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出境医 / 临床实验 / Nivolumab Consolidation in Older (≥ 65) Patients With Primary CNS Lymphoma

Nivolumab Consolidation in Older (≥ 65) Patients With Primary CNS Lymphoma

Study Description
Brief Summary:
The primary objective of Stage 1 is to evaluate the safety of nivolumab consolidation after completion of HD-MTX containing induction chemotherapy in older subjects with PCNSL in terms of a tolerated dose (based on dose-limiting toxicities) for the expansion phase of the study (Stage 2).The primary objective of Stage 2 is to evaluate the efficacy of nivolumab consolidation after completion of HD-MTX containing induction chemotherapy in terms of the 2-year progression-free survival rate and compare to relevant historical controls

Condition or disease Intervention/treatment Phase
Brain and Nervous System Eye and Orbit Drug: Nivolumab Phase 1

Detailed Description:
This is a 2-stage phase 1B study of nivolumab consolidation following completion of HD-MTX containing induction chemotherapy in older (≥ 65 years old) patients with previously untreated primary CNS lymphoma. Stage 1 is designed to evaluate the safety of nivolumab consolidation. We plan to use 3+3 design and start at the FDA approved single agent dose of nivolumab 480 mg intravenously every 4 weeks. Stage 2 is designed to evaluate the safety as well as efficacy of nivolumab consolidation after HD-MTX containing induction chemotherapy in an expansion cohort.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B Trial Nivolumab Consolidation Following Completion of High-Dose Methotrexate Containing Induction Chemotherapy in Older (≥ 65) Patients With Primary CNS Lymphoma
Actual Study Start Date : July 25, 2019
Estimated Primary Completion Date : May 2025
Estimated Study Completion Date : May 2025
Arms and Interventions
Arm Intervention/treatment
Experimental: Stage 1
Safety Run-In
Drug: Nivolumab
HD-MTX containing induction chemotherapy (per standard of care) followed by Nivolumab consolidation.

Experimental: Stage 2
Expansion Cohort
Drug: Nivolumab
HD-MTX containing induction chemotherapy (per standard of care) followed by Nivolumab consolidation.

Outcome Measures
Primary Outcome Measures :
  1. Safety of Nivolumab in Older Subjects [ Time Frame: Until up to 6 subjects can be adequately assessed for DLT. ]
    The primary endpoint for the Stage 1 phase of the study is dose-limiting toxicity which will be assessed for each Stage 1 subject using the DLT criteria

  2. Efficacy of Nivolumab [ Time Frame: 2 years ]
    The primary endpoint for the Stage 1 phase of the study is the 2-year progression-free endpoint which will be determined for each subject as a binary variable indicating if they are alive and progression-free at 2 years (PFS2)


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 2 years ]
    PFS is defined as the duration of time from enrollment to first occurrence of either progressive disease or death.

  2. Overall Survival (OS) [ Time Frame: 2 years ]
    OS is defined as the duration from enrollment to the date of death from any cause.

  3. Objective and Complete Response Rates [ Time Frame: approx. 2 years ]
    Objective response will be determined for each subject as a binary variable indicating if they have achieved a best overall response of CR or PR as determined by the International Criteria for PCNSL (IPCG). Complete response will be determined for each subject as a binary variable indicating if they have achieved a best overall response of CR as determined by the International Criteria for PCNSL(IPCG).

  4. Conversion Rate from Partial to Complete Response [ Time Frame: approx. 2 years ]
    Response conversion will be determined for each subject who achieve a best overall response of PR during induction therapy as a binary variable indicating if the subsequently achieve a best overall response of CR to nivolumab consolidation therapy.


Eligibility Criteria
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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects must meet all of the following criteria to participate in this study:

  1. Written informed consent and HIPAA authorization for release of personal health information of subject or subject's legally authorized representative.
  2. Age ≥ 65 years at the time of consent
  3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 3 within 14 days prior to day 1 of treatment
  4. Histological or cytological confirmation of PCNSL, CD20 positive by immunohistochemistry
  5. Received at least 2 cycles of high-dose methotrexate (HD-MTX) containing induction chemotherapy per institutional standard (R-MPV preferred; see Appendix VI ) without evidence of progressive disease. No less than 4 weeks and no more than 8 weeks may have elapsed between last dose of HD-MTX containing induction chemotherapy and day 1 of study treatment
  6. Recovered from all reversible acute toxic effects of prior therapy (other than alopecia) to ≤ Grade 1 or baseline)
  7. Measurable disease at the time of diagnosis (i.e. prior to pre-study HD-MTX containing induction chemotherapy) including lesions that can be accurately measured in 2 dimensions by CT or MRI of brain and with a greatest transverse diameter of ≥ 1 cm. The following disease assessments must have been obtained prior to initiation of pre-study HD-MTX containing induction chemotherapy: MRI of the brain (and spine if indicated)
  8. Deemed poor candidate for whole brain irradiation (WBI) or autologous stem cell transplant (ASCT) due to advanced age, ECOG performance status of 2, or in the opinion of the treating physician, subject would not tolerate the administration of WBI or ASCT for other reasons
  9. Life expectancy of at least 3 months
  10. Demonstrate adequate organ function as defined below (all screening labs to be obtained within 14 days prior to day 1 of treatment):

