Clinical Trial: NCT04759586 - My Cancer Genome

NCT04759586

Description:

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.

Related Conditions:

Primary Mediastinal B-Cell Lymphoma

Recruiting Status:

Suspended

Phase:

Phase 3

URL:

https://clinicaltrials.gov/show/NCT04759586

Trial Eligibility

Document

Title

Brief Title: Nivolumab in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma
Official Title: 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

Clinical Trial IDs

ORG STUDY ID: NCI-2021-01071
SECONDARY ID: NCI-2021-01071
SECONDARY ID: ANHL1931
SECONDARY ID: ANHL1931
SECONDARY ID: U10CA180886
NCT ID: NCT04759586

Conditions

Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Interventions

Drug	Synonyms	Arms
Cyclophosphamide	(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719	Arm A (DA-EPOCH-R)
Doxorubicin Hydrochloride	5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, Rubex	Arm A (DA-EPOCH-R)
Etoposide Phosphate	Etopophos	Arm A (DA-EPOCH-R)
Filgrastim	Filgrastim-aafi, G-CSF, Neupogen, Nivestym, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tevagrastim	Arm A (DA-EPOCH-R)
Nivolumab	BMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo	Arm B (DA-EPOCH-R, nivolumab)
Pegfilgrastim	Filgrastim SD-01, filgrastim-SD/01, Fulphila, HSP-130, Jinyouli, Neulasta, Neulastim, Nyvepria, Pegcyte, Pegfilgrastim Biosimilar HSP-130, Pegfilgrastim Biosimilar Nyvepria, Pegfilgrastim Biosimilar Pegcyte, Pegfilgrastim Biosimilar Udenyca, Pegfilgrastim Biosimilar Ziextenzo, pegfilgrastim-apgf, pegfilgrastim-bmez, pegfilgrastim-cbqv, Pegfilgrastim-jmdb, SD-01, SD-01 sustained duration G-CSF, Udenyca, Ziextenzo	Arm A (DA-EPOCH-R)
Prednisolone	(11beta)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione, .delta.1-Hydrocortisone, Adnisolone, Aprednislon, Capsoid, Cortalone, Cortisolone, Dacortin H, Decaprednil, Decortin H, Delta(1)Hydrocortisone, Delta- Cortef, Delta-Cortef, Delta-Diona, Delta-F, Delta-Phoricol, Delta1-dehydro-hydrocortisone, Deltacortril, Deltahydrocortisone, Deltasolone, Deltidrosol, Dhasolone, Di-Adreson-F, Dontisolon D, Estilsona, Fisopred, Frisolona, Gupisone, Hostacortin H, Hydeltra, Hydeltrasol, Klismacort, Kuhlprednon, Lenisolone, Lepi-Cortinolo, Linola-H N, Linola-H-Fett N, Longiprednil, Metacortandralone, Meti Derm, Meticortelone, Opredsone, Panafcortelone, Precortisyl, Pred-Clysma, Predeltilone, Predni-Coelin, Predni-Helvacort, Prednicortelone, Prednisolonum, Prelone, Prenilone, Sterane	Arm A (DA-EPOCH-R)
Prednisone	.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-Prednisone	Arm A (DA-EPOCH-R)
Rituximab	ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, Truxima	Arm A (DA-EPOCH-R)
Rituximab and Hyaluronidase Human	Rituxan Hycela, Rituximab Plus Hyaluronidase, Rituximab/Hyaluronidase, Rituximab/Hyaluronidase Human	Arm A (DA-EPOCH-R)
Vincristine Sulfate	Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate	Arm A (DA-EPOCH-R)

Purpose

Detailed 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 randomized to 1 of 6 arms.

      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 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. Treatment repeats every 21 days for up to 6 cycles in
      the absence of disease progression or unacceptable toxicity.

      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 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. Treatment repeats every 21 days for up to 6 cycles in
      the absence of disease progression or unacceptable toxicity.

      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.

