A Randomized Phase 3 Trial of Nivolumab (NSC# 748726) in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma

  • STATUS
    Recruiting
  • End date
    Jun 30, 2028
  • participants needed
    192
  • sponsor
    National Cancer Institute (NCI)
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Updated on 24 October 2022
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Summary

This phase III trial compares the effects of nivolumab with chemo-immunotherapy versus chemo-immunotherapy alone in treating patients with newly diagnosed primary mediastinal B-cell lymphoma (PMBCL). 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. Treatment for PMBCL involves chemotherapy combined with an immunotherapy called rituximab. Chemotherapy drugs 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. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving nivolumab with chemo-immunotherapy may help treat patients with PMBCL.

Description

PRIMARY OBJECTIVE:

I. To determine if nivolumab + chemo-immunotherapy results in a superior long term progression-free survival (PFS) (events defined as disease progression confirmed by central review or death) when compared with chemo-immunotherapy alone in patients with newly diagnosed primary mediastinal B-cell lymphoma.

SECONDARY OBJECTIVES:

I. To compare the rates of "efficacy-related event-free survival (EFS)" (eEFS) (events defined as progression, change in therapy due to finding that led to concern about efficacy, biopsy + disease after 6 cycles of therapy, or death) between chemo-immunotherapy alone and chemo-immunotherapy + nivolumab in patients with newly diagnosed PMBCL.

II. To compare the rates of "therapy-related EFS" (tEFS) (events defined as relapse/progression, change in therapy for any reason, biopsy + disease after 6 cycles of therapy, secondary malignancy [SMN] or death) between chemo-immunotherapy alone and chemo-immunotherapy + nivolumab in patients with newly diagnosed PMBCL.

III. To compare the rates of overall survival (OS) between chemo-immunotherapy alone and chemo-immunotherapy + nivolumab in patients with newly diagnosed PMBCL.

IV. To establish the rate of a positive positron emission tomography (PET)-computed tomography (CT) (defined as Deauville score 4 or 5) at the completion of 6 cycles of nivolumab + rituximab (R)- cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/dose-adjusted (DA)-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH)-R and R-CHOP/DA-EPOCH-R in patients with newly diagnosed PMBCL and evaluate the prognostic significance of such a finding.

EXPLORATORY OBJECTIVES:

I. To bank radiology images for further studies. II. To bank specimens for future correlative studies. III. Characterize the immune profile of patients treated with nivolumab + chemo-immunotherapy to identify markers predictive of response.

IV. Define the rate of complete response at the completion of initial planned therapy.

OUTLINE: Patients are randomly assigned to backbone therapy or backbone therapy + nivolumab within each of 6 strata. The strata are determined by physician's choice of backbone (DA-EPOCH-R vs. R-CHOP vs. R-CHOP + RT) and whether or not the patient had 1 prior cycle of therapy.

ARM A (DA-EPOCH-R): Patients receive prednisone or prednisolone orally (PO) once daily (QD) on days 1-5 and rituximab intravenously (IV) or rituximab and hyaluronidase human subcutaneously (SC) over 5 minutes on day 1 or 5. Patients also receive etoposide phosphate, doxorubicin hydrochloride, and vincristine sulfate IV over 96 hours on days 1-4 and cyclophosphamide IV over 30-60 minutes on day 5. Beginning 24-72 hours after completing cyclophosphamide, patients receive filgrastim or pegylated filgrastim SC daily until absolute neutrophil count (ANC) is >= 500/uL after the expected nadir. Treatment repeats every 21 days for up to 6 cycles (5 if the patient had 1 prior cycle of treatment) in the absence of disease progression or unacceptable toxicity.

ARM B (DA-EPOCH-R + NIVOLUMAB): Patients receive treatment as in Arm A. Patients also receive nivolumab IV over 30 minutes on day 1.

ARM C (R-CHOP): Patients receive prednisone or prednisolone PO QD on days 1-5 and rituximab IV or rituximab and hyaluronidase human SC over 5 minutes on day 1 or 5. Patients also receive cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV over 1-15 minutes or up to 60 minutes, and vincristine sulfate IV over 1 or up to 60 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles (5 if the patient had 1 prior cycle of treatment) in the absence of disease progression or unacceptable toxicity.

