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出境医 / 临床实验 / Phase II Study of Short Course FOLFOX Chemotherapy With Either Nivolumab or Nivolumab + Radiation in the First Line Treatment of Metastatic or Unresectable Gastroesophageal Cancers (BMS Protocol CA209-76L)

Phase II Study of Short Course FOLFOX Chemotherapy With Either Nivolumab or Nivolumab + Radiation in the First Line Treatment of Metastatic or Unresectable Gastroesophageal Cancers (BMS Protocol CA209-76L)

Study Description
Brief Summary:
This is a randomized phase II study examining nivolumab alone versus radiation therapy with nivolumab in subjects who did not have disease progression to initial therapy with the combination of FOLFOX and Nivolumab.

Condition or disease Intervention/treatment Phase
Gastroesophageal Adenocarcinoma Drug: Nivolumab 240 MG Phase 2

Detailed Description:
This is a randomized phase II study examining nivolumab alone versus radiation therapy with nivolumab in subjects who did not have disease progression to initial therapy with the combination of FOLFOX and Nivolumab. Subjects with advanced unresectable or metastatic gastroesophageal adenocarcinoma are eligible. All subjects will receive FOLFOX + nivolumab therapy. Subjects who demonstrate at least stable disease, as per RECIST 1.1, on their first imaging assessment at two months will receive one additional month of FOLFOX + nivolumab (3 months total), and then will be randomly assigned at a 1:1 ratio to receive either nivolumab alone or nivolumab plus radiation therapy. Radiation therapy fields and technique will be approved by central review. Radiation will be planned at 4Gy x 5 doses (20 Gy total), given concurrently with nivolumab. After 4 months of therapy, patients who remain on study will receive nivolumab 480 mg every 4 weeks. Subjects will be on study (intervention + follow-up) for approximately 24 months. The projected end date of the study, including data analysis, is December 2023
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 74 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Short Course FOLFOX Chemotherapy With Either Nivolumab or Nivolumab + Radiation in the First Line Treatment of Metastatic or Unresectable Gastroesophageal Cancers (BMS Protocol CA209-76L)
Actual Study Start Date : July 22, 2019
Estimated Primary Completion Date : January 8, 2022
Estimated Study Completion Date : January 8, 2022
Arms and Interventions
Arm Intervention/treatment
Cohort 1

Subjects will receive standard dose FOLFOX plus nivolumab 240mg IV every 2 weeks for 2 months. If you are responding to treatment, you will receive FOLFOX plus nivolumab for one additional month and then you will be randomized to Cohort 1 or Cohort 2.

Subjects in Cohort 1 will receive Nivolumab alone (every 2 weeks for two doses, and then every 4 weeks)

Drug: Nivolumab 240 MG
Nivolumab (OpdivoTM) is a potent and highly selective humanized monoclonal antibody (mAB) designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Cancer cells are able to send a signal to the PD-1 via the PD-L1 molecule, tricking the T-cell into recognizing the cancer cell as normal. Nivolumab is designed to disrupt that signal and expose the cancer cell to the immune system. Nivolumab is given intravenously over a 60-minute period, usually every two weeks.

Experimental: Cohort 2

Subjects will receive standard dose FOLFOX plus nivolumab 240mg IV every 2 weeks for 2 months. If you are responding to treatment, you will receive FOLFOX plus nivolumab for one additional month and then you will be randomized to Cohort 1 or Cohort 2.

Subjects in Cohort 2 will receive Nivolumab (every 2 weeks for two doses, and then every 4 weeks) plus radiation therapy (total 5 sessions)

Drug: Nivolumab 240 MG
Nivolumab (OpdivoTM) is a potent and highly selective humanized monoclonal antibody (mAB) designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Cancer cells are able to send a signal to the PD-1 via the PD-L1 molecule, tricking the T-cell into recognizing the cancer cell as normal. Nivolumab is designed to disrupt that signal and expose the cancer cell to the immune system. Nivolumab is given intravenously over a 60-minute period, usually every two weeks.

Outcome Measures
Primary Outcome Measures :
  1. Number of patients with 12-month progression free survival [ Time Frame: 12 months ]
    This will be measured by number of patients without disease progression at 12 months in the two study arms (patients who receive nivolumab with radiation and those who receive nivolumab alone)


Secondary Outcome Measures :
  1. Number of subjects who receive short course chemotherapy with immunotherapy that achieve 12-month progression free survival [ Time Frame: 12 months ]
    This will be measured by the number of patients without disease progression at 12 months in all enrolled patients.

