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Study of Alpelisib (BYL719) in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy in Patients With HER2-positive Advanced Breast Cancer With a PIK3CA Mutation (EPIK-B2)

Primary Purpose

Advanced HER2+Breast Cancer

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Alpelisib
Alpelisib matching Placebo
Trastuzumab
Pertuzumab
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced HER2+Breast Cancer focused on measuring BYL719, alpelisib, Advance Breast Cancer, maintenance, HER2 positive, induction, PI3K, Trastuzumab, Pertuzumab

Eligibility Criteria

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

Inclusion Criteria:

  • Participant has histologically-confirmed HER2-positive breast cancer that is advanced (loco-regionally not amenable to surgery or is metastatic).
  • Participant has received pre-study induction therapy with up to and including a maximum of 8 cycles of a taxane (docetaxel, paclitaxel, or nab-paclitaxel), plus trastuzumab and pertuzumab. 4 or 5 cycles of induction therapy are permitted if discontinuation of taxane was due to taxane toxicity. Of note, participants enrolled in Part 1 of this study received 4-6 cycles of pre-study induction therapy.
  • Participant has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Participant has adequate bone marrow and organ function
  • Applies only to Part 2: Participant has a PIK3CA mutation(s) present in tumor prior to enrollment, locally confirmed per test listed in protocol or as determined by a Novartis designated central laboratory.

Exclusion Criteria:

  • Participant with inflammatory breast cancer at screening.
  • Participant with evidence of disease progression during the pre-study induction therapy and prior to first dose of alpelisib (or alpelisib/alpelisib matching-placebo for Part 2)
  • Participant with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on fasting plasma glucose (FPG) and HbA1c.
  • Participant has a known history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis
  • Participant has clinically significant, uncontrolled heart disease and/or recent cardiac events
  • Participant has a history of Steven-Johnson Syndrome (SJS), erythema multiforme (EM) or Toxic Epidermal Necrolysis (TEN).
  • Participant has currently documented pneumonitis/interstitial lung disease

Other protocol-defined Inclusion/Exclusion may apply.

Sites / Locations

  • Highlands Oncology Group Main
  • University Of California Los Angeles Reg-5
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Part 1: Alpelisib + Trastuzumab + Pertuzumab

Part 2: Alpelisib + Trastuzumab + Pertuzumab

Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab

Arm Description

In the Part 1, up to 3 alpelisib dose levels may be sequentially tested in 3 cohorts of subjects: Cohort A: Alpelisib 300mg + trastuzumab (6mg/kg) + pertuzumab (420 mg) Cohort B: Alpelisib 250 mg+ trastuzumab (6mg/kg) + pertuzumab (420 mg) Cohort C: Alpelisib 200mg + trastuzumab (6mg/kg) + pertuzumab (420 mg)

Trastuzumab (6mg/kg) + pertuzumab (420 mg) in combination with 200mg alpelisib, with potential for intra-participant dose escalation to 250 mg

Trastuzumab (6mg/kg) + pertuzumab (420 mg) in combination with 200 mg alpelisib matching placebo, with potential for intra-participant dose escalation to 250 mg

Outcomes

Primary Outcome Measures

Part 1: Incidence of dose limiting toxicities (DLTs) for each dose level
Incidence of DLTs during the first 6 weeks of treatment for each dose level associated with administration of alpelisib in combination with trastuzumab and pertuzumab
Part 2: Progression Free Survival (PFS)
PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is based on local investigator assessment and using RECIST 1.1 criteria