ARM D (R-CHOP + NIVOLUMAB): Patients receive treatment as in Arm C. Patients also receive nivolumab IV over 30 minutes on day 1.

ARM E (R-CHOP + RADIOTHERAPY): Patients receive treatment as in Arm C. Within 6-8 weeks after completion of chemotherapy, patients undergo radiation therapy over 25 fractions.

ARM F (R-CHOP + RADIOTHERAPY + NIVOLUMAB): Patients receive treatment as in Arm D. Within 6-8 weeks after completion of chemotherapy, patients undergo radiation therapy over 25 fractions.

After completion of study treatment, patients are followed up every 3 months for year 1, every 6 months for years 2-3, and annually thereafter.

Details
Condition Primary Mediastinal (Thymic) Large B-Cell Lymphoma
Treatment Rituximab, radiation therapy, cyclophosphamide, filgrastim, doxorubicin hydrochloride, prednisone, vincristine sulfate, Nivolumab, pegfilgrastim, Etoposide Phosphate, Prednisolone, Rituximab and Hyaluronidase Human
Clinical Study IdentifierNCT04759586
SponsorNational Cancer Institute (NCI)
Last Modified on24 October 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Age >= 2 years
Patient must have histologically confirmed primary mediastinal B-cell lymphoma (PMBCL) as defined by World Health Organization (WHO) criteria
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 or ECOG performance status of 3 if poor performance is related to lymphoma
Children's Oncology Group (COG) Institutions: Use Karnofsky for patients >= 17 and < 18 years of age and Lansky for patients < 17 years of age
Adults (age 18 or older): Creatinine clearance >= 30 mL/min, as estimated by the
Pediatric Patients (age < 18 years): The following must have been obtained within 14 days prior to registration
Cockcroft and Gault formula. The creatinine value used in the calculation must
Measured or calculated (based on institutional standard) creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2, or
have been obtained within 28 days prior to registration. Estimated creatinine
Serum creatinine =< 1.5 x institutional upper limit of normal (IULN), or a serum creatinine based on age/gender as follows
clearance is based on actual body weight
Age : 2 to < 6 year; Maximum serum creatinine (mg/dL): 0.8 (male; 0.8 (female)
Age : 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male); 1 (female)
Age : 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
Age : 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
Age : >= 16 years to < 18 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
Age >= 18 years: Ejection fraction of >= 50% by echocardiogram
Age < 18 years: Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide angiogram
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
Patients with abnormal liver function will be eligible to enroll if the lab
abnormality is thought to be due to the lymphoma or Gilbert's syndrome
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
All patients and/or their parents or legal guardians must sign a written informed consent
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

Administration of prior anti-cancer therapy except as outlined below
A short course (=< 2 weeks) of corticosteroids for the relief of lymphoma-related symptoms
A single course of COP (cyclophosphamide, vincristine, and prednisone)
One cycle of chemo-immunotherapy including R-CHOP, DA-EPOCH-R, or a pediatric mature B-cell non-Hodgkin lymphoma (B-NHL) induction therapy (such as ANHL1131) that has not started more than 21 days prior to enrollment
Active ischemic heart disease or heart failure
Active uncontrolled infection
Central nervous system (CNS) involvement of lymphoma
Previous cancer that required systemic chemotherapy and/or thoracic radiation. Other cancers will be permitted if in remission x 3 years
Active autoimmune disease that has required systemic treatment (such as disease modifying agents, corticosteroids, or immunosuppressive agents) in the past 2 years. Replacement therapy such as thyroxine, insulin or physiologic corticosteroid for adrenal or pituitary insufficiency is not considered a form of systemic treatment
In patients < 18 years of age hepatitis B serologies consistent with past or current infections
Patients with severe hepatic impairment (Child-Pugh class C or serum total bilirubin > 5.0 mg/dL) unless thought to be due to lymphoma or Gilbert's syndrome
Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
Sexually active patients of reproductive potential who have not agreed to use a highly effective contraceptive method (failure rate of < 1% per year when used consistently and correctly) for the duration of their study participation
Lactating females are not eligible unless they have agreed not to breastfeed their infants starting with the first dose of study therapy and for at least 6 months after the last dose of rituximab
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