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Panobinostat, Gemcitabine Hydrochloride, Busulfan, and Melphalan Before Stem Cell Transplant in Treating Patients With Refractory or Relapsed Multiple Myeloma

Primary Purpose

Plasma Cell Leukemia, Plasmacytoma, Recurrent Plasma Cell Myeloma

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Autologous Hematopoietic Stem Cell Transplantation
Busulfan
Gemcitabine Hydrochloride
Laboratory Biomarker Analysis
Melphalan
Panobinostat
Peripheral Blood Stem Cell Transplantation
Pharmacological Study
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Plasma Cell Leukemia

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Refractory or relapsed myeloma, defined as one or more of the following:

    • Treated with first-line therapy including at least 2 cycles of lenalidomide, bortezomib or thalidomide, and one or more of the following:

      • Less than partial response (PR) to first-line therapy
      • Relapse after first (1st) line therapy
    • High-risk cytogenetics, defined by deletion (del)(13q) by conventional cytogenetics, or by del(17p), t(4;14), t(14;16), t(14;20) or 1q+ by fluorescence in situ hybridization (FISH)
    • Relapse after a prior autologous stem cell transplant (ASCT)
    • Plasma cell leukemia
    • Soft tissue plasmacytoma
  • Serum creatinine =< 1.8 mg/dL and/or estimated serum creatinine clearance >= 50 ml/min
  • Serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamate pyruvate transaminase (SGPT) =< 3 x upper limit of normal
  • Serum bilirubin =< 2 x upper limit of normal, unless proven to be due to disease involvement
  • Alkaline phosphatase =< 2 x upper limit of normal, unless proven to be due to disease involvement
  • Adequate pulmonary function with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% of expected corrected for hemoglobin and/or volume
  • Adequate cardiac function with left ventricular ejection fraction >= 40%
  • No uncontrolled arrhythmias or symptomatic cardiac disease
  • Clinically euthyroid; note: patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism
  • Zubrod performance status < 2
  • Negative beta-human chorionic gonadotropin (HCG) test in a woman of child-bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization
  • Availability of >= 2.5 million cluster of differentiation (CD)34+ cells/kg previously apheresed
  • Ability to provide written informed consent

Exclusion Criteria:

  • Prior whole brain irradiation
  • Having received radiation therapy to head and neck (excluding eyes), and internal organs of chest, abdomen or pelvis in the month prior to enrollment
  • Active hepatitis B, either active carrier (hepatitis B surface antigen positive [HBsAg +]) or viremic (hepatitis B virus [HBV] deoxyribonucleic acid [DNA] >= 10,000 copies/mL, or >= 2,000 IU/mL)
  • Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology
  • Active infection requiring parenteral antibiotics
  • Known positivity for human immunodeficiency virus (HIV)
  • Autologous stem-cell transplant in the previous six months
  • Needing valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat
  • Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol
  • Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:

    • History or presence of sustained ventricular tachyarrhythmia; (patients with a history of atrial arrhythmia are eligible but should be discussed with Secura Bio, Inc (Secura Bio) prior to enrollment)
    • Any history of ventricular fibrillation or torsade de pointes
    • Bradycardia defined as heart rate (HR) < 50 beats per minute (bpm); patients with pacemakers are eligible if HR >= 50 bpm
    • Screening electrocardiogram (ECG) with a corrected QT (QTc) > 470 msec
    • Right bundle branch block + left anterior hemiblock (bifascicular block)
    • Myocardial infarction or unstable angina =< 12 months prior to starting study drug
    • Other clinically significant heart disease (e.g., congestive heart failure [CHF] New York [NY] Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
  • Have undergone major surgery =< 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  • Prior malignancy with in the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix)
  • Any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff
  • Received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies
  • Having received immunotherapy or chemotherapy within 2 weeks; or radiation therapy to > 30% of marrow-bearing bone within =< 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies
  • Grade >= 3 nonhematological toxicity from prior therapy that has not resolved to =< grade 1

Sites / Locations

  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (panobinostat, Gem/Bu/Mel, ASCT)

Arm Description

Patients receive panobinostat PO QD on days -9 to -2, gemcitabine hydrochloride IV over 4 hours on days -8 and -3, busulfan IV over 3 hours on days -8 to -5, and melphalan IV over 30 minutes on days -3 and -2. Patients then undergo autologous peripheral blood stem cell transplant on day 0.

