Clinical Trials /

Pembrolizumab and Combination Chemotherapy in Treating Patients With Previously Untreated Diffuse Large B-cell Lymphoma or Grade 3b Follicular Lymphoma

NCT02541565

Description:

This pilot phase I trial studies the side effects of pembrolizumab and combination chemotherapy in treating patients with previously untreated diffuse large B-cell lymphoma or grade 3b follicular lymphoma. Monoclonal antibodies, such as pembrolizumab and rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, 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 pembrolizumab together with combination chemotherapy may be with a better treatment for diffuse large B-cell lymphoma or follicular lymphoma.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Grade 3b Follicular Lymphoma
  • Transformed Lymphoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Combination Chemotherapy in Treating Patients With Previously Untreated Diffuse Large B-cell Lymphoma or Grade 3b Follicular Lymphoma
  • Official Title: MK-3475 in Combination With Standard RCHOP Therapy for Previously Untreated Diffuse Large B-Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 9291
  • SECONDARY ID: NCI-2015-01309
  • SECONDARY ID: MK-3475
  • SECONDARY ID: 9291
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT02541565

Conditions

  • Composite Lymphoma
  • Grade 3b Follicular Lymphoma
  • Stage I Diffuse Large B-Cell Lymphoma
  • Stage I Follicular Lymphoma
  • Stage II Diffuse Large B-Cell Lymphoma
  • Stage II Follicular Lymphoma
  • Stage III Diffuse Large B-Cell Lymphoma
  • Stage III Follicular Lymphoma
  • Stage IV Diffuse Large B-Cell Lymphoma
  • Stage IV Follicular 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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (pembrolizumab, combination chemotherapy)
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, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexTreatment (pembrolizumab, combination chemotherapy)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, combination chemotherapy)
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, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisonum, Prednitone, Promifen, Servisone, SK-PrednisoneTreatment (pembrolizumab, combination chemotherapy)
RituximabABP 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 Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83Treatment (pembrolizumab, combination chemotherapy)
Vincristine SulfateKyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateTreatment (pembrolizumab, combination chemotherapy)

Purpose

This pilot clinical trial studies the side effects of pembrolizumab and combination chemotherapy in treating patients with previously untreated diffuse large B-cell lymphoma or grade 3b follicular lymphoma. Monoclonal antibodies, such as pembrolizumab and rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, 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 pembrolizumab together with combination chemotherapy may be with a better treatment for diffuse large B-cell lymphoma or follicular lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To measure the toxicity profile of pembrolizumab (MK-3475) when co-administered with
      full-course RCHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine
      sulfate, and prednisone) in subjects with previously untreated diffuse large B-cell lymphoma
      (DLBCL).

      SECONDARY OBJECTIVES:

      I. To assess clinical outcomes including response rate, event-free survival, and overall
      survival after MK-3475 + RCHOP induction for subjects with previously untreated DLBCL.

      TERTIARY OBJECTIVES:

      I. To measure baseline expression of proteins in the programmed death-1 (PD-1) family on
      tumor cells and coexisting immune infiltrates, using archival tissue when available.

      II. To measure peripheral blood T cell subsets before and after treatment using flow
      cytometry, and to measure baseline vitamin D (25-hydroxy, total).

      III. To explore relationships with these parameters and likelihood of response to therapy
      and outcomes.

      OUTLINE:

      Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and prednisone
      orally (PO) on days 1-5. Patients also receive rituximab IV, cyclophosphamide IV,
      doxorubicin hydrochloride IV, and vincristine sulfate IV on day 2 of course 1 and on day 1
      of subsequent courses. Treatment repeats every 21 days for 6 courses in the absence of
      disease progression or unacceptable toxicity.

      After completion of the study treatment, patients are followed up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, combination chemotherapy)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1 and prednisone PO on days 1-5. Patients also receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 2 of course 1 and on day 1 of subsequent courses. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  • Cyclophosphamide
  • Doxorubicin Hydrochloride
  • Prednisone
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  Previously untreated diffuse large B-cell lymphoma or grade 3B follicular lymphoma
             (of any stage); subjects must be planned to receive full course (6 cycles) of RCHOP
             chemoimmunotherapy as per clinical standard of care; patients may have de novo DLBCL,
             and /or any of the following:

               -  Composite lymphomas, which include both diffuse DLBCL and another histology
                  (most commonly follicular lymphoma) in the same lymph node

               -  Transformed lymphoma with DLBCL histology, as long as the patient has not
                  received prior therapy for lymphoma