Secondary Outcome Measures

Part 1: Alpelisib concentrations by timepoint and dose level
Characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab
Part 2: Overall survival (OS) (Key Secondary)
OS is defined as the time from date of randomization to date of death due to any cause
Part 2: Summary statistics of alpelisib concentrations by timepoint and dose level
Characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab
Part 2: Overall response rate (ORR) with confirmed response
ORR is defined as the percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1.
Part 2: Clinical Benefit Rate (CBR) with confirmed response
Clinical benefit rate is defined as the percentage of patients with a best overall response of complete response (CR) or patial response (PR) or Stable disease (SD) or Non-CR/Non-rogressive disease (PD) lasting more than 24 weeks based on local investigator assessment.
Part 2: Time to response (TTR) based on local radiology assessments
Time to response (TTR) is defined as the time from the date of randomization to the first documented response of either complete response (CR) or partial response (PR), which must be subsequently confirmed (although date of initial response is used, not date of confirmation). TTR will be assessed using RESIST 1.1 criteria.
Part 2: Duration of response (DOR) with confirmed response
DOR is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer.
Part 2: Change in Functional Assessment of Cancer Therapy - Breast (FACT-B) treatment outcomes index (TOI) from baseline
The FACT-B is a 37-item instrument designed to measure five domains of Health-Relaed Quality of Life (HRQOL) in breast cancer patients: Physical Well-being (PWB), Social/family Well-being (SWB), Emotional Well-being (EWB), Functional Well-being (FWB) as well as a Breast Cancer Subscale (BCS). The FACT-B TOI is a composite of PWB, FWB and BCS scores. Total score ranges from 0 to 96. Higher FACT-B TOI scores represent better QoL. Change from baseline in FACT-B TOI scores will be calculated
Part 2: Time to deterioration in FACT-B TOI (defined as a ≥ 5 point decrease from baseline)
The FACT-B is a 37-item instrument designed to measure five domains of Health-Relaed Quality of Life (HRQOL) in breast cancer patients: Physical Well-being (PWB), Social/family Well-being (SWB), Emotional Well-being (EWB), Functional Well-being (FWB) as well as a Breast Cancer Subscale (BCS). The FACT-B TOI is a composite of PWB, FWB and BCS scores. Total score ranges from 0 to 96. Higher FACT-B TOI scores represent better QoL. Definitive deterioration is defined as the time from the date of randomization to the date of event defined as at least 5-point worsening from baseline with no later improvement above this threshold observed during the course of the treatment or until death due to any cause in FACT-B TOI score
Part 2: PFS based on local radiology assessments by PIK3CA mutation status
Evaluate the association between PIK3CA mutation status as measured in ctDNA at baseline with PFS upon treatment with alpelisib. PFS will be assessed using RECIST 1.1 criteria for patients by PIK3CA mutation status assessed in ctDNA at baseline.
Part 2: Time to definitive deterioration of Eastern Cooperative Group of Oncology Group (ECOG) performance status
ECOG: participant's performance status was measured on a 6-point scale: 0= fully active/able to carry on all pre-disease activities without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light and sedentary nature; 2= ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50 percent (%) of waking hours; 3= capable of only limited self-care, confined to bed/chair >50% of waking hours; 4= completely disabled, cannot carry on any self-care, totally confined to bed/chair: 5= dead. Time to definitive deterioration in ECOG PS is defined as the time from the date of randomization to the date when the ECOG PS has definitely deteriorated by at least one category compared with baseline. Deterioration is considered definitive if there is no subsequent improvement in ECOG PS back to baseline category or above.

Full Information

First Posted
December 12, 2019
Last Updated
October 16, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT04208178
Brief Title
Study of Alpelisib (BYL719) in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy in Patients With HER2-positive Advanced Breast Cancer With a PIK3CA Mutation
Acronym
EPIK-B2
Official Title
EPIK-B2: A Two Part, Phase III, Multicenter, Randomized (1:1), Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Alpelisib (BYL719) in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy in Patients With HER2-positive Advanced Breast Cancer With a PIK3CA Mutation
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 16, 2020 (Actual)
Primary Completion Date
April 2, 2024 (Anticipated)
Study Completion Date
April 2, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

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

5. Study Description

Brief Summary
The purpose of this two part multicenter, randomized, double-blind, placebo-controlled, Phase III study is to evaluate the efficacy and safety of alpelisib compared to alpelisib matching-placebo in combination with trastuzumab and pertuzumab as maintenance treatment of patients with HER2-positive advanced breast cancer whose tumor harbors a PIK3CA mutation following induction therapy with a taxane in combination with trastuzumab and pertuzumab. Part 1 is the open-label, safety run-in part of the study, designed to confirm the recommended phase 3 dose (RP3D) dose of alpelisib in combination with trastuzumab and pertuzumab. Following Part 1, Part 2 will be initiated, which is the randomized, Phase III part of the study.
Detailed Description
The recruitment for this study was permanently halted as of 07-Dec-2022 with the intent of ending the study early because of the evolving treatment landscape and changing paradigms for HER-2 positive BC therapy. This decision was not triggered by any new or unexpected safety findings. Participants in Part 1 will be allowed to continue study treatment (alpelisib in combination with trastuzumab and pertuzumab) if they are deriving clinical benefit as assessed by the investigator and after discussion with the participant and documentation in the medical record. All participants in Part 2 will be unblinded for knowledge of treatment allocation and continuity treatment planning.Participants in the experimental arm will be allowed to continue alpelisib in combination with trastuzumab and pertuzumab based on investigator's judgement and benefit/risk assessment.Participants in Part 2 who are still receiving study treatment in the control arm with alpelisib matching-placebo will not be allowed cross-over to the experimental arm. These participants will be allowed to continue on trastuzumab and pertuzumab if they are deriving clinical benefit as assessed by the investigator and after discussion with the participant and documentation in the medical record.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced HER2+Breast Cancer
Keywords
BYL719, alpelisib, Advance Breast Cancer, maintenance, HER2 positive, induction, PI3K, Trastuzumab, Pertuzumab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Part 1 was the open-label, safety run-in part of the study designed to confirm the recommended phase 3 dose (RP3D) dose of alpelisib in combination with trastuzumab and pertuzumab. Following Part 1, Part 2 was initiated, which is the randomized, Phase III part of the study with two treatment arms.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Part 1 was the open-label, safety run-in part of the study designed to confirm the recommended phase 3 dose (RP3D) dose of alpelisib in combination with trastuzumab and pertuzumab. Once the alpelisib dose was confirmed, Part 2 with masking for participant, care provider, investigator and outcome assessor started. Participants in Part 2 are to be unblinded with the implementation of protocol amendment 03.
Allocation
Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part 1: Alpelisib + Trastuzumab + Pertuzumab
Arm Type
Experimental
Arm Description
In the Part 1, up to 3 alpelisib dose levels may be sequentially tested in 3 cohorts of subjects: Cohort A: Alpelisib 300mg + trastuzumab (6mg/kg) + pertuzumab (420 mg) Cohort B: Alpelisib 250 mg+ trastuzumab (6mg/kg) + pertuzumab (420 mg) Cohort C: Alpelisib 200mg + trastuzumab (6mg/kg) + pertuzumab (420 mg)
Arm Title
Part 2: Alpelisib + Trastuzumab + Pertuzumab
Arm Type
Experimental
Arm Description
Trastuzumab (6mg/kg) + pertuzumab (420 mg) in combination with 200mg alpelisib, with potential for intra-participant dose escalation to 250 mg
Arm Title
Part 2: Alpelisib matching Placebo + Trastuzumab + Pertuzumab
Arm Type
Placebo Comparator
Arm Description
Trastuzumab (6mg/kg) + pertuzumab (420 mg) in combination with 200 mg alpelisib matching placebo, with potential for intra-participant dose escalation to 250 mg
Intervention Type
Drug
Intervention Name(s)
Alpelisib
Other Intervention Name(s)
BYL719
Intervention Description
Alpelisib orally taken - continuous once daily, in a 21-day cycle.
Intervention Type
Drug
Intervention Name(s)
Alpelisib matching Placebo
Intervention Description
Alpelisib matching placebo orally taken - continuous once daily, in a 21-day cycle
Intervention Type
Drug
Intervention Name(s)
Trastuzumab
Intervention Description