Trial Arms

Name	Type	Description	Interventions
Arm A (DA-EPOCH-R)	Active Comparator	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 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 ANC is >= 500/uL after the expected nadir. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.	Cyclophosphamide Doxorubicin Hydrochloride Etoposide Phosphate Filgrastim Pegfilgrastim Prednisolone Prednisone Rituximab Rituximab and Hyaluronidase Human Vincristine Sulfate
Arm B (DA-EPOCH-R, nivolumab)	Experimental	Patients receive treatment as in Arm A. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.	Cyclophosphamide Doxorubicin Hydrochloride Etoposide Phosphate Filgrastim Nivolumab Pegfilgrastim Prednisolone Prednisone Rituximab Rituximab and Hyaluronidase Human Vincristine Sulfate
Arm C (R-CHOP)	Active Comparator	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 in the absence of disease progression or unacceptable toxicity.	Doxorubicin Hydrochloride Prednisolone Prednisone Rituximab Rituximab and Hyaluronidase Human Vincristine Sulfate
Arm D (R-CHOP, nivolumab)	Experimental	Patients receive treatment as in Arm C. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.	Doxorubicin Hydrochloride Nivolumab Prednisolone Prednisone Rituximab Rituximab and Hyaluronidase Human Vincristine Sulfate
Arm E (R-CHOP, radiation therapy)	Active Comparator	Patients receive treatment as in Arm C. Within 6-8 weeks after completion of chemotherapy, patients undergo radiation therapy over 25 fractions.	Doxorubicin Hydrochloride Prednisolone Prednisone Rituximab Vincristine Sulfate
Arm F (R-CHOP, nivolumab, radiation therapy)	Experimental	Patients receive treatment as in Arm D. Within 6-8 weeks after completion of chemotherapy, patients undergo radiation therapy over 25 fractions.	Doxorubicin Hydrochloride Nivolumab Prednisolone Prednisone Rituximab Rituximab and Hyaluronidase Human

Eligibility Criteria

        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, 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

Maximum Eligible Age:	N/A
Minimum Eligible Age:	2 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Progression-free survival (PFS)
Time Frame:	From enrollment on the study to first occurrence of relapse/progression or death, assessed up to 5 years
Safety Issue:
Description:	The primary analysis will be a one-sided Log-rank test stratified by choice of backbone and radiation therapy and whether the patient had a cycle of therapy prior to enrolling.

Secondary Outcome Measures

Measure:	Efficacy-related event-free survival
Time Frame:	Up to 5 years
Safety Issue:
Description:	Will be analyzed using a one-sided stratified Log-rank test at alpha = 0.05 or 0.025, as appropriate, with events defined as progression, change in therapy due to a finding that led to concern about efficacy, biopsy + disease after 6 cycles of therapy, and death.

Measure:	Therapy-related event-free survival
Time Frame:	Up to 5 years
Safety Issue:
Description:	Will be analyzed using a one-sided stratified Log-rank test at alpha = 0.05 or 0.025, as appropriate, with events defined as progression, change in therapy due to a finding that led to concern about efficacy, biopsy + disease after 6 cycles of therapy, and death.

Measure:	Overall survival
Time Frame:	Up to 5 years
Safety Issue:
Description:	Will be analyzed using a one-sided stratified Log-rank test at alpha = 0.05 or 0.025, as appropriate, with events defined as only death.

Measure:	Proportion of positive positron emission tomography (PET) scans
Time Frame:	Up to 6 cycle (1 cycle = 21 days)
Safety Issue:
Description:	Will be analyzed descriptively with a point estimate and Clopper-Pearson 95% confidence interval in the trial overall and in each treatment arm separately. The prognostic significance of positive PET after 6 cycles of therapy will be evaluated using a Cox proportional hazards regression on PFS with PET result (positive versus [vs.] negative), choice of backbone (rituximab [R]-cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] + radiation therapy [RT] regardless of end-of-therapy imaging vs. R-CHOP without RT unless biopsy positive at end-of-therapy vs. dose-adjusted [DA]-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin [EPOCH]-R without RT unless biopsy positive at end of therapy), and assignment to nivolumab (yes vs. no) as covariates.

Details

Phase:	Phase 3
Primary Purpose:	Interventional
Overall Status:	Suspended
Lead Sponsor:	National Cancer Institute (NCI)

Last Updated

August 26, 2021

Clinical Trials /

Nivolumab in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma