Phase I/II Study to Evaluate the Safety and Efficacy of Nivolumab in Combination With R-CHOP in a Cohort of Patients With DLBCL/tFL/ High Grade B-NHL
Overview
- Phase
- Phase 1
- Intervention
- Cyclophosphamide
- Conditions
- Aggressive Non-Hodgkin Lymphoma
- Sponsor
- Northwestern University
- Enrollment
- 30
- Locations
- 4
- Primary Endpoint
- Maximum tolerated dose (MTD) for the combination treatment of nivolumab and R-CHOP
- Status
- Suspended
- Last Updated
- 3 years ago
Overview
Brief Summary
This phase I/II trial studies the side effects and best dose of nivolumab and how well it works when giving together with combination chemotherapy in treating participants with diffuse large B-cell lymphoma. Monoclonal antibodies, such as nivolumab, interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, 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 and combination chemotherapy may work better in treating participants with diffuse large B-cell lymphoma.
Detailed Description
PRIMARY OBJECTIVES: I. To identify the maximum tolerated dose (MTD) for the combination treatment of nivolumab and rituximab, cyclophosphamide, doxorubicin hydrochloride (doxorubicin), vincristine sulfate (vincristine), and prednisone (R-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL). (Phase I) II. To assess the impact of nivolumab + R-CHOP on response by looking at complete response (CR) rates. (Phase II) SECONDARY OBJECTIVES: I. To look at preliminary efficacy as measured by overall response rate for combination nivolumab + R-CHOP. II. To assess the impact of nivolumab + R-CHOP on survival outcomes, specifically progression-free survival (PFS), overall survival (OS) and event-free-survival (EFS). III. To assess toxicity and tolerability of patients treated with nivolumab + R-CHOP. IV. To assess quality of life in patients treated with nivolumab + R-CHOP. EXPLORATORY OBJECTIVES: I. To explore the impact of the PD-1:PD-L1 regulatory axis and targeting this axis on the immune microenvironment. II. To identify the process of cachexia as a potential mechanism of resistance to anti-PD-1 therapy. OUTLINE: This is a phase I, dose-escalation study of nivolumab followed by a phase II study. Participants receive nivolumab intravenously (IV) over 30 minutes on day 1. Participants also receive rituximab IV on day 2, cyclophosphamide IV on day 2, doxorubicin hydrochloride IV over 3-5 hours on day 2, vincristine sulfate IV over 30 minutes on day 2, and prednisone orally (PO) on days 2-6 of course 1 and rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV over 3-5 hours on day 1, vincristine sulfate IV over 30 minutes on day 1, and prednisone PO on days 1-5 of courses 2-6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed for up to 18 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patient must have a confirmed diagnosis of:
- •De novo DLBCL including the clinical subtypes of primary mediastinal, - cell/histiocyte-rich large B-cell lymphoma and intravascular DLBCL OR
- •De novo transformed DLBCL from follicular lymphoma (FL) OR
- •Any high grade CD20+ B-cell lymphoma per World Health Organization (WHO) 2016 OR
- •CD20+ aggressive B-cell lymphoma unclassifiable.
- •Patient must be deemed an appropriate candidate for R-CHOP therapy.
- •Patients must be naive to prior therapy for the study diagnosis.
- •Patient must have advanced stage III/IV early stage disease where provider determines single modality therapy with chemo-immunotherapy is most appropriate (i.e radiation deferred).
- •Patient must have measurable disease (defined as \>= 1.5 cm in diameter) with correlated fludeoxyglucose F-18 (FDG)-avidity on positron emission tomography (PET) scan with Deauville score of 4 or 5 at time of diagnosis.
- •Patient must have Eastern Cooperative Oncology Group (ECOG) performance status =\<
Exclusion Criteria
- •Patients who have received prior therapy intended to treat the study diagnosis are not eligible.
- •Patients who have received prior anti-PD-1/L1 therapy for any indication are not eligible.
- •Patients who require urgent cytoreductive therapy (e.g. surgery or radiation) are not eligible.
- •Subjects with known immunodeficiency, known autoimmune disease, or concurrent use of immunomodulatory agents are not eligible.
- •Patients who have a condition requiring systemic treatment with corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications =\< 14 days prior to registration are not eligible.
- •NOTE: Inhaled steroids and adrenal replacement steroid doses \>10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
- •Patients with known central nervous system (CNS) involvement are not eligible.
- •Patients with an active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy are not eligible.
- •NOTE: Exceptions to this are as follows: localized non-melanotic skin cancer and any cancer that in the judgment of the investigator has been treated with curative intent and will not interfere with the study treatment plan and response assessment. Prostate and breast cancer patients undergoing hormone therapy with no currently active disease are eligible.
- •Patients with known human immunodeficiency virus (HIV) are not eligible.
Arms & Interventions
Treatment (nivolumab and R-CHOP)
Participants receive nivolumab IV over 30 minutes on day 1. Participants also rituximab IV on day 2, cyclophosphamide IV on day 2, doxorubicin hydrochloride IV over 3-5 hours on day 2, vincristine sulfate IV over 30 minutes on day 2, and prednisone PO on days 2-6 of course 1 and rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV over 3-5 hours on day 1, vincristine sulfate IV over 30 minutes on day 1, and prednisone PO on days 1-5 of courses 2-6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide
Treatment (nivolumab and R-CHOP)
Participants receive nivolumab IV over 30 minutes on day 1. Participants also rituximab IV on day 2, cyclophosphamide IV on day 2, doxorubicin hydrochloride IV over 3-5 hours on day 2, vincristine sulfate IV over 30 minutes on day 2, and prednisone PO on days 2-6 of course 1 and rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV over 3-5 hours on day 1, vincristine sulfate IV over 30 minutes on day 1, and prednisone PO on days 1-5 of courses 2-6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Doxorubicin Hydrochloride
Treatment (nivolumab and R-CHOP)
Participants receive nivolumab IV over 30 minutes on day 1. Participants also rituximab IV on day 2, cyclophosphamide IV on day 2, doxorubicin hydrochloride IV over 3-5 hours on day 2, vincristine sulfate IV over 30 minutes on day 2, and prednisone PO on days 2-6 of course 1 and rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV over 3-5 hours on day 1, vincristine sulfate IV over 30 minutes on day 1, and prednisone PO on days 1-5 of courses 2-6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Nivolumab
Treatment (nivolumab and R-CHOP)
Participants receive nivolumab IV over 30 minutes on day 1. Participants also rituximab IV on day 2, cyclophosphamide IV on day 2, doxorubicin hydrochloride IV over 3-5 hours on day 2, vincristine sulfate IV over 30 minutes on day 2, and prednisone PO on days 2-6 of course 1 and rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV over 3-5 hours on day 1, vincristine sulfate IV over 30 minutes on day 1, and prednisone PO on days 1-5 of courses 2-6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Prednisone
Treatment (nivolumab and R-CHOP)
Participants receive nivolumab IV over 30 minutes on day 1. Participants also rituximab IV on day 2, cyclophosphamide IV on day 2, doxorubicin hydrochloride IV over 3-5 hours on day 2, vincristine sulfate IV over 30 minutes on day 2, and prednisone PO on days 2-6 of course 1 and rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV over 3-5 hours on day 1, vincristine sulfate IV over 30 minutes on day 1, and prednisone PO on days 1-5 of courses 2-6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Treatment (nivolumab and R-CHOP)
Participants receive nivolumab IV over 30 minutes on day 1. Participants also rituximab IV on day 2, cyclophosphamide IV on day 2, doxorubicin hydrochloride IV over 3-5 hours on day 2, vincristine sulfate IV over 30 minutes on day 2, and prednisone PO on days 2-6 of course 1 and rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV over 3-5 hours on day 1, vincristine sulfate IV over 30 minutes on day 1, and prednisone PO on days 1-5 of courses 2-6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Rituximab
Treatment (nivolumab and R-CHOP)
Participants receive nivolumab IV over 30 minutes on day 1. Participants also rituximab IV on day 2, cyclophosphamide IV on day 2, doxorubicin hydrochloride IV over 3-5 hours on day 2, vincristine sulfate IV over 30 minutes on day 2, and prednisone PO on days 2-6 of course 1 and rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV over 3-5 hours on day 1, vincristine sulfate IV over 30 minutes on day 1, and prednisone PO on days 1-5 of courses 2-6. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Vincristine Sulfate
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD) for the combination treatment of nivolumab and R-CHOP
Time Frame: Up to 18 months
To identify the MTD for the combination treatment of nivolumab and R-CHOP in patients with DLBCL, this will be established during Phase I using a modified 3+3 dose escalation.
Progression Free Survival (PFS)
Time Frame: At 18 months
To assess the impact of nivolumab + R-CHOP on PFS at 18 months: This will be the proportion of patient that will be alive and progression free at 18 months.
Secondary Outcomes
- Frailty/Geriatric Assessments(Up to 18 months)
- Overall survival (OS) rate(At 18 months)
- Overall response rate (ORR)(Up to 18 months)
- Incidence of Adverse Events(Up to 42 days after treatment discontinuation)
- Quality of life Assessment(Up to 18 months)
- Event-free survival (EFS)(At 18 months)
- Overall response rates as defined by the RECIL and LYRIC criteria(Up to 18 months)