Clinical Trials /

A Study of Daratumumab and Dose-Adjusted EPOCH in Plasmablastic Lymphoma

NCT04139304

Description:

This feasibility trial studies how well daratumumab in combination with dose-adjusted etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (DA-EPOCH) works in treating patients with newly diagnosed stage I-IV plasmablastic lymphoma. Plasmablastic lymphoma cells have high levels of a protein called CD38. Daratumumab is a monoclonal antibody that specifically targets CD38 expressing cells, and may help the body?s immune system attack the cancer and interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride, 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 daratumumab may enhance the effectiveness of a standard chemotherapy (DA-EPOCH) in patients with plasmablastic lymphoma.

Related Conditions:
  • Plasmablastic Lymphoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Daratumumab and Dose-Adjusted EPOCH in Plasmablastic Lymphoma
  • Official Title: A Multicenter, Open-Label Feasibility Study of Daratumumab With Dose-Adjusted EPOCH in Newly Diagnosed Plasmablastic Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: AMC-105
  • SECONDARY ID: NCI-2019-04794
  • SECONDARY ID: AMC-105
  • SECONDARY ID: AMC-105
  • SECONDARY ID: UM1CA121947
  • NCT ID: NCT04139304

Conditions

  • Ann Arbor Stage I Diffuse Large B-Cell Lymphoma
  • Ann Arbor Stage II Diffuse Large B-Cell Lymphoma
  • Ann Arbor Stage III Diffuse Large B-Cell Lymphoma
  • Ann Arbor Stage IV Diffuse Large B-Cell Lymphoma
  • Plasmablastic Lymphoma

Interventions

DrugSynonymsArms
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- 138719Treatment (daratumumab, DA-EPOCH)
DaratumumabAnti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414Treatment (daratumumab, DA-EPOCH)
DoxorubicinAdriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinTreatment (daratumumab, DA-EPOCH)
Doxorubicin Hydrochloride5,12-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, RubexTreatment (daratumumab, DA-EPOCH)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Treatment (daratumumab, DA-EPOCH)
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-PrednisoneTreatment (daratumumab, DA-EPOCH)
VincristineLEUROCRISTINE, VCR, VincrystineTreatment (daratumumab, DA-EPOCH)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateTreatment (daratumumab, DA-EPOCH)

Purpose

This feasibility trial studies how well daratumumab in combination with dose-adjusted etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (DA-EPOCH) works in treating patients with newly diagnosed stage I-IV plasmablastic lymphoma. Plasmablastic lymphoma cells have high levels of a protein called CD38. Daratumumab is a monoclonal antibody that specifically targets CD38 expressing cells, and may help the body?s immune system attack the cancer and interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride, 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 daratumumab may enhance the effectiveness of a standard chemotherapy (DA-EPOCH) in patients with plasmablastic lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the feasibility of adding daratumumab to dose-adjusted (DA)-EPOCH by assessing
      the percentage of plasmablastic lymphoma (PBL) patients to complete >= 3 cycles of study
      treatment per protocol.

      SECONDARY OBJECTIVES:

      I. To estimate the complete response (CR) rate as defined by the 2017 Response Evaluation
      Criteria in Lymphoma (RECIL) Criteria in human immunodeficiency virus (HIV) positive and HIV
      negative patients with plasmablastic lymphoma treated with daratumumab and DA-EPOCH.

      II. To evaluate the safety of dose-adjusted EPOCH with daratumumab as assessed by the
      National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
      version 5.0.

      III. To estimate the overall survival (OS), progression free survival (PFS), and event free
      survival (EFS) at 1 year.

      EXPLORATORY OBJECTIVES:

      I. To explore the relationship of tumor characteristics as determined by immunohistochemistry
      (IHC) panels and fluorescent in situ hybridization (FISH) and clinical outcomes.

      II. To assess the relationship between Epstein-Barr virus (EBV)-tumor association and EBV
      plasma copy number and to assess any prognostic significance of clearance of viral
      deoxyribonucleic acid (DNA) from plasma during or at the end of therapy.

      III. To determine the feasibility of identifying circulating tumor DNA (ctDNA) as reflected
      in plasma DNA mutation panels or clonal immunoglobulin DNA and to assess any prognostic
      significance of clearance of tumor DNA from plasma during therapy.

