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Gemcitabine, Bendamustine, and Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma

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ClinicalTrials.gov Identifier: NCT03739619
Recruitment Status : Recruiting
First Posted : November 14, 2018
Last Update Posted : July 1, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Jonathon Cohen, Emory University

Brief Summary:
This phase I/II trial studies the side effects and best dose of gemcitabine, bendamustine, and nivolumab when given together and to see how well they work in treating patients with classic Hodgkin lymphoma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as gemcitabine and bendamustine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving gemcitabine, bendamustine, and nivolumab may work better in treating patients with classic Hodgkin lymphoma.

Condition or disease Intervention/treatment Phase
Recurrent Hodgkin Lymphoma Refractory Hodgkin Lymphoma Classical Hodgkin Lymphoma Hodgkin Lymphoma Drug: Bendamustine Drug: Gemcitabine Biological: Nivolumab Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the toxicity and determine the maximum tolerated dose (MTD) of combined gemcitabine, bendamustine, and nivolumab in patients with relapsed/refractory classical Hodgkin lymphoma.

II. To determine the efficacy of bendamustine, gemcitabine, and nivolumab in patients with relapsed/refractory classical Hodgkin lymphoma.

SECONDARY OBJECTIVES:

I. To evaluate the duration of response, progression-free survival, and overall survival for patients with relapsed/refractory classical Hodgkin lymphoma who receive gemcitabine, bendamustine, and nivolumab, including those who receive nivolumab maintenance.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive gemcitabine intravenously (IV) over 30 minutes on day 1, bendamustine IV over 30 minutes on days 1 and 2, and nivolumab over 60 minutes IV on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may then receive nivolumab IV over 60 minutes on day 1. Treatment with single agent nivolumab repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Gemcitabine, Bendamustine, and Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma
Actual Study Start Date : November 26, 2018
Estimated Primary Completion Date : November 30, 2022
Estimated Study Completion Date : November 30, 2022


Arm Intervention/treatment
Experimental: Gemcitabine, bendamustine, nivolumab
Patients receive gemcitabine IV over 30 minutes on day 1, bendamustine IV over 30 minutes on days 1 and 2, and nivolumab over 60 minutes IV on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may then receive nivolumab IV over 60 minutes on day 1. Treatment with single agent nivolumab repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Drug: Bendamustine
Given IV
Other Names:
  • Bendamustine Hydrochloride
  • Cytostasan Hydrochloride
  • Levact
  • Ribomustin
  • SyB L-0501
  • Treanda

Drug: Gemcitabine
Given IV
Other Names:
  • dFdC
  • dFdCyd
  • Difluorodeoxycytidine

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo




Primary Outcome Measures :
  1. Maximum tolerable dose (Phase I) [ Time Frame: Up to completion of course 2 at 42 days after study start ]
    Maximum tolerable dose will be defined as the highest dose level where at most 1 of 6 patients experience dose limiting toxicity (DLT).

  2. Complete response (CR) rate (Phase II) [ Time Frame: Up to 2 years from discontinuation of study therapy ]
    Complete response rate will be determined by dividing the number of CRs (per Lugano criteria) by the total number of evaluable patients.


Secondary Outcome Measures :
  1. Overall response rate (Phase II) [ Time Frame: Up to 2 years from discontinuation of study therapy ]
    Overall response rate will be evaluated using Lugano criteria of response. Overall response rate will be defined as the total number of patients achieving a partial response or CR as best response through cycle 6 divided by total number of patients treated.

  2. Duration of response (Phase II) [ Time Frame: Up to 2 years from discontinuation of study therapy ]
    Duration of response will be evaluated using Lugano criteria of response and will be determined from date of best response to progression or death.

  3. Progression free survival (PFS) (Phase II) [ Time Frame: Up to 2 years from discontinuation of study therapy ]
    Progression free survival will be evaluated using Lugano criteria and will be determined from date of first dose of study drug to progression or death.

  4. Overall survival (OS) (Phase II) [ Time Frame: Up to 2 years from discontinuation of study therapy ]
    Overall survival will be evaluated using Lugano criteria and will be determined from date of first dose of study drug to death from any cause.