Trastuzumab 6mg/kg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)
Intervention Type
Drug
Intervention Name(s)
Pertuzumab
Intervention Description
Pertuzumab 420 mg given intravenously - Day 1 of Cycle 1, and on Day 1 of every cycle thereafter (Cycle=21 days)
Primary Outcome Measure Information:
Title
Part 1: Incidence of dose limiting toxicities (DLTs) for each dose level
Description
Incidence of DLTs during the first 6 weeks of treatment for each dose level associated with administration of alpelisib in combination with trastuzumab and pertuzumab
Time Frame
6 weeks
Title
Part 2: Progression Free Survival (PFS)
Description
PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is based on local investigator assessment and using RECIST 1.1 criteria
Time Frame
Up to approximately 38 months
Secondary Outcome Measure Information:
Title
Part 1: Alpelisib concentrations by timepoint and dose level
Description
Characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab
Time Frame
Day 8 of Cycle 1 and then Day 1 of Cycle 2, Cycle 4, Cycle 6 and Cycle 10 (Cycle = 21 days)
Title
Part 2: Overall survival (OS) (Key Secondary)
Description
OS is defined as the time from date of randomization to date of death due to any cause
Time Frame
Up to approximately 70 months
Title
Part 2: Summary statistics of alpelisib concentrations by timepoint and dose level
Description
Characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab
Time Frame
Day 8 of Cycle 1 and then Day 1 of Cycle 2, Cycle 4, Cycle 6 and Cycle 10 (Cycle = 21 days)
Title
Part 2: Overall response rate (ORR) with confirmed response
Description
ORR is defined as the percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1.
Time Frame
Up to approximately 38 months
Title
Part 2: Clinical Benefit Rate (CBR) with confirmed response
Description
Clinical benefit rate is defined as the percentage of patients with a best overall response of complete response (CR) or patial response (PR) or Stable disease (SD) or Non-CR/Non-rogressive disease (PD) lasting more than 24 weeks based on local investigator assessment.
Time Frame
Up to approximately 38 months
Title
Part 2: Time to response (TTR) based on local radiology assessments
Description
Time to response (TTR) is defined as the time from the date of randomization to the first documented response of either complete response (CR) or partial response (PR), which must be subsequently confirmed (although date of initial response is used, not date of confirmation). TTR will be assessed using RESIST 1.1 criteria.
Time Frame
Up to approximately 38 months
Title
Part 2: Duration of response (DOR) with confirmed response
Description
DOR is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer.
Time Frame
Up to approximately 38 months
Title
Part 2: Change in Functional Assessment of Cancer Therapy - Breast (FACT-B) treatment outcomes index (TOI) from baseline
Description
The FACT-B is a 37-item instrument designed to measure five domains of Health-Relaed Quality of Life (HRQOL) in breast cancer patients: Physical Well-being (PWB), Social/family Well-being (SWB), Emotional Well-being (EWB), Functional Well-being (FWB) as well as a Breast Cancer Subscale (BCS). The FACT-B TOI is a composite of PWB, FWB and BCS scores. Total score ranges from 0 to 96. Higher FACT-B TOI scores represent better QoL. Change from baseline in FACT-B TOI scores will be calculated
Time Frame
Baseline, up to approximately 38 months
Title
Part 2: Time to deterioration in FACT-B TOI (defined as a ≥ 5 point decrease from baseline)
Description
The FACT-B is a 37-item instrument designed to measure five domains of Health-Relaed Quality of Life (HRQOL) in breast cancer patients: Physical Well-being (PWB), Social/family Well-being (SWB), Emotional Well-being (EWB), Functional Well-being (FWB) as well as a Breast Cancer Subscale (BCS). The FACT-B TOI is a composite of PWB, FWB and BCS scores. Total score ranges from 0 to 96. Higher FACT-B TOI scores represent better QoL. Definitive deterioration is defined as the time from the date of randomization to the date of event defined as at least 5-point worsening from baseline with no later improvement above this threshold observed during the course of the treatment or until death due to any cause in FACT-B TOI score
Time Frame
Baseline, up to approximately 38 months
Title
Part 2: PFS based on local radiology assessments by PIK3CA mutation status
Description
Evaluate the association between PIK3CA mutation status as measured in ctDNA at baseline with PFS upon treatment with alpelisib. PFS will be assessed using RECIST 1.1 criteria for patients by PIK3CA mutation status assessed in ctDNA at baseline.