Outcomes

Primary Outcome Measures

Progression free survival (PFS)
Estimated by the Kaplan-Meier method. Comparison of time to event endpoints by subgroups will be made using the log-rank test. Cox proportional hazards regression will be employed for univariate and multivariate analysis on time-to-event outcomes.

Secondary Outcome Measures

Complete response (CR) rate
Assessed using the International Myeloma Working Group (IMWG) uniform response criteria. Reported along with corresponding 95% confidence intervals. Logistic regression will be used to model the association between response rates and prognostic factors.
Overall survival (OS)
Estimated by the Kaplan-Meier method. Comparison of time to event endpoints by subgroups will be made using the log-rank test. Cox proportional hazards regression will be employed for univariate and multivariate analysis on time-to-event outcomes.
Complete response (CR) + very good partial response (VGPR) rate
Assessed using the International Myeloma Working Group (IMWG) uniform response criteria. Reported along with corresponding 95% confidence intervals. Logistic regression will be used to model the association between response rates and prognostic factors.
Response rate
Assessed using the International Myeloma Working Group (IMWG) uniform response criteria. Reported along with corresponding 95% confidence intervals. Logistic regression will be used to model the association between response rates and prognostic factors.
Minimal residual disease post-transplant
Minimal residual disease post-transplant will be measured by multiparametric flow cytometry.
Incidence of grade 3 or greater side effects
Assessed according to Common Terminology Criteria for Adverse Events version 4.0. The treatment-related morality rate will be computed and presented with 95% confidence interval. Adverse events will be tabulated for all patients.
Predictive value of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc
Correlation with PFS and OS of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc will be analyzed using the log-rank test. The correlation with CR, VGPR+CR and RR of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc will be analyzed using Fisher's F test.
Prognostic effect of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc
Correlation with PFS and OS of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc will be analyzed using the log-rank test. The correlation with CR, VGPR+CR and RR of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc will be analyzed using Fisher's F test.

Full Information

First Posted
July 22, 2015
Last Updated
June 29, 2023
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02506959
Brief Title
Panobinostat, Gemcitabine Hydrochloride, Busulfan, and Melphalan Before Stem Cell Transplant in Treating Patients With Refractory or Relapsed Multiple Myeloma
Official Title
Panobinostat Combined With High-Dose Gemcitabine/Busulfan/Melphalan With Autologous Stem Cell Transplant for Patients With Refractory/Relapsed Myeloma
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
September 14, 2015 (Actual)
Primary Completion Date
August 30, 2024 (Anticipated)
Study Completion Date
August 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