    1. Absolute Neutrophil Count (ANC) ≥ 1000K/mm3
    2. Platelet Count ≥ 75 K/mm3
    3. Hemoglobin (Hgb) ≥ 8 g/dL
    4. Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 cc/minute as measured by a 24-hour urine collection or estimated by the Cockcroft and Gault formula
    5. Bilirubin ≤ 1.5 x upper limit of normal (ULN) (except subjects with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN)
    6. Aspartate aminotransferase (AST) ≤ 3 x ULN
    7. Alanine aminotransferase (ALT) ≤ 3 x ULN
  11. Females of childbearing potential (FCBP) must have a negative serum pregnancy test within 3 days prior to day 1 of treatment. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause).
  12. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a failure rate of <1% per year when used consistently and correctly) from the time of informed consent until 5 months after treatment discontinuation. Contraceptive methods with low user dependency are preferable but not required. (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf)
  13. Male subjects must be willing to use condoms from the time of treatment initiation until 7 months after last dose of nivolumab. For a non-pregnant FCBP partner, contraception recommendations should also be considered.
  14. As determined by the enrolling physician, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria:

Subjects must not meet any of the following criteria:

  1. Documented or suspected ophthalmologic involvement at the time of enrollment as determined by the investigator. Subjects with ophthalmologic involvement prior to or during pre-study induction are allowed if there is no evidence of ophthalmologic involvement prior to enrollment as determined by the investigator.
  2. Any concurrent systemic involvement by lymphoma outside CNS or intraocular lymphoma without evidence of brain disease
  3. Any previous chemotherapy or radiation therapy for PCNSL except for treatment with a HD-MTX containing induction chemotherapy. Subjects treated with corticosteroids for PCNSL are allowed.
  4. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
  5. Has a known additional malignancy within the past 5 years that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or carcinoma of the prostrate with a current PSA value of <0.5 ng/mL or other cancer for which subject has completed treatment, been disease-free for at least five years, and is considered by Sponsor-Investigator to be at <30% risk of relapse, or on hormonal therapy for a history of either prostate cancer or breast cancer, provided that there has been no evidence of disease progression during the previous three years.
  6. Treatment with any investigational drug (including drugs not FDA-approved for the indication for which they are given) within 28 days prior to day 1 of treatment
  7. Subjects with active, uncontrolled infections (subjects must be afebrile for >48 hours off systemic antibiotics).
  8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements as determined by the investigator.
  9. Major surgery and/or radiotherapy within 14 days prior to initiation of study treatment
  10. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally.
  11. Active infectious hepatitis, type B or C. Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) may be included if HBV DNA is undetectable.
  12. Subjects with active interstitial pneumonitis.
  13. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Kelly Bumgarner, RN 704-403-2520 Kelly.Bumgarner@atriumhealth.org