Time Frame
Up to approximately 38 months
Title
Part 2: Time to definitive deterioration of Eastern Cooperative Group of Oncology Group (ECOG) performance status
Description
ECOG: participant's performance status was measured on a 6-point scale: 0= fully active/able to carry on all pre-disease activities without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light and sedentary nature; 2= ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50 percent (%) of waking hours; 3= capable of only limited self-care, confined to bed/chair >50% of waking hours; 4= completely disabled, cannot carry on any self-care, totally confined to bed/chair: 5= dead. Time to definitive deterioration in ECOG PS is defined as the time from the date of randomization to the date when the ECOG PS has definitely deteriorated by at least one category compared with baseline. Deterioration is considered definitive if there is no subsequent improvement in ECOG PS back to baseline category or above.
Time Frame
Baseline, up to approximately 38 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participant has histologically-confirmed HER2-positive breast cancer that is advanced (loco-regionally not amenable to surgery or is metastatic). Participant has received pre-study induction therapy with up to and including a maximum of 8 cycles of a taxane (docetaxel, paclitaxel, or nab-paclitaxel), plus trastuzumab and pertuzumab. 4 or 5 cycles of induction therapy are permitted if discontinuation of taxane was due to taxane toxicity. Of note, participants enrolled in Part 1 of this study received 4-6 cycles of pre-study induction therapy. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Participant has adequate bone marrow and organ function Applies only to Part 2: Participant has a PIK3CA mutation(s) present in tumor prior to enrollment, locally confirmed per test listed in protocol or as determined by a Novartis designated central laboratory. Exclusion Criteria: Participant with inflammatory breast cancer at screening. Participant with evidence of disease progression during the pre-study induction therapy and prior to first dose of alpelisib (or alpelisib/alpelisib matching-placebo for Part 2) Participant with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on fasting plasma glucose (FPG) and HbA1c. Participant has a known history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis Participant has clinically significant, uncontrolled heart disease and/or recent cardiac events Participant has a history of Steven-Johnson Syndrome (SJS), erythema multiforme (EM) or Toxic Epidermal Necrolysis (TEN). Participant has currently documented pneumonitis/interstitial lung disease Other protocol-defined Inclusion/Exclusion may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Highlands Oncology Group Main
City
Fayetteville
State/Province
Arkansas
ZIP/Postal Code
72703
Country
United States
Facility Name
University Of California Los Angeles Reg-5
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Novartis Investigative Site
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Liege
ZIP/Postal Code
4000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Chang Chun
State/Province
Jilin
ZIP/Postal Code
130021
Country
China
Facility Name
Novartis Investigative Site
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200032
Country
China
Facility Name
Novartis Investigative Site
City
Saint-Cloud
State/Province
Hauts De Seine
ZIP/Postal Code
92210
Country
France
Facility Name
Novartis Investigative Site
City
Creteil
ZIP/Postal Code
94000
Country
France
Facility Name
Novartis Investigative Site
City
Saint-Herblain Cédex
ZIP/Postal Code
44805
Country
France
Facility Name
Novartis Investigative Site
City
Firenze
State/Province
FI
ZIP/Postal Code
50134
Country
Italy
Facility Name
Novartis Investigative Site
City
Kuala Lumpur
ZIP/Postal Code
59100
Country
Malaysia
Facility Name
Novartis Investigative Site
City
Hospitalet de LLobregat
State/Province
Catalunya
ZIP/Postal Code
08907
Country
Spain
Facility Name
Novartis Investigative Site
City
Samsun
ZIP/Postal Code
55200
Country
Turkey

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
IPD Sharing URL
https://www.clinicalstudydatarequest.com

Learn more about this trial

Study of Alpelisib (BYL719) in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy in Patients With HER2-positive Advanced Breast Cancer With a PIK3CA Mutation

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