Azacitidine and Pembrolizumab in Treating Patients With Myelodysplastic Syndrome

Sponsor
M.D. Anderson Cancer Center (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT03094637
Collaborator
National Cancer Institute (NCI) (NIH)
40
1
1
60.8
0.7

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects of azacitidine and pembrolizumab and to see how well they work in treating patients with myelodysplastic syndrome. Azacitidine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving azacitidine and pembrolizumab may work better at treating myelodysplastic syndrome.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. To assess the safety of the combination of azacitidine and MK3475 (pembrolizumab) in patients with higher risk myelodysplastic syndrome (MDS).

  2. To explore the clinical activity (response, survival effect) of the combination of azacitidine with MK-3475 in patients with higher risk MDS.

EXPLORATORY OBJECTIVES:
  1. To study the biological effects of the combination of azacitidine and pembrolizumab in patients with MDS treated on this study.
OUTLINE:

Patients receive azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days, every 12 weeks for 1 year, then annually thereafter.

Study Design

Study Type:
Interventional
Actual Enrollment :
40 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Study of the Combination of Azacitidine and Pembrolizumab for Patients With MDS
Actual Study Start Date :
Nov 6, 2017
Anticipated Primary Completion Date :
Nov 30, 2022
Anticipated Study Completion Date :
Nov 30, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (azacitidine, pembrolizumab)

Patients receive azacitidine Intravenous (IV) over 10-40 minutes or Subcutaneous (SC) on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Drug: Azacitidine
Given IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza
  • Biological: Pembrolizumab
    Given IV
    Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475
  • Outcome Measures

    Primary Outcome Measures

    1. Overall Response Rate (ORR) Defined as Complete Response + Partial Response + Hematological Improvement [Up to 2 years 4 months]

      Will estimate the ORR for the experimental treatments, along with the 95% credible intervals. The association between ORR and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.

    2. Event Free Survival [Up to 4 years]

      Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.

    3. Overall Survival [Up to 4 years]

      Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests. Overall Survival will be presented by median survival, which is the time point at which the cumulative survival drops below 50%. If there is no median survival (not reached), it means the cumulative survival was more than 50%.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Voluntary signed informed consent before performance of any study related procedure not part of normal medical care indicating that the patient is aware of the investigation and nature of this study in keeping with institutional policies and with the understanding that the consent may be withdrawn with the subject at any time without prejudice to future medical care

    • Intermediate 1 (INT-1) or higher risk MDS defined by International Prognostic Scoring System (IPSS) criteria

    • Patients can or cannot have receive prior therapy with hypomethylating agent but will be allocated to specific patient cohorts based on their prior exposure. Patients that had received prior hypomethylating agent therapy should have at least received 6 cycles of therapy and not achieved any response or had progressed after any given number of cycles

    • Eastern Cooperative Oncology Group (ECOG) performance of 0 to 2

    • Male patients, even if surgically sterilized, should agree to practice effective barrier contraception for the entire study treatment period and through 120 days after the last dose of the study treatment or agree to completely abstain from heterosexual intercourse. Female patients who are postmenopausal for at least one year before the screening visit or are surgical sterile or if they are of child bearing potential must have a negative pregnancy test within 72 hours of treatment of the start date and agree to practice two effective methods of contraception forms at the same time from the time of signing the informed consent through 120 days of the last dose of the study treatment or agree to completely abstain from heterosexual intercourse

    • Willingness and ability to comply with scheduled visits treatment plans, laboratory tests and other study procedures

    • Serum creatinine or measured or calculated creatine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrcL]) =< 2.0 x upper limit of normal (ULN) or >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (performed within 10 days of treatment initiation). Creatinine clearance should be calculated per institutional standard

    • Serum total bilirubin =< 2.0 x ULN (unless considered due to Gilbert's disease or leukemia disease) or direct bilirubin =< ULN for subjects with total bilirubin levels

    1.5 ULN (performed within 10 days of treatment initiation)

    • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (unless considered due to Gilbert's disease or leukemia disease) or =< 5 x ULN for subjects with liver metastases (performed within 10 days of treatment initiation)

    • Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

    • Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year

    • Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

    • Patients must receive a minimum dose of azacitidine of 75mg/(m)(2) dose

    Exclusion Criteria:
    • Significant medical psychiatric cognitive or other conditions that may compromise the patient ability to understand the patient information to give informed consent to comply with the study protocol or to complete the study

    • Any severe or concurrent disease or condition including uncontrolled systemic infection, congestive heart failure, angina pectoris or cardiac arrhythmia and autoimmune processes that in the opinion of the investigator would make the patient inappropriate for study participation