      OUTLINE:

      Patients receive daratumumab intravenously (IV) on days 1, 8, and 15 of cycles 1-3, and on
      day 1 of cycles 4-6. Patients also receive etoposide, doxorubicin hydrochloride, and
      vincristine sulfate IV continuous over 96 hours on days 1-4, prednisone orally (PO) on days
      1-5, and cyclophosphamide IV over 1 hour on day 5. Treatment repeats every 21 days for up to
      6 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for up to 2
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (daratumumab, DA-EPOCH)ExperimentalPatients receive daratumumab IV on days 1, 8, and 15 of cycles 1-3, and on day 1 of cycles 4-6. Patients also receive etoposide, doxorubicin hydrochloride, and vincristine sulfate IV continuous over 96 hours on days 1-4, prednisone PO on days 1-5, and cyclophosphamide IV over 1 hour on day 5. Treatment repeats every 21 days for up to 6 cycles in absence of disease progression or unacceptable toxicity.
  • Cyclophosphamide
  • Daratumumab
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Etoposide
  • Prednisone
  • Vincristine
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically and immunophenotypically (via at least a core or
             ideally, incisional or excisional biopsy) documented plasmablastic lymphoma.

          -  Stage II-IV disease (Ann Arbor staging criteria) or stage I disease with elevated
             lactate dehydrogenase (LDH) or bulky tumor (> 7.5 cm).

          -  Known HIV status. At most 7 HIV negative patients will be allowed on the study. Once 7
             HIV negative patients have been enrolled, future enrollment will allow only HIV
             positive patients. Participants may be HIV positive, with documentation of HIV
             infection by means of any one of the following:

               -  Documentation of HIV diagnosis in the medical record by a licensed health care
                  provider;

               -  Documentation of receipt of highly active antiretroviral therapy (HAART) (at
                  least three different medications) by a licensed health care provider
                  (documentation may be a record of an HAART prescription in the participant?s
                  medical record, a written prescription in the name of the participant for HAART,
                  or pill bottles for HAART with a label showing the participant?s name);

               -  HIV-1 ribonucleic acid (RNA) detection by a licensed HIV-1 RNA assay
                  demonstrating >1000 RNA copies/mL;

               -  Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay
                  confirmed by a second licensed HIV assay such as a HIV-1 Western blot
                  confirmation or HIV rapid multispot antibody differentiation assay.

                    -  NOTE: A ?licensed? assay refers to a U.S. Food and Drug Administration
                       (FDA)-approved assay, which is required for all Investigational New Drug
                       (IND) studies.

               -  Participants without HIV infection must have evidence of a negative result using
                  any licensed HIV screening antibody assay and/or HIV antibody/antigen combination
                  assay.

          -  Participants must have measurable disease (unless marrow-only disease is present),
             defined as at least one lesion that can be accurately measured in at least one
             dimension (longest diameter) as >= 15 mm (>= 1.5cm) by computed tomography (CT) or
             positron emission tomography (PET) scan or evaluable by bone marrow.

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%).

          -  Absolute neutrophil count >= 1,000 cells/mcL unless decreased due to bone marrow
             involvement.

          -  Platelets >= 75,000 cells/mcL unless decreased due to bone marrow involvement.

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (< 3.0 x ULN for
             patients with Gilbert syndrome). If, however, the elevated bilirubin is felt to be
             secondary to antiretroviral therapy, the total bilirubin must be =< 3.5 mg/dL,
             provided that the direct bilirubin is normal and the aspartate aminotransferase (AST)
             and alanine aminotransferase (ALT) =< 3 x the upper limit of normal.

          -  AST (serum glutamic oxaloacetic transaminase [SGOT])/ALT (serum glutamate pyruvate
             transaminase [SGPT]) =< 2.5 x institutional ULN (=< 5 x ULN is acceptable if liver
             metastases are present).

          -  Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 45
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal, as
             calculated by the Cockcroft-Gault formula.

          -  Adequate cardiac function defined as an ejection fraction on echocardiogram (ECHO) or
             multigated acquisition scan (MUGA) that is at or above 45%.

