A Phase II Study of Nivolumab in Combination With DA-REPOCH Followed by Short Course Nivolumab Consolidation in Patients With Aggressive B-Cell Non-Hodgkin's Lymphoma
Overview
- Phase
- Phase 2
- Intervention
- Cyclophosphamide
- Conditions
- Aggressive Non-Hodgkin Lymphoma
- Sponsor
- David Bond, MD
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Progression-free survival (PFS)
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
This phase II trial studies how well nivolumab works with the DA-REPOCH chemotherapy regimen in treating patients with aggressive B-cell non-Hodgkin lymphoma. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body?s immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as dose-adjusted rituximab, etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (DA-REPOCH), work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab with DA-REPOCH may work better in treating patients with aggressive B-cell non-Hodgkin lymphoma.
Detailed Description
PRIMARY OBJECTIVES: I. To determine 2-year progression-free survival (PFS) of nivolumab in combination with DA-REPOCH with short course nivolumab maintenance. SECONDARY OBJECTIVES: I. To determine the objective response rate (ORR), complete response (CR) rate, and duration of response to nivolumab in combination with DA REPOCH with short course nivolumab maintenance. II. To establish that nivolumab in combination with DA-REPOCH with short course nivolumab maintenance is feasible at standard dosing. III. To establish the toxicity profile of nivolumab in combination with DA-REPOCH with short course nivolumab maintenance at standard dosing. EXPLORATORY OBJECTIVES: I. To correlate the presence of major histocompatibility complex (MHC) class I and II by immunohistochemistry (IHC) with PFS. II. To correlate tumor and microenvironment expression of PD-L1 and microenvironment expression of PD-1 with PFS. III. To correlate cell of origin, MYC and Bcl-2 expression, Epstein-Barr virus (EBV)-positivity, and Ki67 proliferation index with response to treatment. IV. To determine the effect of nivolumab in combination with DA-REPOCH on immune cell subsets in the peripheral blood over time. V. To correlate circulating tumor (ct) deoxyribonucleic acid (DNA) with disease response by positron emission tomography (PET) imaging. VI. To track clonal evolution and detect the emergence of treatment-resistance by ct-DNA monitoring. OUTLINE: Patients receive rituximab intravenously (IV) and nivolumab IV over 60 minutes on day 1. Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV continuously over 96 hours, cyclophosphamide IV bolus, and prednisone orally (PO) on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60 minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 3 months for 3 years, and then every 6 months for 5 years.
Investigators
David Bond, MD
Principal Investigator
Ohio State University Comprehensive Cancer Center
Eligibility Criteria
Inclusion Criteria
- •Be willing and able to provide written informed consent/assent for the trial.
- •Measurable disease (defined as \>= 1.5 cm in diameter) or at least one PET avid area of disease.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Absolute neutrophil count (ANC) \>= 1,000 /mcL (within 16 days of treatment initiation).
- •Platelets \>= 75,000 / mcL in the absence of transfusion support within 7 days of determining eligibility (within 16 days of treatment initiation).
- •Hemoglobin \>= 8 g/dL (within 16 days of treatment initiation).
- •Serum creatinine =\< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance \>= 40 mL/min creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) (within 16 days of treatment initiation).
- •Creatinine clearance should be calculated per institutional standard.
- •Serum total bilirubin =\< 1.5 X ULN OR except subjects with Gilbert syndrome, who can have total bilirubin \< 3.0 mg/dL (within 16 days of treatment initiation).
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3.0 X ULN (within 16 days of treatment initiation).
Exclusion Criteria
- •Known hypersensitivity to any of the study drugs.
- •History of other malignancy that could affect compliance with the protocol or interpretation of the results.
- •Has a diagnosis of immunodeficiency excluding human immunodeficiency virus (HIV) infection or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Subjects may use topical or inhaled corticosteroids or low-dose steroids (=\< 10 mg of prednisone or equivalent per day) as therapy for comorbid conditions. During study participation, subjects may receive systemic or enteric corticosteroids as needed for treatment-emergent comorbid conditions.
- •Has a known history of active TB (Bacillus tuberculosis).
- •Prior systemic chemotherapy for lymphoma with the exception of corticosteroids for palliation of symptoms and patients with prior indolent non-Hodgkin lymphoma (NHL) treated with single agent rituximab.
- •Has known active central nervous system (CNS) lymphoma.
- •Richter?s transformation from chronic lymphocytic leukemia (CLL).
- •Major surgery within 3 weeks prior to start of study treatment.
- •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 (thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Conditions expected to not recur in the absence of an external trigger.
- •Has an active infection requiring intravenous systemic therapy or uncontrolled systemic infection including viral, bacterial, or fungal.
Arms & Interventions
Treatment (nivolumab, DA-REPOCH)
Patients receive rituximab IV and nivolumab IV over 60 minutes on day 1. Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV continuously over 96 hours, cyclophosphamide IV bolus, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60 minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide
Treatment (nivolumab, DA-REPOCH)
Patients receive rituximab IV and nivolumab IV over 60 minutes on day 1. Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV continuously over 96 hours, cyclophosphamide IV bolus, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60 minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Doxorubicin Hydrochloride
Treatment (nivolumab, DA-REPOCH)
Patients receive rituximab IV and nivolumab IV over 60 minutes on day 1. Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV continuously over 96 hours, cyclophosphamide IV bolus, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60 minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Etoposide
Treatment (nivolumab, DA-REPOCH)
Patients receive rituximab IV and nivolumab IV over 60 minutes on day 1. Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV continuously over 96 hours, cyclophosphamide IV bolus, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60 minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Nivolumab
Treatment (nivolumab, DA-REPOCH)
Patients receive rituximab IV and nivolumab IV over 60 minutes on day 1. Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV continuously over 96 hours, cyclophosphamide IV bolus, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60 minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Prednisone
Treatment (nivolumab, DA-REPOCH)
Patients receive rituximab IV and nivolumab IV over 60 minutes on day 1. Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV continuously over 96 hours, cyclophosphamide IV bolus, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60 minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Rituximab
Treatment (nivolumab, DA-REPOCH)
Patients receive rituximab IV and nivolumab IV over 60 minutes on day 1. Patients also receive etoposide, vincristine sulfate and doxorubicin hydrochloride IV continuously over 96 hours, cyclophosphamide IV bolus, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After course 6, patients receive nivolumab IV over 60 minutes on day 1 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Vincristine Sulfate
Outcomes
Primary Outcomes
Progression-free survival (PFS)
Time Frame: From start of treatment to progression or death, whichever occurs first, assessed at 2 years
Will be estimated by the method of Kaplan-Meier and the estimate will be provided with 95% confidence intervals. Depending on the number of events, Cox regression model may be used to explore the association between baseline clinical variables and PFS in a univariable manner.
Secondary Outcomes
- Objective response rate(Up to 8 years)
- Duration of response defined for all patients who have achieved an objective response (CR or PR)(From date of which patient?s response is documented to the date of progression or death, censoring event-free patients at the time of last follow-up, assessed up to 8 years)
- Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0(Up to 30 days post-treatment)