CLINICAL TRIAL / NCT04759586
Nivolumab in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma
- Interventional
- Recruiting
- NCT04759586
Contact Information
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
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.
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 versus [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. Patients
undergo echocardiography (ECHO) during screening and as clinically indicated and alumbar
puncture (LP) for cerebral spinal fluid (CSF) collection optionally during screening.
Patients also undergo computed tomography (CT) or positron emission tomography (PET)/CT
throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration
optionally during screening and as clinically indicated on study. Patients undergo blood
sample collection on study.
ARM B (DA-EPOCH-R + NIVOLUMAB): Patients receive treatment as in Arm A. Patients also
receive nivolumab IV over 30 minutes on day 1. Patients undergo ECHO during screening and
as clinically indicated and LP for CSF collection optionally during screening. Patients
also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone
marrow biopsy and aspiration optionally during screening and as clinically indicated on
study. Patients undergo blood sample collection on study.
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. Patients undergo ECHO during screening and as clinically indicated and LP for
CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout
the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally
during screening and as clinically indicated on study. Patients undergo blood sample
collection on study.
ARM D (R-CHOP + NIVOLUMAB): Patients receive treatment as in Arm C. Patients also receive
nivolumab IV over 30 minutes on day 1. Patients undergo ECHO during screening and as
clinically indicated and LP for CSF collection optionally during screening. Patients also
undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow
biopsy and aspiration optionally during screening and as clinically indicated on study.
Patients undergo blood sample collection on study.
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.
Patients undergo ECHO during screening and as clinically indicated and LP for CSF
collection optionally during screening. Patients also undergo CT or PET/CT throughout the
trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during
screening and as clinically indicated on study. Patients undergo blood sample collection
on study.
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. Patients undergo ECHO during screening and as clinically indicated and LP for
CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout
the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally
during screening and as clinically indicated on study. Patients undergo blood sample
collection on study.
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.
Gender
All
Age Group
2 Years and up
Accepting Healthy Volunteers
No
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
Cockcroft and Gault formula. The creatinine value used in the calculation must have
been obtained within 28 days prior to registration. Estimated creatinine clearance
is based on actual body weight
- Pediatric Patients (age < 18 years): The following must have been obtained within 14
days prior to registration:
- Measured or calculated (based on institutional standard) creatinine clearance
or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2, or
- Serum creatinine =< 1.5 x institutional upper limit of normal (IULN), or a
serum creatinine based on age/gender as follows:
- 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)
- 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
- 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
- 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, a pediatric
mature B-cell non-Hodgkin lymphoma (B-NHL) induction therapy (such as
ANHL1131), or intrathecal chemotherapy 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
- Patients with a prior or concurrent malignancy whose natural history or treatment
has the potential to interfere with safety or efficacy assessment of this trial
- 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