          -  CD4 count >= 100 cell/mL for HIV-positive participants.

          -  If HIV-positive, participant must not have a history of acquired immunodeficiency
             syndrome (AIDS)-defining opportunistic infection within the past year.

          -  If HIV-positive, participant should have concurrent treatment with effective highly
             active antiretroviral therapy (HAART) or agree to start HAART.

          -  The effects of daratumumab on the developing human fetus are unknown. For this reason
             and because another monoclonal antibody (mAb), rituximab, crosses the placenta and
             other therapeutic agents used in this trial are known to be teratogenic, women of
             child-bearing potential and men must agree to use adequate contraception (hormonal or
             barrier method of birth control; abstinence) prior to study entry, the duration of
             study participation, and 90 days after completion of therapy. Should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she should inform her treating physician immediately. Men with female partners
             treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study, for the duration of study participation, and 90 days after
             completion of daratumumab administration.

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  Prior cytotoxic chemotherapy or radiotherapy for this lymphoma other than palliative
             radiation for medical emergencies (like cord compression) or the following
             chemotherapy:

               -  A maximum of one cycle of combination chemotherapy, including EPOCH or
                  cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like therapy.
                  The start of the previous chemotherapy cycle must occur at least 21 days but no
                  more than 28 days prior to the beginning of therapy under this protocol, and such
                  cycle will count towards the maximum of 6 cycles under this study (i.e. cycle off
                  study will count as cycle 1 in terms of feasibility determination as per primary
                  endpoint).

        OR

          -  One prior cycle of limited therapy including cyclophosphamide and/or glucocorticoids
             to improve performance status or hepatic or renal function impaired due to lymphoma
             involvement. The start of this therapy may occur up to 28 days prior to the beginning
             of study treatment under this protocol. Cyclophosphamide administration must have been
             completed at least 14 days prior to initiation of study treatment. Such treatment will
             not count towards the maximum of 6 cycles under this study (i.e. participants will
             receive 6 cycles on study).

               -  Patients who are receiving any other investigational agents.

               -  Participants should not have had previous anthracycline treatment within the last
                  two years, except for liposomal doxorubicin. Any prior exposure to liposomal
                  doxorubicin is allowed as long as the left ventricular ejection fraction (LVEF)
                  is >= 45%

               -  Participants who have previously received daratumumab for another indication.

               -  Participants must not be on cobicistat, indinavir, or ritonavir, or agents that
                  are strong CYP3A4 inhibitors. If on a strong CYP3A4 inhibitor regimen prior to
                  study enrollment, participants must be switched to alternative drugs at least one
                  week prior to administration of study therapy.

          -  All concomitant medications must be reviewed by the study chair or co-chair prior to
             enrollment by email.

               -  Participants with peripheral neuropathy grade >= 3 or neuropathic pain grade >=
                  2.

               -  Expected survival < 2 months.

               -  Participants with known brain metastases from solid tumors will be excluded from
                  this clinical trial because of their poor prognosis and because they often
                  develop progressive neurologic dysfunction that would confound the evaluation of
                  neurologic and other adverse events.

               -  Patients with known or suspected parenchymal brain or spinal cord disease, and/or
                  suspected or symptomatic leptomeningeal disease from lymphoma, prior to study
                  enrolled will be excluded. Asymptomatic leptomeningeal disease only will be
                  allowed.

               -  Patients who are seropositive for hepatitis B (defined by a positive test for
                  hepatitis B surface antigen [HBsAg]). All participants will be required to be
                  screened for hepatitis B. Participants with resolved infection (i.e. participants
                  who are HBsAg negative but positive for antibodies to hepatitis B core antigen
                  [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs] must be
                  screened using real-time polymerase chain reaction (PCR) measurement of HBV DNA
                  levels. Participants who are PCR positive will be excluded. EXCEPTION:
                  Participants with serologic findings suggestive of HBV vaccination (anti-HBs
                  positivity as the only serologic marker) AND a known history of prior HBV
                  vaccination, do not need to be tested for HBV DNA by PCR.

