV infection. However, patients treated for HCV are considered suitable for inclusion if antiviral therapy has been completed ≥ 30 days prior to first administration of study drug.

Exclusion Criteria:

  1. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the follow-up period of an interventional study.
  2. Participation in another clinical study with an investigational product within 21 days prior to the first dose of the study treatment.
  3. Prior immunotherapy or use of other investigational agents, including prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen-4 (anti-CTLA-4) antibody, therapeutic cancer vaccines.
  4. Presence of peritoneal carcinomatosis or brain metastases.
  5. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
  6. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is acceptable.
  7. Prior radiotherapy treatment before the first dose of any study drug.
  8. Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into the study; patients must have recovered from effects of any major surgery. Note: Local non-major surgery for palliative intent (e.g. surgery of isolated lesions, per-cutaneous biliary drainage or biliary stenting) is acceptable.
  9. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis].
  10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, , serious active, uncontrolled, gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
  11. History of non-infectious pneumonitis requiring steroids, or patients with Grade ≥ 2 pneumonitis.
  12. History of another primary malignancy except for:

    • Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of IP and of low potential risk for recurrence
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    • Adequately treated carcinoma in situ without evidence of disease
  13. History of leptomeningeal carcinomatosis
  14. Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a CT/ MRI of the brain prior to study entry.
  15. History of active primary immunodeficiency
  16. History of allogenic organ transplantation.
  17. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), or human immunodeficiency virus (positive HIV 1/2 antibodies) or active hepatitis B/hepatitis C co-infection.
  18. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab.
  19. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 180 days after the last dose of durvalumab.
  20. Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the product.
  21. Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
  22. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
  23. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
  24. Receipt of live attenuated vaccine within 30 days prior to the first administration of any of the IMPs and without need to receive any live attenuated vaccines during study conduct and for up to 30 days after end of Durvalumab treatment or 90 days after end of Tremelimumab treatment respectively.

Sites / Locations

  • University Hospital Dresden
  • Clinic Essen Center
  • University Hospital Essen
  • University Hospital HalleRecruiting
  • Hannover Medical SchoolRecruiting
  • University Hospital JenaRecruiting
  • Munich Clinic Bogenhausen
  • University Hospital Munich Grosshadern

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm 1

Arm 2

Arm Description

Durvalumab

Durvalumab in combination with Tremelimumab

Outcomes

Primary Outcome Measures

Objective Response rate (ORR) according to RECIST 1.1
Proportion of allocated subjects with best response of complete or partial response

Secondary Outcome Measures

Safety (rate of adverse events)
Type, incidence and severity of AEs and SAEs graded according to NCI CTCAE v5.0
Duration of response (DoR)
Time from that the measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that the PD is objectively documented or death
Progression free survival (PFS)
Time from the date of randomization to the date of first observed disease progression (investigator assessment according to RECIST 1.1) or death from any cause
Overall Survival (OS)
time from the date of treatment allocation to the date of death.

Full Information

First Posted
December 19, 2019
Last Updated
April 13, 2022
Sponsor
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Collaborators
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT04238637
Brief Title
Immunotherapy Combined With Y-90 SIRT Therapy in Advanced Stage Intrahepatic Biliary Tract Cancer (BTC)
Official Title
Phase II Study of Immunotherapy With Durvalumab (MEDI4736) or Durvalumab and Tremelimumab, Both Combined With Y-90 SIRT Therapy in Advanced Stage Intrahepatic Biliary Tract Cancer (BTC)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
November 1, 2019 (Actual)
Primary Completion Date
December 2025 (Anticipated)
Study Completion Date
December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Collaborators
AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
A multicenter Phase II, randomized, prospective, open-label Trial investigating the clinical impact on combining Specific Internal Radiotherapy (SIRT) with the PD1-L Inhibitor Durvalumab and the CTLA-4 Inhibitor Tremelimumab in patients with intrahepatic Biliary Tract Cancer
Detailed Description
IMMUWHY Phase II Clinical Trial will test the Addition of the immunotherapeutic agents Durvalumab and Tremelimumab after an initial Standard of Care SIRT in patients suffering from non-resectable intrahepatic Biliary Tract Cancer. Patients will be randomized into two experimental arms, one receiving Durvalumab only, the other one receiving Durvalumab + Tremelimumab. Clinical Outcomes will be compared vs. historical datasets.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Intrahepatic Cholangiocarcinoma
Keywords
Intrahepatic Bile Duct Cancer, Intrahepatic Biliary Tract Carcinoma, Intrahepatic Cholangiocarcinoma, BTC, iBTC, iCCA

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Two randomized Treatment arms
Masking
None (Open Label)
Allocation
Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm 1
Arm Type
Experimental
Arm Description
Durvalumab
Arm Title
Arm 2
Arm Type
Experimental
Arm Description
Durvalumab in combination with Tremelimumab
Intervention Type
Drug
Intervention Name(s)
Durvalumab
Other Intervention Name(s)
Other Name: MEDI4736
Intervention Description
Durvalumab IV (intravenous Infusion)
Intervention Type
Drug
Intervention Name(s)
Tremelimumab
Other Intervention Name(s)
Study treatment
Intervention Description
Tremelimumab IV (intravenous Infusion)
Primary Outcome Measure Information:
Title
Objective Response rate (ORR) according to RECIST 1.1
Description
Proportion of allocated subjects with best response of complete or partial response
Time Frame
20 months
Secondary Outcome Measure Information:
Title
Safety (rate of adverse events)
Description
Type, incidence and severity of AEs and SAEs graded according to NCI CTCAE v5.0
Time Frame
From first patient included until study closure (approx. 43 months after First Patient Included)
Title
Duration of response (DoR)
Description
Time from that the measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that the PD is objectively documented or death
Time Frame
From first measurement of CR or PR per RECIST 1.1 until disease progression occurs (up to 43 months until Study Closure)
Title
Progression free survival (PFS)
Description
Time from the date of randomization to the date of first observed disease progression (investigator assessment according to RECIST 1.1) or death from any cause
Time Frame
From date of randomization until disease progression occurs (up to 43 months until Study Closure)
Title
Overall Survival (OS)
Description
time from the date of treatment allocation to the date of death.
Time Frame
Date of enrollment until date of death if applicable (up to 43 months until Study Closure)
Other Pre-specified Outcome Measures:
Title
Translational research
Description
Exploratory: Predictive biomarkers that with a potential effect on Objective Response Rate, Duration of Response, Progression Free Survival and Overall Survival via blood sample collection + genetic subset analysis. The following translational research is currently planned, but may be adapted taking into account new research data: Tumors will be tested for mRNA expression of PD-1, PD-L1 and PD-L2 expression, Immune cell infiltrates (IGHM, CD3, CD8, FOXP3, CD68, CD205), Chemokines (CXCL9. CXCL10, CXCL13) and invasion markers (MMP7, MMP9)
Time Frame
3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Fully-informed written consent and locally required authorization (European Union [EU]: General Data Privacy Regulation (GDPR)) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations. Age ≥ 18 years. Histologically documented diagnosis of locally-advanced OR limited metasized intrahepatic BTC not amenable to curative treatment (tumor resection or ablation), specified as Tumor being confined to the liver or In case of presence of extrahepatic lesions, metastasis must be stable AND of limited extent* AND patient must have a potential benefit from study participation in comparison to standard of care systemic therapy per local tumor board evaluation. *Limited extent is defined in this protocol as presence of EITHER ≤3 malignant extrahepatic lymph nodes (short axis diameter ≥3cm) OR metastatic lesions in one organ other than liver (if only single lesion is present diameter MUST be < 3cm; if up to 3 lesions in one organ each lesion MUST be ≤ 1cm). Presence of peritoneal or brain metastatsis excludes patients from study participation (see exclusion criterion #4) Tumor tissue (block or at least 4 slides) is available for translational research. Patients with prior chemotherapy can be enrolled if ONE of the following criteria is met: Capecitabin or gemcitabine+cisplatin in the adjuvant setting Experienced progressive disease under gemcitabine+cisplatin therapy in the advanced setting Stable disease after 3 months of gemcitabine+cisplatin treatment Has been considered candidate for standard-of-care Y-90 SIRT therapy per Investigator decision and after prior consultation with the tumor board if available at site and does not display contraindications against SIRT. Contraindications against SIRT would be hepatic tumor load > 50% any Gastrointestinal deposition that cannot be corrected via angiographic techniques irreversibly elevated serum bilirubin renal insufficiency increased pulmonary shunt fraction being able to deliver > 16.5 mCi to the lungs gastrointestinal ulceration hepatic dysfunction biliary complications portal hypertension vascular injury and lymphopenia. Performance status (PS) ≤ 1 (ECOG scale). Body weight >30 kg At least one measurable site of disease as defined by RECIST 1.1 criteria. Adequate bone marrow and renal function Adequate hepatic function (with stenting for any obstruction, if required) Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations. Must have a life expectancy of at least 12 weeks. If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection, meets the following criteria: Patients with HBV or HCV infection should be monitored for viral levels during study participation. Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should have HBV DNA < 100 IU/ml and should be managed per local treatment guidelines. Controlled (treated) hepatitis B subjects will be allowed if they started treatment at the time point of enrollment into the study by the latest and treatment is continued during study participation and for ≥ 6 months after end of study treatment. - HCV patients with advanced BTC are mostly not treated for their HCV infection. However, patients treated for HCV are considered suitable for inclusion if antiviral therapy has been completed ≥ 30 days prior to first administration of study drug. Exclusion Criteria: Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the follow-up period of an interventional study. Participation in another clinical study with an investigational product within 21 days prior to the first dose of the study treatment. Prior immunotherapy or use of other investigational agents, including prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen-4 (anti-CTLA-4) antibody, therapeutic cancer vaccines. Presence of peritoneal carcinomatosis or brain metastases. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is acceptable. Prior radiotherapy treatment before the first dose of any study drug. Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into the study; patients must have recovered from effects of any major surgery. Note: Local non-major surgery for palliative intent (e.g. surgery of isolated lesions, per-cutaneous biliary drainage or biliary stenting) is acceptable. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis]. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, , serious active, uncontrolled, gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent. History of non-infectious pneumonitis requiring steroids, or patients with Grade ≥ 2 pneumonitis. History of another primary malignancy except for: Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of IP and of low potential risk for recurrence Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease History of leptomeningeal carcinomatosis Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a CT/ MRI of the brain prior to study entry. History of active primary immunodeficiency History of allogenic organ transplantation. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), or human immunodeficiency virus (positive HIV 1/2 antibodies) or active hepatitis B/hepatitis C co-infection. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 180 days after the last dose of durvalumab. Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the product. Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG]. Receipt of live attenuated vaccine within 30 days prior to the first administration of any of the IMPs and without need to receive any live attenuated vaccines during study conduct and for up to 30 days after end of Durvalumab treatment or 90 days after end of Tremelimumab treatment respectively.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Arndt Vogel, Professor
Phone
+49 511 5326
Ext
760
Email
Vogel.Arndt@mh-hannover.de
First Name & Middle Initial & Last Name or Official Title & Degree
Doerthe Vortmeyer, Doctor
Phone
+49 069 7601
Ext
4196
Email
vortmeyer.doerthe@ikf-khnw.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Salah-Eddin Al-Batran, Professor
Organizational Affiliation
IKF Klinische Krebsforschung GmbH
Official's Role
Study Director
Facility Information:
Facility Name
University Hospital Dresden
City
Dresden
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gunnar Folprecht
Facility Name
Clinic Essen Center
City
Essen
Country
Germany
Individual Site Status
Completed
Facility Name
University Hospital Essen
City
Essen
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ken Herrmann
Facility Name
University Hospital Halle
City
Halle
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Petra Buechner-Steudel
Facility Name
Hannover Medical School
City
Hannover
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Arndt Vogel
Facility Name
University Hospital Jena
City
Jena
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Udo Lindig
Facility Name
Munich Clinic Bogenhausen
City
Munich
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Martin Fuchs
Facility Name
University Hospital Munich Grosshadern
City
Munich
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jens Ricke

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
No IPD will be shared.

Learn more about this trial

Immunotherapy Combined With Y-90 SIRT Therapy in Advanced Stage Intrahepatic Biliary Tract Cancer (BTC)

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