Information from the National Library of Medicine

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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:

  • Histologically documented classical Hodgkin lymphoma that is recurrent or refractory after standard chemotherapy. Core biopsies are acceptable if they contain adequate tissue for primary diagnosis and immunophenotyping. Bone marrow biopsies as the sole means of diagnosis are not acceptable. At least one biopsy-proven relapse is required for enrollment, but patients who have multiply relapsed disease do not require repeat biopsy if not clinically indicated
  • Prior treatment: patients must have relapsed or progressed after at least one prior therapy

    • Patients with relapsed or refractory disease following autologous stem cell transplantation are permitted. Due to the risk of treatment-refractory graft versus host disease (GVHD), patients who have previously completed an allogeneic transplant are excluded.
    • Patients may have received gemcitabine, bendamustine, or nivolumab in the past but may not have discontinued therapy due to toxicity felt to be related to that specific drug
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Measurable disease must be present either on physical examination or imaging studies. Non-measurable disease alone is not acceptable

    • Measurable disease

      • Lesions that can be accurately measured in at least two dimensions as ≥ 1.0 x 1.0 cm by computerized tomography (CT), positron emission tomography (PET)/CT (positron emission tomography/CT), or magnetic resonance imaging (MRI).
      • If identified by PET/CT, there must be at least one lesion that demonstrates abnormal fludeoxyglucose (FDG) avidity, consistent with active disease. Ultrasound or physical examination alone may not be utilized to confirm measurable disease
    • Non-measurable disease

      • All other lesions, including small lesions (less than 1.0 x 1.0 cm) and truly non-measurable lesions
      • Lesions that are considered non-measurable include the following:

        • Bone lesions (lesions if present should be noted)
        • Ascites
        • Pleural/pericardial effusion
        • Lymphangitis cutis/pulmonis
        • Bone marrow (involvement by Hodgkin lymphoma should be noted)
  • Non-pregnant and non-nursing. Women and men of reproductive potential should agree to use an effective means of birth control
  • Patients with human immunodeficiency virus (HIV) infection are eligible. Patients with HIV infection must meet the following: no evidence of co-infection with hepatitis B or C; cluster of differentiation 4+ (CD4+) count ≥ 400/mm; no evidence of resistant strains of HIV; on anti-HIV therapy with an HIV viral load < 50 copies HIV ribonucleic acid (RNA)/mL. Patients with HIV must have ongoing follow-up with an infectious disease specialist and must have been evaluated within 90 days of cycle 1 day 1
  • Patients with a history of hepatitis C are eligible as long as the hepatitis C has been treated and cleared and they have no evidence of hepatic dysfunction related to hepatitis C. Patients must have been seen by a hepatologist within 6 months of cycle 1 day 1
  • Patients who test positive for hepatitis B core antibody may enroll on the study as long as they test negative for both hepatitis B surface antigen and hepatitis B deoxyribonucleic acid (DNA), and if they have no evidence of hepatic dysfunction that is felt to be related to hepatitis B
  • Patients must have adequate pulmonary function, defined as the following:

    • No history of drug-related, radiation-induced, or autoimmune pneumonitis requiring hospital admission
    • Baseline pulse oximetry reading of ≥ 92% on room air
    • Patients with a history of asthma or chronic obstructive pulmonary disease (COPD) must have no oxygen requirement, must have not had a hospital admission for COPD/asthma exacerbation within the past 2 years, and must not have received systemic steroids (≥ 10 mg prednisone for more than 7 days) for asthma/COPD within the past 2 years
  • Patients with hypothyroidism or type 1 diabetes mellitus that are on chronic hormonal therapy and which are well-controlled are eligible
  • Granulocytes ≥ 1000/µl
  • Platelet count ≥ 75,000/µl
  • Creatinine clearance ≥ 50 mL/min
  • Bilirubin ≤ 2.0 mg/dL
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.0 x upper limits of normal

Exclusion Criteria:

  • Due to the teratogenic potential of these agents, pregnant or nursing patients may not be enrolled
  • Patients may not have an auto-immune disease requiring systemic immunosuppression, biologic therapy, and/or steroid use (≥ 10 mg daily of prednisone or equivalent)
  • Patients with current or prior central nervous system (CNS) involvement with lymphoma are not eligible

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03739619


Contacts
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Contact: Jonathon Cohen, MD, MS 404-778-2419 jonathon.cohen@emory.edu

Locations
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United States, Georgia
Emory University Hospital/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Vanessa Smith    404-778-2419    vanessa.smith@emory.edu   
Contact: Bushra Patail    404-778-4449    bushra.patail@emoryhealthcare.org   
Emory Saint Joseph's Hospital Recruiting
Atlanta, Georgia, United States, 30342
Contact: Alicia Escobar    678-843-7029    alicia.m.escobar@emory.edu   
Contact: Krystal Reese    678-843-5911    krystal.reese@emory.edu   
Sponsors and Collaborators
Emory University
Bristol-Myers Squibb
Investigators
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Principal Investigator: Jonathon Cohen, MD, MS Emory University

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Responsible Party: Jonathon Cohen, Principal Investigator, Emory University
ClinicalTrials.gov Identifier: NCT03739619     History of Changes
Other Study ID Numbers: IRB00104033
NCI-2018-02221 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Winship4388-18 ( Other Identifier: Emory University Hospital/Winship Cancer Institute )
First Posted: November 14, 2018    Key Record Dates
Last Update Posted: July 1, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Bendamustine Hydrochloride
Lymphoma
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Gemcitabine
Nivolumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents, Alkylating
Alkylating Agents