               -  Patients diagnosed with hepatitis C who are hepatitis C antibody positive,
                  whether hepatitis C RNA level is measurable or not, must have no evidence of
                  cirrhosis

               -  History of allergic reactions, hypersensitivity, or intolerance attributed to
                  compounds of similar chemical or biologic composition to daratumumab or other
                  agents used in the study or known sensitivity to mammalian-derived products.

               -  Uncontrolled intercurrent illness including, but not limited to, ongoing or
                  active infection, symptomatic congestive heart failure, unstable angina pectoris,
                  cardiac arrhythmia, or psychiatric illness/social situations that would limit
                  compliance with study requirements.

               -  Pregnancy or breastfeeding. A pregnancy test must be performed within 7 days
                  prior to therapy administration in women of childbearing potential. Pregnant
                  women are excluded from this study because the effects of daratumumab on the
                  developing human fetus are unknown. Immunoglobulin G1 (IgG1) monoclonal
                  antibodies are transferred across the placenta. Based on its mechanism of action,
                  daratumumab may cause fetal myeloid or lymphoid-cell depletion and decreased bone
                  density. Because there is an unknown but potential risk for adverse events in
                  nursing infants secondary to treatment of the mother with daratumumab,
                  breastfeeding should be discontinued if the mother is treated with daratumumab.
                  These potential risks may also apply to other agents used in this study. Both
                  male and female participants must use effective methods of birth control during
                  the course of the study and for 3 months after stopping daratumumab.

               -  Unable to comply with the requirements of the protocol, or unable to provide
                  adequate informed consent in the opinion of the principal investigator.

               -  Serious, ongoing, non-malignant disease or infection, which in the opinion of the
                  investigator and/or the sponsor would compromise other protocol objectives.
                  Participants with active opportunistic infections are ineligible.

               -  Major surgery, other than diagnostic surgery, occurring 4 weeks prior to study
                  entry. Splenectomy will not be considered an exclusionary major surgery.

               -  Myocardial infarction (MI) within 6 months prior to study entry, New York Heart
                  Association (NYHA) class II or greater heart failure, uncontrolled angina, severe
                  uncontrolled ventricular arrhythmias, clinically significant pericardial disease,
                  or electrocardiographic evidence of acute ischemic or active conduction system
                  abnormalities.

               -  Either of the following:

          -  Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in
             1 second (FEV1) is < 50% of predicted normal. Note that FEV1 testing also is required
             for subjects suspected of having COPD and subjects must be excluded if FEV1 is < 50%
             of predicted normal.

          -  Known moderate or severe persistent asthma, or a history of asthma within the last 2
             years, or currently has uncontrolled asthma of any classification. (Subjects who
             currently have controlled intermittent asthma or controlled mild persistent asthma are
             allowed to participate in the study.)

               -  Participants with prior malignancies are ineligible unless:

          -  Treatment for the prior malignancy was completed at least 2 years prior to the
             lymphoma treatment start date and the participant has no evidence of the concurrent
             malignancy.

        OR

          -  The concurrent malignancy is clinically stable and does not require tumor-directed
             treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of newly diagnosed plasmablastic lymphoma patients who complete at least 3 cycles of daratumumab with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH)
Time Frame:Up to the completion of 3 cycles (each cycle is 21 days)
Safety Issue:
Description:The proportion of participants completing >= 3 cycles of DA-EPOCH with daratumumab will be calculated with the denominator being eligible, evaluable participants.

Secondary Outcome Measures

Measure:Complete response (CR) rate
Time Frame:Up to the completion of 3 cycles (each cycle is 21 days)
Safety Issue:
Description:Defined by the 2017 Response Evaluation Criteria in Lymphoma (RECIL) Criteria.
Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:The frequency of various adverse events and proportion of participants affected will be calculated. Toxicity data will be presented by type and severity. Incidence of toxicity related dose reductions and treatment discontinuations will be summarized.
Measure:Progression free survival (PFS)
Time Frame:Up to 1 year
Safety Issue:
Description:Will be estimated by Kaplan-Meier method as well as the corresponding 95% confidence intervals.
Measure:Overall survival (OS)
Time Frame:Up to 1 year
Safety Issue:
Description:Will be estimated by Kaplan-Meier method as well as the corresponding 95% confidence intervals.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AIDS Malignancy Consortium

Last Updated

January 27, 2020