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

5. Study Description

Brief Summary
This phase II trial studies how well panobinostat, gemcitabine hydrochloride, busulfan, and melphalan before stem cell transplant work in treating patients with multiple myeloma that does not respond to treatment (refractory) or has returned (relapsed). Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving high-dose chemotherapy, such as gemcitabine hydrochloride, busulfan, and melphalan, before a peripheral blood stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Previously collected stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the progression-free survival (PFS) in patients with refractory or relapsed myeloma receiving panobinostat/gemcitabine hydrochloride (gemcitabine)/busulfan/melphalan (panobinostat/Gem/Bu/Mel) with autologous stem-cell transplant, either as a first or a salvage stem-cell transplant. SECONDARY OBJECTIVES: I. To evaluate the complete response (CR) rate. II. To determine the overall survival (OS). III. To determine the CR + very good partial remission (VGPR) rate. IV. To determine the overall response rate (ORR). V. To determine minimal residual disease posttransplant, measured by multiparametric flow cytometry (MFC). VI. To describe the toxicity profile of panobinostat/Gem/Bu/Mel. VII. To analyze the predictive value of pretransplant levels in myeloma cells of X-box binding protein 1 (XBP1), inositol-requiring enzyme 1 (IRE1), unspliced XBP1 (XBP1u), sliced XBP1 (XPB1s), XBP1u/XPBs ratio and v-myc myelocytomatosis viral oncogene homolog (avian) (Myc), by analyzing their correlation with CR, VGPR+CR and response rate (RR). VIII. To study the prognostic effect of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, by analyzing their correlation with PFS and OS. OUTLINE: Patients receive panobinostat orally (PO) once daily (QD) on days -9 to -2, gemcitabine hydrochloride intravenously (IV) over 4 hours on days -8 and -3, busulfan IV over 3 hours on days -8 to -5, and melphalan IV over 30 minutes on days -3 and -2. Patients then undergo autologous peripheral blood stem cell transplant on day 0. After completion of study treatment, patients are followed up at 1 month, 100 days, 6 months, 1 year, and then every 3-6 months for at least 2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Plasma Cell Leukemia, Plasmacytoma, Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
83 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (panobinostat, Gem/Bu/Mel, ASCT)
Arm Type
Experimental
Arm Description
Patients receive panobinostat PO QD on days -9 to -2, gemcitabine hydrochloride IV over 4 hours on days -8 and -3, busulfan IV over 3 hours on days -8 to -5, and melphalan IV over 30 minutes on days -3 and -2. Patients then undergo autologous peripheral blood stem cell transplant on day 0.
Intervention Type
Procedure
Intervention Name(s)
Autologous Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
AHSCT, Autologous, Autologous Hematopoietic Cell Transplantation, Autologous Stem Cell Transplant, Autologous Stem Cell Transplantation, Stem Cell Transplantation, Autologous
Intervention Description
Undergo autologous peripheral blood stem cell transplant
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Gemcitabine Hydrochloride
Other Intervention Name(s)
dFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Melphalan
Other Intervention Name(s)
Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Panobinostat
Other Intervention Name(s)
Faridak, LBH589
Intervention Description
Given PO
Intervention Type
Procedure
Intervention Name(s)
Peripheral Blood Stem Cell Transplantation
Other Intervention Name(s)
PBPC transplantation, PBSCT, Peripheral Blood, Peripheral Blood Progenitor Cell Transplantation, PERIPHERAL BLOOD STEM CELL TRANSPLANT, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation
Intervention Description
Undergo autologous peripheral blood stem cell transplant
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Progression free survival (PFS)
Description
Estimated by the Kaplan-Meier method. Comparison of time to event endpoints by subgroups will be made using the log-rank test. Cox proportional hazards regression will be employed for univariate and multivariate analysis on time-to-event outcomes.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Complete response (CR) rate
Description
Assessed using the International Myeloma Working Group (IMWG) uniform response criteria. Reported along with corresponding 95% confidence intervals. Logistic regression will be used to model the association between response rates and prognostic factors.
Time Frame
By day 100
Title
Overall survival (OS)
Description
Estimated by the Kaplan-Meier method. Comparison of time to event endpoints by subgroups will be made using the log-rank test. Cox proportional hazards regression will be employed for univariate and multivariate analysis on time-to-event outcomes.
Time Frame
Up to 2 years
Title
Complete response (CR) + very good partial response (VGPR) rate
Description
Assessed using the International Myeloma Working Group (IMWG) uniform response criteria. Reported along with corresponding 95% confidence intervals. Logistic regression will be used to model the association between response rates and prognostic factors.
Time Frame
By day 100
Title
Response rate
Description
Assessed using the International Myeloma Working Group (IMWG) uniform response criteria. Reported along with corresponding 95% confidence intervals. Logistic regression will be used to model the association between response rates and prognostic factors.
