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A(B)VD Followed by Nivolumab as Frontline Therapy for Higher Risk Patients With Classical Hodgkin Lymphoma (HL)

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ClinicalTrials.gov Identifier: NCT03033914
Recruitment Status : Recruiting
First Posted : January 27, 2017
Last Update Posted : April 10, 2019
Sponsor:
Collaborators:
Bristol-Myers Squibb
Barbara Ann Karmanos Cancer Institute
British Columbia Cancer Agency
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Tracking Information
First Submitted Date  ICMJE January 25, 2017
First Posted Date  ICMJE January 27, 2017
Last Update Posted Date April 10, 2019
Actual Study Start Date  ICMJE January 25, 2017
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 20, 2018)
  • number of patients who have dose limiting toxicity [ Time Frame: 2 years ]
    For this objective, the standard 3+3 scheme will be used. Initially, 3 patients will enroll onto dose level 1. If no patients experience DLT, enrollment will proceed to the next dose level. If 1 DLT is observed, 3 additional patients will enroll onto dose level 1. If 1 or fewer patients out of 6 experience DLT, enrollment will proceed to the next dose level. If 2 or more DLTs are observed at a given dose level, the previous dose will be declared the MTD. Adverse events will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be used.
  • Phase II- progression free survival [ Time Frame: 2 year ]
    The updated response criteria entitled "The Lugano Classification" system will be applied to define complete response, partial response, and progression of disease in this study.
Original Primary Outcome Measures  ICMJE
 (submitted: January 25, 2017)
number of patients who have dose limiting toxicity [ Time Frame: 2 years ]
For this objective, the standard 3+3 scheme will be used. Initially, 3 patients will enroll onto dose level 1. If no patients experience DLT, enrollment will proceed to the next dose level. If 1 DLT is observed, 3 additional patients will enroll onto dose level 1. If 1 or fewer patients out of 6 experience DLT, enrollment will proceed to the next dose level. If 2 or more DLTs are observed at a given dose level, the previous dose will be declared the MTD. Adverse events will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be used.
Change History Complete list of historical versions of study NCT03033914 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A(B)VD Followed by Nivolumab as Frontline Therapy for Higher Risk Patients With Classical Hodgkin Lymphoma (HL)
Official Title  ICMJE Phase I/II of Nivolumab and A(B)VD in the Front-line Setting for High Risk Hodgkin Lymphoma
Brief Summary The aim of this study is to improve the chance of cure for people with higher risk Hodgkin lymphoma. The purpose of the Phase I study is to test any good and bad effects of the study drug called Nivolumab when combined with ABVD for the front-line treatment of HL.The purpose of this Phase II study is to test whether including nivolumab in treatment for untreated Hodgkin lymphoma can improve the chance of cure for patients with abnormal PET scans after 2 cycles of ABVD.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Cohort A will include patients less than 60 years of age with advanced stage (Stage III or IV) classical Hodgkin lymphoma (HL) who are at higer risk for relapse due to baseline international prognostic score (IPS) of 3-7 or positive PET scan after 2 cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) ("PET-2 positive").
Masking: None (Open Label)
Masking Description:
Cohort B will include patients 60 years of age and older with HL (any stage). AVD (adriamycin,vinblastine, dacarbazine)
Primary Purpose: Treatment
Condition  ICMJE Hodgkin Lymphoma
Intervention  ICMJE
  • Drug: doxorubicin
    Doxorubicin: 25 mg/m^2 will be administered by IV infusion on Days 1 and 15 of each 28-day cycle
  • Drug: Bleomycin
    Bleomycin: 10 units/m^2 will be administered by IV infusion on Days 1 and 15 of each 28-day cycle
  • Drug: vinblastine
    Vinblastine: 6 mg/m^2 will be administered by IV infusion on Days 1 and 15 of each 28-day cycle
  • Drug: dacarbazine
    Dacarbazine (DTIC): 375 mg/m^2 will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.
  • Drug: Nivolumab
    nivolumab 240mg q14 days
Study Arms  ICMJE
  • Experimental: < 60 years of age with advanced stage (HL) untreated
    The study will employ a 3+3 design and include 3 treatment cohorts. In each cohort, patients will receive 6 cycles of A(B)VD and 8 doses of nivolumab. In dose level 1, patients will receive nivolumab in combination with AVD during cycle 6 only followed by 6 additional doses of nivolumab. In subsequent dose levels, nivolumab will be combined with increasing numbers of cycles of AVD. Based upon safety data from another study with Nivolumab, we will no longer need to evaluate dose level 2. If we determine that dose level 1 is safe, the next group of patients will enroll onto dose level 3. A PET scan will be performed after 2 cycles of ABVD and those with a PET-negative response (defined by Deauville 1, 2 or 3) will proceed with 4 additional cycles of ABVD or AVD (per treating physician preference).
    Interventions:
    • Drug: doxorubicin
    • Drug: Bleomycin
    • Drug: vinblastine
    • Drug: dacarbazine
    • Drug: Nivolumab
  • Experimental: 60 years of age and older with HL (any stage) untreated
    The study will employ a 3+3 design and include 3 treatment cohorts. In each cohort, patients will receive 6 cycles of AVD and 12 doses of nivolumab. In this cohort, patients will receive nivolumab in combination with AVD during cycles 5 and 6 only, followed by 8 additional doses of nivolumab. In subsequent cohorts, nivolumab will be combined with increasing numbers of cycles of AVD. Based upon safety data from another study with Nivolumab, we will no longer need to evaluate dose level 2. If we determine that dose level 1 is safe, the next group of patients will enroll onto dose level 3.
    Interventions:
    • Drug: doxorubicin
    • Drug: vinblastine
    • Drug: dacarbazine
    • 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: January 25, 2017)
26
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2020
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Cohort A overview: Patients age less than 60 with untreated stage III or IV classical Hodgkin lymphoma will be eligible for cohort A. In phase I, patients could enroll onto cohort A if they had have a baseline IPS ≥3 OR if their PET scan after 2 cycles of ABVD is positive (Deauville 4 or 5). Enrollment onto phase I has now ceased and enrollment will begin for phase II. In phase II, patients less than 60 years of age with stage III or IV HL are eligible. Patients may enroll anytime within the first 2 cycles of ABVD or after PET-2.
  • Cohort B overview: Patients 60 or older with untreated classical Hodgkin lymphoma (regardless of stage) will be eligible for cohort B.