               -  Discordant presentations, such as DLBCL in a lymph node and low-grade lymphoma
                  such as follicular lymphoma in the bone marrow

          -  Be willing and able to provide written informed consent/assent for the trial

          -  Have measurable nodal disease, including at least 1 disease site measuring 1.5 cm in
             longest dimension on computed tomography (CT) or fludeoxyglucose (FDG)-positron
             emission tomography (PET)

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale (PS), or ECOG PS 2 if related to DLBCL and associated
             manifestations

          -  Absolute neutrophil count (ANC) >= 1,500/mcL except in cases of marrow infiltration
             by lymphoma

          -  Platelets >= 100,000/mcL except in cases of marrow infiltration by lymphoma

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L except in cases of marrow infiltration by
             lymphoma

          -  Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
             creatinine clearance >= 60 ml/min for subject with creatinine levels > 1.5 X
             institutional ULN (glomerular filtration rate [GFR] can also be used in place of
             creatinine or creatinine clearance [CrCl])

          -  Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 ULN

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 X ULN or =< 5 X ULN for subjects with liver metastases

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
             subject is receiving anticoagulant therapy; as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants; activated
             partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
             anticoagulant therapy; as long as PT or PTT is within therapeutic range of intended
             use of anticoagulants, or subject is shown to have an antiphospholipid antibody on
             workup

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication; if
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required

          -  Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the
             course of the study through 120 days after the last dose of study medication;
             subjects of childbearing potential are those who have not been surgically sterilized
             or have not been free from menses for > 1 year

          -  Male subjects should agree to use an adequate method of barrier contraception
             starting with the first dose of study therapy through 120 days after the last dose of
             study therapy

        Exclusion Criteria:

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study drug or using an investigation device
             within 4 weeks of the first dose of treatment

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of
             trial treatment

          -  Has a known additional malignancy that is progressing or requires active treatment;
             exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis; subjects with previously treated brain metastases may participate
             provided they are stable (without evidence of progression by imaging for at least
             four weeks prior to the first dose of trial treatment and any neurologic symptoms
             have returned to baseline), have no evidence of new or enlarging brain metastases,
             and are not using steroids for at least 7 days prior to trial treatment

          -  No active autoimmune disease that has required systemic treatment in past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has history of non-infectious pneumonitis that required steroids or current
             pneumonitis

          -  Has an active infection requiring intravenous antibiotic therapy

          -  Has a history or current evidence of any condition, therapy, or laboratory
             abnormality that might confound the results of the trial, interfere with the
             subject's participation for the full duration of the trial, or is not in the best
             interest of the subject to participate, in the opinion of the treating investigator

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment

          -  Has received prior therapy with an anti-PD-1, anti-programmed cell death ligand 1
             (PD-L1), anti-programmed cell death ligand 2 (PD-L2), anti-tumor necrosis factor
             receptor superfamily, member 9 (CD137), or anti-cytotoxic T-lymphocyte-associated
             antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug
             specifically targeting T-cell co-stimulation or checkpoint pathways)

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Has known active hepatitis B (e.g., hepatitis B virus surface protein antigen [HBsAg]
             reactive or hepatitis B virus [HBV] deoxyribonucleic acid [DNA] detectable) or
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
             detected)

          -  Has received a live vaccine within 30 days prior to the first dose of trial treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of toxicity graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 90 days after completion of study treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Event-free survival
Time Frame:Time from diagnosis until relapse or progression, non-protocol re-treatment of lymphoma, or death as a result of any cause, assessed up to 5 years
Safety Issue:
Description:Statistical analysis will entail descriptive statistics, and survival analysis including Kaplan-Meier estimates, log-rank testing of univariate prognostic factors, Cox proportional hazards analysis, as well as T-testing and regression analysis for comparing continuous variables in correlative study data.
Measure:Overall survival
Time Frame:Date of diagnosis to death from any cause, assessed up to 5 years
Safety Issue:
Description:Statistical analysis will entail descriptive statistics, and survival analysis including Kaplan-Meier estimates, log-rank testing of univariate prognostic factors, Cox proportional hazards analysis, as well as T-testing and regression analysis for comparing continuous variables in correlative study data.
Measure:Response rate measured by tumor imaging
Time Frame:Up to 6 weeks after course 6
Safety Issue:
Description:Tumor imaging at baseline and 4-6 weeks, +/-7 days, after 6 courses of induction therapy with MK-3475 + RCHOP to determine remission status. Response will be measured according to 2014 Criteria ("The Lugano Classification").

Details

Phase:N/A
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Washington

Last Updated

November 21, 2016