    • Patients with known hypersensitivity to 5-azacitidine or MK3475 or any of their excipients

    • Prior history of stem cell transplantation

    • For patients in the relapse or refractory cohort, any other therapy not being a hypomethylating agent after hypomethylating agents (HMA) failure or more than 4 months since completion of last cycle of hypomethylating agent. Please note that hypomethylating agent may include second generation compounds such as SGI-110, oral decitabine or oral azacitidine and will also include combinations with investigational agents

    • Treatment with other investigational agents including chemotherapy, immunotherapy, or radiation therapy within a month prior to the start of this clinical trial

    • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment

    • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment

    • Has a known history of active TB (Bacillus tuberculosis)

    • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier

    • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

    • Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer

    • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability

    • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment

    • Has known history of, or any evidence of active, non-infectious pneumonitis

    • Has an active infection requiring systemic therapy

    • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

    • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

    • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment

    • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

    • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

    • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

    • Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 M D Anderson Cancer Center Houston Texas United States 77030

    Sponsors and Collaborators

    • M.D. Anderson Cancer Center
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Guillermo Garcia-Manero, M.D. Anderson Cancer Center

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT03094637
    Other Study ID Numbers:
    • 2016-0343
    • NCI-2018-01238
    • 2016-0343
    First Posted:
    Mar 29, 2017
    Last Update Posted:
    Aug 15, 2022
    Last Verified:
    Aug 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Recruitment Period: November 2017 to March 2020
    Pre-assignment Detail
    Arm/Group Title Treatment (Azacitidine, Pembrolizumab) in Untreated Patients Treatment (Azacitidine, Pembrolizumab) Patients With Hypomethylating Agent (HMA) failureHMA Failure
    Arm/Group Description Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV
    Period Title: Overall Study
    STARTED 17 20
    COMPLETED 17 20
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Treatment (Azacitidine, Pembrolizumab) in Untreated Patients Treatment (Azacitidine, Pembrolizumab) Patients With Hypomethylating Agent (HMA) Failure Total
    Arm/Group Description Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV Total of all reporting groups
    Overall Participants 17 20 37
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    4
    23.5%
    0
    0%
    4
    10.8%
    >=65 years
    13
    76.5%
    20
    100%
    33
    89.2%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    72
    75
    74
    Sex: Female, Male (Count of Participants)
    Female
    7
    41.2%
    5
    25%
    12
    32.4%
    Male
    10
    58.8%
    15
    75%
    25
    67.6%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    White
    16
    94.1%
    19
    95%
    35
    94.6%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    1
    5.9%
    1
    5%
    2
    5.4%
    Region of Enrollment (participants) [Number]
    United States
    17
    100%
    20
    100%
    37
    100%

    Outcome Measures

    1. Primary Outcome
    Title Overall Response Rate (ORR) Defined as Complete Response + Partial Response + Hematological Improvement
    Description Will estimate the ORR for the experimental treatments, along with the 95% credible intervals. The association between ORR and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
    Time Frame Up to 2 years 4 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Azacitidine, Pembrolizumab) in Untreated Patients Treatment (Azacitidine, Pembrolizumab) Patients With Hypomethylating Agent (HMA) Failure
    Arm/Group Description Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV
    Measure Participants 17 20
    Count of Participants [Participants]
    13
    76.5%
    5
    25%
    2. Primary Outcome
    Title Event Free Survival
    Description Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.
    Time Frame Up to 4 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Azacitidine, Pembrolizumab) in Untreated Patients Treatment (Azacitidine, Pembrolizumab) Patients With Hypomethylating Agent (HMA) failureHMA Failure
    Arm/Group Description Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV
    Measure Participants 17 20
    Median (95% Confidence Interval) [Months]
    9.24
    5.39
    3. Primary Outcome
    Title Overall Survival
    Description Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests. Overall Survival will be presented by median survival, which is the time point at which the cumulative survival drops below 50%. If there is no median survival (not reached), it means the cumulative survival was more than 50%.
    Time Frame Up to 4 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Azacitidine, Pembrolizumab) in Untreated Patients Treatment (Azacitidine, Pembrolizumab) Patients With Hypomethylating Agent (HMA) failureHMA Failure
    Arm/Group Description Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV
    Measure Participants 17 20
    Median (Full Range) [Months]
    NA
    5.79

    Adverse Events

    Time Frame Up to 3 years
    Adverse Event Reporting Description
    Arm/Group Title Treatment (Azacitidine, Pembrolizumab) in Untreated Patients Treatment (Azacitidine, Pembrolizumab) Patients With Hypomethylating Agent (HMA) Failure
    Arm/Group Description Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Azacitidine: Given IV Pembrolizumab: Given IV
    All Cause Mortality
    Treatment (Azacitidine, Pembrolizumab) in Untreated Patients Treatment (Azacitidine, Pembrolizumab) Patients With Hypomethylating Agent (HMA) Failure
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/17 (5.9%) 2/20 (10%)
    Serious Adverse Events
    Treatment (Azacitidine, Pembrolizumab) in Untreated Patients Treatment (Azacitidine, Pembrolizumab) Patients With Hypomethylating Agent (HMA) Failure
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 9/17 (52.9%) 13/20 (65%)
    Blood and lymphatic system disorders
    Neutropenic Fever 1/17 (5.9%) 1 2/20 (10%) 4
    anemia 1/17 (5.9%) 1 1/20 (5%) 1
    Leukocytes 0/17 (0%) 0 1/20 (5%) 1
    Neutrophils 0/17 (0%) 0 1/20 (5%) 1
    Gastrointestinal disorders
    Colitis 1/17 (5.9%) 1 0/20 (0%) 0
    General disorders
    Fatigue 0/17 (0%) 0 1/20 (5%) 1
    fever 1/17 (5.9%) 1 0/20 (0%) 0
    Pain 1/17 (5.9%) 1 1/20 (5%) 1
    Hepatobiliary disorders
    Hepatobiliary/Pancreas 1/17 (5.9%) 1 0/20 (0%) 0
    Infections and infestations
    Infection 4/17 (23.5%) 6 11/20 (55%) 12
    Infection G 3 or 4 neutrophils 1/17 (5.9%) 1 1/20 (5%) 1
    Injury, poisoning and procedural complications
    Intra-operative Injury 0/17 (0%) 0 1/20 (5%) 1
    Investigations
    Hyperbilirubinemia 1/17 (5.9%) 2 0/20 (0%) 0
    Nervous system disorders
    Syncope 1/17 (5.9%) 1 0/20 (0%) 0
    Renal and urinary disorders
    Renal/Genitourinary 1/17 (5.9%) 1 0/20 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 1/17 (5.9%) 1 1/20 (5%) 1
    Skin and subcutaneous tissue disorders
    Pruritis/itching 0/17 (0%) 0 1/20 (5%) 1
    Other (Not Including Serious) Adverse Events
    Treatment (Azacitidine, Pembrolizumab) in Untreated Patients Treatment (Azacitidine, Pembrolizumab) Patients With Hypomethylating Agent (HMA) Failure
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 15/17 (88.2%) 14/20 (70%)
    Blood and lymphatic system disorders
    anemia 2/17 (11.8%) 2 0/20 (0%) 0
    Gastrointestinal disorders
    Nausea 3/17 (17.6%) 4 1/20 (5%) 1
    Anorexia 1/17 (5.9%) 1 1/20 (5%) 1
    Constipation 2/17 (11.8%) 2 6/20 (30%) 6
    Diarrhea 2/17 (11.8%) 2 0/20 (0%) 0
    General disorders
    Fever 0/17 (0%) 0 2/20 (10%) 2
    Injection Site Reaction 1/17 (5.9%) 1 2/20 (10%) 2
    Pain 6/17 (35.3%) 6 3/20 (15%) 3
    Infections and infestations
    Infection 3/17 (17.6%) 3 1/20 (5%) 2
    Investigations
    Alanine Aminotransferase 1/17 (5.9%) 1 4/20 (20%) 4
    Asparatate Aminotransferase 0/17 (0%) 0 4/20 (20%) 4
    Neutropenia 3/17 (17.6%) 3 7/20 (35%) 7
    Skin and subcutaneous tissue disorders
    Dermatology Skin/Other 2/17 (11.8%) 2 1/20 (5%) 1
    Pruritis/itching 1/17 (5.9%) 1 1/20 (5%) 1
    Rash/desquamation 3/17 (17.6%) 4 2/20 (10%) 2

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Guillermo Garcia-Manero MD/Professor
    Organization The University of Texas MD Anderson Cancer Center
    Phone 713-745-3428
    Email ggarciam@mdanderson.org
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT03094637
    Other Study ID Numbers:
    • 2016-0343
    • NCI-2018-01238
    • 2016-0343
    First Posted:
    Mar 29, 2017
    Last Update Posted:
    Aug 15, 2022
    Last Verified:
    Aug 1, 2022