Time Frame
By day 100
Title
Minimal residual disease post-transplant
Description
Minimal residual disease post-transplant will be measured by multiparametric flow cytometry.
Time Frame
Up to 2 years
Title
Incidence of grade 3 or greater side effects
Description
Assessed according to Common Terminology Criteria for Adverse Events version 4.0. The treatment-related morality rate will be computed and presented with 95% confidence interval. Adverse events will be tabulated for all patients.
Time Frame
Up to day 100
Title
Predictive value of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc
Description
Correlation with PFS and OS of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc will be analyzed using the log-rank test. The correlation with CR, VGPR+CR and RR of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc will be analyzed using Fisher's F test.
Time Frame
Up to 2 years
Title
Prognostic effect of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc
Description
Correlation with PFS and OS of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc will be analyzed using the log-rank test. The correlation with CR, VGPR+CR and RR of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio, and Myc will be analyzed using Fisher's F test.
Time Frame
Up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Refractory or relapsed myeloma, defined as one or more of the following: Treated with first-line therapy including at least 2 cycles of lenalidomide, bortezomib or thalidomide, and one or more of the following: Less than partial response (PR) to first-line therapy Relapse after first (1st) line therapy High-risk cytogenetics, defined by deletion (del)(13q) by conventional cytogenetics, or by del(17p), t(4;14), t(14;16), t(14;20) or 1q+ by fluorescence in situ hybridization (FISH) Relapse after a prior autologous stem cell transplant (ASCT) Plasma cell leukemia Soft tissue plasmacytoma Serum creatinine =< 1.8 mg/dL and/or estimated serum creatinine clearance >= 50 ml/min Serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamate pyruvate transaminase (SGPT) =< 3 x upper limit of normal Serum bilirubin =< 2 x upper limit of normal, unless proven to be due to disease involvement Alkaline phosphatase =< 2 x upper limit of normal, unless proven to be due to disease involvement Adequate pulmonary function with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% of expected corrected for hemoglobin and/or volume Adequate cardiac function with left ventricular ejection fraction >= 40% No uncontrolled arrhythmias or symptomatic cardiac disease Clinically euthyroid; note: patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism Zubrod performance status < 2 Negative beta-human chorionic gonadotropin (HCG) test in a woman of child-bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization Availability of >= 2.5 million cluster of differentiation (CD)34+ cells/kg previously apheresed Ability to provide written informed consent Exclusion Criteria: Prior whole brain irradiation Having received radiation therapy to head and neck (excluding eyes), and internal organs of chest, abdomen or pelvis in the month prior to enrollment Active hepatitis B, either active carrier (hepatitis B surface antigen positive [HBsAg +]) or viremic (hepatitis B virus [HBV] deoxyribonucleic acid [DNA] >= 10,000 copies/mL, or >= 2,000 IU/mL) Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology Active infection requiring parenteral antibiotics Known positivity for human immunodeficiency virus (HIV) Autologous stem-cell transplant in the previous six months Needing valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: History or presence of sustained ventricular tachyarrhythmia; (patients with a history of atrial arrhythmia are eligible but should be discussed with Secura Bio, Inc (Secura Bio) prior to enrollment) Any history of ventricular fibrillation or torsade de pointes Bradycardia defined as heart rate (HR) < 50 beats per minute (bpm); patients with pacemakers are eligible if HR >= 50 bpm Screening electrocardiogram (ECG) with a corrected QT (QTc) > 470 msec Right bundle branch block + left anterior hemiblock (bifascicular block) Myocardial infarction or unstable angina =< 12 months prior to starting study drug Other clinically significant heart disease (e.g., congestive heart failure [CHF] New York [NY] Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen) Have undergone major surgery =< 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy Prior malignancy with in the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix) Any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff Received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies Having received immunotherapy or chemotherapy within 2 weeks; or radiation therapy to > 30% of marrow-bearing bone within =< 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies Grade >= 3 nonhematological toxicity from prior therapy that has not resolved to =< grade 1
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yago L Nieto
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
MD Anderson Cancer Center Website

Learn more about this trial

Panobinostat, Gemcitabine Hydrochloride, Busulfan, and Melphalan Before Stem Cell Transplant in Treating Patients With Refractory or Relapsed Multiple Myeloma

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