Locations
Layout table for location information
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Brookline, Massachusetts, United States, 02215
Contact: Meghan Cifrino, RN    617-632-2166    Meghan_Cifrino@DFCI.HARVARD.EDU   
Principal Investigator: Lakshmi Nayak, MD         
United States, North Carolina
UNC Hospitals, The University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Kelly Hoye    919-843-9819    kelly_hoye@med.unc.edu   
Principal Investigator: Christopher Dittus, MD         
Levine Cancer Institute Recruiting
Charlotte, North Carolina, United States, 28204
Contact: Kelly Bumgarner, RN    704-403-2520    Kelly.Bumgarner@atriumhealth.org   
Principal Investigator: Steven Park, MD         
United States, Texas
The University of Texas - MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Anuoluwa Ogunlere, RN    713-563-1630    AOOgunlere@mdanderson.org   
Principal Investigator: Raphael Steiner, MD         
Sponsors and Collaborators
Steven Park, MD
Bristol-Myers Squibb
Investigators
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Principal Investigator: Steven Park, MD Atrium Health
Tracking Information
First Submitted Date  ICMJE July 12, 2019
First Posted Date  ICMJE July 17, 2019
Last Update Posted Date May 7, 2021
Actual Study Start Date  ICMJE July 25, 2019
Estimated Primary Completion Date May 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 16, 2020)
  • Safety of Nivolumab in Older Subjects [ Time Frame: Until up to 6 subjects can be adequately assessed for DLT. ]
    The primary endpoint for the Stage 1 phase of the study is dose-limiting toxicity which will be assessed for each Stage 1 subject using the DLT criteria
  • Efficacy of Nivolumab [ Time Frame: 2 years ]
    The primary endpoint for the Stage 1 phase of the study is the 2-year progression-free endpoint which will be determined for each subject as a binary variable indicating if they are alive and progression-free at 2 years (PFS2)
Original Primary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
  • Stage 1 is to evaluate the safety of Nivolumab consolidation after R-MPV [ Time Frame: Until up to 6 subjects can be adequately assessed for DLT. ]
    Stage 1 is to evaluate the safety of Nivolumab consolidation after R-MPV induction chemotherapy in older subjects with previously untreated PCNSL in terms of a tolerated dose (based on dose-limiting toxicities (DLT)) for the expansion phase of the study (Stage 2).
  • The primary objective of Stage 2 is to evaluate the efficacy of Nivolumab consolidation after R-MPV [ Time Frame: 2 years. ]
    The primary objective of Stage 2 is to evaluate the efficacy of Nivolumab consolidation after R-MPV induction chemotherapy in terms of the 2-year progression-free survival rate.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 16, 2020)
  • Progression Free Survival (PFS) [ Time Frame: 2 years ]
    PFS is defined as the duration of time from enrollment to first occurrence of either progressive disease or death.
  • Overall Survival (OS) [ Time Frame: 2 years ]
    OS is defined as the duration from enrollment to the date of death from any cause.
  • Objective and Complete Response Rates [ Time Frame: approx. 2 years ]
    Objective response will be determined for each subject as a binary variable indicating if they have achieved a best overall response of CR or PR as determined by the International Criteria for PCNSL (IPCG). Complete response will be determined for each subject as a binary variable indicating if they have achieved a best overall response of CR as determined by the International Criteria for PCNSL(IPCG).
  • Conversion Rate from Partial to Complete Response [ Time Frame: approx. 2 years ]
    Response conversion will be determined for each subject who achieve a best overall response of PR during induction therapy as a binary variable indicating if the subsequently achieve a best overall response of CR to nivolumab consolidation therapy.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
  • To evaluate progression-free survival (PFS) in older subjects with previously untreated PCNSL who received R-MPV induction chemotherapy followed by Nivolumab consolidation therapy. [ Time Frame: 2 years. ]
  • To evaluate overall survival (OS) and estimate the OS rate at 2 years in older subjects with previously untreated PCNSL who received R-MPV induction chemotherapy followed by Nivolumab consolidation therapy. [ Time Frame: 2 years. ]
  • To estimate objective and complete response rates in this subject population. [ Time Frame: Through study completion, an average of 2 years. ]
  • To estimate conversion rate from partial to complete response before and after Nivolumab consolidation therapy. [ Time Frame: Through study completion, an average of 2 years. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nivolumab Consolidation in Older (≥ 65) Patients With Primary CNS Lymphoma
Official Title  ICMJE A Phase 1B Trial Nivolumab Consolidation Following Completion of High-Dose Methotrexate Containing Induction Chemotherapy in Older (≥ 65) Patients With Primary CNS Lymphoma
Brief Summary The primary objective of Stage 1 is to evaluate the safety of nivolumab consolidation after completion of HD-MTX containing induction chemotherapy in older subjects with PCNSL in terms of a tolerated dose (based on dose-limiting toxicities) for the expansion phase of the study (Stage 2).The primary objective of Stage 2 is to evaluate the efficacy of nivolumab consolidation after completion of HD-MTX containing induction chemotherapy in terms of the 2-year progression-free survival rate and compare to relevant historical controls
Detailed Description This is a 2-stage phase 1B study of nivolumab consolidation following completion of HD-MTX containing induction chemotherapy in older (≥ 65 years old) patients with previously untreated primary CNS lymphoma. Stage 1 is designed to evaluate the safety of nivolumab consolidation. We plan to use 3+3 design and start at the FDA approved single agent dose of nivolumab 480 mg intravenously every 4 weeks. Stage 2 is designed to evaluate the safety as well as efficacy of nivolumab consolidation after HD-MTX containing induction chemotherapy in an expansion cohort.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Brain and Nervous System
  • Eye and Orbit
Intervention  ICMJE Drug: Nivolumab
HD-MTX containing induction chemotherapy (per standard of care) followed by Nivolumab consolidation.
Study Arms  ICMJE
  • Experimental: Stage 1
    Safety Run-In
    Intervention: Drug: Nivolumab
  • Experimental: Stage 2
    Expansion Cohort
    Intervention: Drug: Nivolumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 15, 2019)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2025
Estimated Primary Completion Date May 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Subjects must meet all of the following criteria to participate in this study:

  1. Written informed consent and HIPAA authorization for release of personal health information of subject or subject's legally authorized representative.
  2. Age ≥ 65 years at the time of consent
  3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 3 within 14 days prior to day 1 of treatment
  4. Histological or cytological confirmation of PCNSL, CD20 positive by immunohistochemistry
  5. Received at least 2 cycles of high-dose methotrexate (HD-MTX) containing induction chemotherapy per institutional standard (R-MPV preferred; see Appendix VI ) without evidence of progressive disease. No less than 4 weeks and no more than 8 weeks may have elapsed between last dose of HD-MTX containing induction chemotherapy and day 1 of study treatment
  6. Recovered from all reversible acute toxic effects of prior therapy (other than alopecia) to ≤ Grade 1 or baseline)
  7. Measurable disease at the time of diagnosis (i.e. prior to pre-study HD-MTX containing induction chemotherapy) including lesions that can be accurately measured in 2 dimensions by CT or MRI of brain and with a greatest transverse diameter of ≥ 1 cm. The following disease assessments must have been obtained prior to initiation of pre-study HD-MTX containing induction chemotherapy: MRI of the brain (and spine if indicated)
  8. Deemed poor candidate for whole brain irradiation (WBI) or autologous stem cell transplant (ASCT) due to advanced age, ECOG performance status of 2, or in the opinion of the treating physician, subject would not tolerate the administration of WBI or ASCT for other reasons
  9. Life expectancy of at least 3 months
  10. Demonstrate adequate organ function as defined below (all screening labs to be obtained within 14 days prior to day 1 of treatment):

    1. Absolute Neutrophil Count (ANC) ≥ 1000K/mm3
    2. Platelet Count ≥ 75 K/mm3
    3. Hemoglobin (Hgb) ≥ 8 g/dL
    4. Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 cc/minute as measured by a 24-hour urine collection or estimated by the Cockcroft and Gault formula
    5. Bilirubin ≤ 1.5 x upper limit of normal (ULN) (except subjects with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN)
    6. Aspartate aminotransferase (AST) ≤ 3 x ULN
    7. Alanine aminotransferase (ALT) ≤ 3 x ULN
  11. Females of childbearing potential (FCBP) must have a negative serum pregnancy test within 3 days prior to day 1 of treatment. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause).
  12. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a failure rate of <1% per year when used consistently and correctly) from the time of informed consent until 5 months after treatment discontinuation. Contraceptive methods with low user dependency are preferable but not required. (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf)
  13. Male subjects must be willing to use condoms from the time of treatment initiation until 7 months after last dose of nivolumab. For a non-pregnant FCBP partner, contraception recommendations should also be considered.
  14. As determined by the enrolling physician, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria:

Subjects must not meet any of the following criteria:

  1. Documented or suspected ophthalmologic involvement at the time of enrollment as determined by the investigator. Subjects with ophthalmologic involvement prior to or during pre-study induction are allowed if there is no evidence of ophthalmologic involvement prior to enrollment as determined by the investigator.
  2. Any concurrent systemic involvement by lymphoma outside CNS or intraocular lymphoma without evidence of brain disease
  3. Any previous chemotherapy or radiation therapy for PCNSL except for treatment with a HD-MTX containing induction chemotherapy. Subjects treated with corticosteroids for PCNSL are allowed.
  4. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
  5. Has a known additional malignancy within the past 5 years that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or carcinoma of the prostrate with a current PSA value of <0.5 ng/mL or other cancer for which subject has completed treatment, been disease-free for at least five years, and is considered by Sponsor-Investigator to be at <30% risk of relapse, or on hormonal therapy for a history of either prostate cancer or breast cancer, provided that there has been no evidence of disease progression during the previous three years.
  6. Treatment with any investigational drug (including drugs not FDA-approved for the indication for which they are given) within 28 days prior to day 1 of treatment
  7. Subjects with active, uncontrolled infections (subjects must be afebrile for >48 hours off systemic antibiotics).
  8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements as determined by the investigator.
  9. Major surgery and/or radiotherapy within 14 days prior to initiation of study treatment
  10. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally.
  11. Active infectious hepatitis, type B or C. Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) may be included if HBV DNA is undetectable.
  12. Subjects with active interstitial pneumonitis.
  13. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 65 Years and older   (Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kelly Bumgarner, RN 704-403-2520 Kelly.Bumgarner@atriumhealth.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04022980
Other Study ID Numbers  ICMJE LCI-HEM-PCNSL-RMPV-001
00036735 ( Other Identifier: Advarra IRB )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Steven Park, MD, Atrium Health
Study Sponsor  ICMJE Steven Park, MD
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Steven Park, MD Atrium Health
PRS Account Atrium Health
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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