  2. Overall Survival, as measured by the rate of survival in patients [ Time Frame: 2 year ]
    In both study arms, and in all patients together, we will examine the rate of survival in patients over time from registration through their treatment

  3. Occurrence of Significant Toxicity, as measured by Number of Grade 3 and Grade 4 Adverse Events (Combined) Attributable to Immunotherapy [ Time Frame: 2 year ]
    We will measure the rate of grade 3 or 4 adverse events attributable to immunotherapy in both study arms


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Subjects with a diagnosis of advanced unresectable or metastatic gastroesophageal adenocarcinoma (eg. gastric, gastroesophageal junction, and esophageal adenocarcinoma)
  • Be willing and able to provide written informed consent/assent for the trial
  • Age > 18 years
  • ECOG performance status ≤ 1
  • Absolute neutrophil count ≥ 1,500/mL
  • Platelets ≥ 100,000/mL
  • Total bilirubin ≤ 1.5x upper limits of normal, unless the patient has known Gilbert's disease.
  • AST/ALT ≤ 2.5 upper limits of normal, or < 5x ULN for subjects with liver metastases
  • Creatinine ≤ 1.5 mg/dl. If Creatinine > 1.5 mg/dl, creatinine clearance > 60 ml/min
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 28 days prior to initiation of treatment on Day 1.
  • For all males and females of childbearing potential, they should be agreeable to use an adequate method of contraception or birth control. For females of child bearing potential, a negative pregnancy test within 7 days of start of study drug is required

Exclusion Criteria

  • Prior cytotoxic therapy for metastatic or incurable disease.
  • Patients may have had prior therapy with curative intent for localized disease, if their recurrence or disease progression was more than six months from completing prior therapy.
  • HER2 positive adenocarcinoma
  • 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.
  • Known history of active TB (Bacillus Tuberculosis)
  • Known additional malignancy that is active. 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.
  • Previous invasive malignancy treated with curative intent less than 3 years from time of registration. Exceptions include prostate cancer or basal cell skin cancer.
  • 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Known history of, or any evidence of active, non-infectious pneumonitis.
  • Active infection requiring systemic therapy.
  • 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.
  • 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.
  • Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Has received a live vaccine within 30 days of planned start of study therapy.
Contacts and Locations

Contacts
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Contact: Sarbina Machado, RN 646.962.3378 sam4006@med.cornell.edu
Contact: June Greenberg, BSN,RN,OCN,CCRP,CCRC (212)-746-2651 jdg2002@med.cornell.edu

Locations
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United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Rutika Mehta, MD, MPH       rutika.mehta@moffitt.org   
Principal Investigator: Rutika Mehta, MD, MPH         
United States, New York
Brooklyn Methodist Hospital Recruiting
Brooklyn, New York, United States, 11215
Contact: Lina Flores, RN       Lif9061@nyp.org   
Principal Investigator: Uqba Khan, MD         
Weill Cornell Medicine Recruiting
New York, New York, United States, 10065
Contact: Sabrina Machado, RN    646.962.3378    sam4006@med.cornell.edu   
Contact: June Greenberg, BSN,RN,OCN,CCRP,CCRC    (212)-746-2651    jdg2002@med.cornell.edu   
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
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Principal Investigator: Manish Shah, MD Weill Medical College of Cornell University
Tracking Information
First Submitted Date  ICMJE July 12, 2019
First Posted Date  ICMJE July 16, 2019
Last Update Posted Date June 24, 2020
Actual Study Start Date  ICMJE July 22, 2019
Estimated Primary Completion Date January 8, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 12, 2019)
Number of patients with 12-month progression free survival [ Time Frame: 12 months ]
This will be measured by number of patients without disease progression at 12 months in the two study arms (patients who receive nivolumab with radiation and those who receive nivolumab alone)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 12, 2019)
  • Number of subjects who receive short course chemotherapy with immunotherapy that achieve 12-month progression free survival [ Time Frame: 12 months ]
    This will be measured by the number of patients without disease progression at 12 months in all enrolled patients.
  • Overall Survival, as measured by the rate of survival in patients [ Time Frame: 2 year ]
    In both study arms, and in all patients together, we will examine the rate of survival in patients over time from registration through their treatment
  • Occurrence of Significant Toxicity, as measured by Number of Grade 3 and Grade 4 Adverse Events (Combined) Attributable to Immunotherapy [ Time Frame: 2 year ]
    We will measure the rate of grade 3 or 4 adverse events attributable to immunotherapy in both study arms
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase II Study of Short Course FOLFOX Chemotherapy With Either Nivolumab or Nivolumab + Radiation in the First Line Treatment of Metastatic or Unresectable Gastroesophageal Cancers (BMS Protocol CA209-76L)
Official Title  ICMJE Phase II Study of Short Course FOLFOX Chemotherapy With Either Nivolumab or Nivolumab + Radiation in the First Line Treatment of Metastatic or Unresectable Gastroesophageal Cancers (BMS Protocol CA209-76L)
Brief Summary This is a randomized phase II study examining nivolumab alone versus radiation therapy with nivolumab in subjects who did not have disease progression to initial therapy with the combination of FOLFOX and Nivolumab.
Detailed Description This is a randomized phase II study examining nivolumab alone versus radiation therapy with nivolumab in subjects who did not have disease progression to initial therapy with the combination of FOLFOX and Nivolumab. Subjects with advanced unresectable or metastatic gastroesophageal adenocarcinoma are eligible. All subjects will receive FOLFOX + nivolumab therapy. Subjects who demonstrate at least stable disease, as per RECIST 1.1, on their first imaging assessment at two months will receive one additional month of FOLFOX + nivolumab (3 months total), and then will be randomly assigned at a 1:1 ratio to receive either nivolumab alone or nivolumab plus radiation therapy. Radiation therapy fields and technique will be approved by central review. Radiation will be planned at 4Gy x 5 doses (20 Gy total), given concurrently with nivolumab. After 4 months of therapy, patients who remain on study will receive nivolumab 480 mg every 4 weeks. Subjects will be on study (intervention + follow-up) for approximately 24 months. The projected end date of the study, including data analysis, is December 2023
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Gastroesophageal Adenocarcinoma
Intervention  ICMJE Drug: Nivolumab 240 MG
Nivolumab (OpdivoTM) is a potent and highly selective humanized monoclonal antibody (mAB) designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Cancer cells are able to send a signal to the PD-1 via the PD-L1 molecule, tricking the T-cell into recognizing the cancer cell as normal. Nivolumab is designed to disrupt that signal and expose the cancer cell to the immune system. Nivolumab is given intravenously over a 60-minute period, usually every two weeks.
Study Arms  ICMJE
  • Cohort 1

    Subjects will receive standard dose FOLFOX plus nivolumab 240mg IV every 2 weeks for 2 months. If you are responding to treatment, you will receive FOLFOX plus nivolumab for one additional month and then you will be randomized to Cohort 1 or Cohort 2.

    Subjects in Cohort 1 will receive Nivolumab alone (every 2 weeks for two doses, and then every 4 weeks)

    Intervention: Drug: Nivolumab 240 MG
  • Experimental: Cohort 2

    Subjects will receive standard dose FOLFOX plus nivolumab 240mg IV every 2 weeks for 2 months. If you are responding to treatment, you will receive FOLFOX plus nivolumab for one additional month and then you will be randomized to Cohort 1 or Cohort 2.

    Subjects in Cohort 2 will receive Nivolumab (every 2 weeks for two doses, and then every 4 weeks) plus radiation therapy (total 5 sessions)

    Intervention: Drug: Nivolumab 240 MG
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 12, 2019)
74
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 8, 2022
Estimated Primary Completion Date January 8, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • Subjects with a diagnosis of advanced unresectable or metastatic gastroesophageal adenocarcinoma (eg. gastric, gastroesophageal junction, and esophageal adenocarcinoma)
  • Be willing and able to provide written informed consent/assent for the trial
  • Age > 18 years
  • ECOG performance status ≤ 1
  • Absolute neutrophil count ≥ 1,500/mL
  • Platelets ≥ 100,000/mL
  • Total bilirubin ≤ 1.5x upper limits of normal, unless the patient has known Gilbert's disease.
  • AST/ALT ≤ 2.5 upper limits of normal, or < 5x ULN for subjects with liver metastases
  • Creatinine ≤ 1.5 mg/dl. If Creatinine > 1.5 mg/dl, creatinine clearance > 60 ml/min
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 28 days prior to initiation of treatment on Day 1.
  • For all males and females of childbearing potential, they should be agreeable to use an adequate method of contraception or birth control. For females of child bearing potential, a negative pregnancy test within 7 days of start of study drug is required

Exclusion Criteria

  • Prior cytotoxic therapy for metastatic or incurable disease.
  • Patients may have had prior therapy with curative intent for localized disease, if their recurrence or disease progression was more than six months from completing prior therapy.
  • HER2 positive adenocarcinoma
  • 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.
  • Known history of active TB (Bacillus Tuberculosis)
  • Known additional malignancy that is active. 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.
  • Previous invasive malignancy treated with curative intent less than 3 years from time of registration. Exceptions include prostate cancer or basal cell skin cancer.
  • 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Known history of, or any evidence of active, non-infectious pneumonitis.
  • Active infection requiring systemic therapy.
  • 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.
  • 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.
  • Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Has received a live vaccine within 30 days of planned start of study therapy.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sarbina Machado, RN 646.962.3378 sam4006@med.cornell.edu
Contact: June Greenberg, BSN,RN,OCN,CCRP,CCRC (212)-746-2651 jdg2002@med.cornell.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04021108
Other Study ID Numbers  ICMJE 1812019872
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
Plan to Share IPD: No
Responsible Party Weill Medical College of Cornell University
Study Sponsor  ICMJE Weill Medical College of Cornell University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Manish Shah, MD Weill Medical College of Cornell University
PRS Account Weill Medical College of Cornell University
Verification Date June 2020

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

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