The following eligibility criteria applies to both cohort A and B except when stated otherwise:

  • Histologic diagnosis of classical Hodgkin lymphoma

    • FDG-avid disease by FDG-PET/CT
    • Ann Arbor Stage III or IV disease (Cohort A only)
    • WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 2 weeks prior to the start of study drug. Women who undergo fertility preservation within 2 weeks of beginning chemotherapy are expected to have false-positive pregnancy tests and therefore testing may be waived for these patients.
    • WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. Women who undergo fertility preservation within 2 weeks of beginning chemotherapy are expected to have false-positive pregnancy tests and therefore testing may be waived for these patients.
    • Women must not be breastfeeding
  • Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 5 half-lives of study drug plus 90 days (duration of sperm turnover) for a total of 31 weeks posttreatment completion
  • Age ≥ 18
  • Serum creatinine ≤ 1.5 x Upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 40 mL/min (measured using the Cockcroft-Gault formula
  • AST/ALT ≤ 3 x ULN (5x ULN for those with lymphoma involvement of the liver)
  • Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

Exclusion Criteria:

  • Subjects with active brain metastases or leptomeningeal metastases.
  • Subjects with nodular lymphocyte-predominant HL
  • Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
  • Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
  • 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.
  • Subjects with a condition requiring systemic treatment with systemic corticosteroids (equivalent of >10mg/day of prednisone). Patients may receive steroid therapy if steroids are tapered down to 10mg or less by 4 weeks after initiating A(B)VD to control lymphoma-related symptoms.
  • Any of the following cardiovascular conditions or values within 6 months before the first dose of study drug:

    • A left-ventricular ejection fraction < 50%
    • Myocardial infarction within 2 years of randomization
    • New York Heart Association (NYHA) Class III or IV heart failure
  • Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  • Any positive test for hepatitis B virus or hepatitis C virus indicating acute infection.
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  • History of severe hypersensitivity reaction to any monoclonal antibody.
  • Adjusted DLCO <60%
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: Alison Moskowitz, MD 212-639-4839 moskowia@mskcc.org
Contact: Anas Younes, MD 212-639-5059
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03033914
Other Study ID Numbers  ICMJE 16-1536
CA209-447 ( Other Identifier: BMS )
Has Data Monitoring Committee Not Provided
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 Memorial Sloan Kettering Cancer Center
Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE
  • Bristol-Myers Squibb
  • Barbara Ann Karmanos Cancer Institute
  • British Columbia Cancer Agency
Investigators  ICMJE
Principal Investigator: Alison Moskowitz, MD Memorial Sloan Kettering Cancer Center
PRS Account Memorial Sloan Kettering Cancer Center
Verification Date April 2019

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