Atezolizumab, Gemcitabine, Oxaliplatin, and Rituximab in Treating Patients With Relapsed or Refractory Transformed Diffuse Large B-Cell Lymphoma

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Brief Title

Atezolizumab, Gemcitabine, Oxaliplatin, and Rituximab in Treating Patients With Relapsed or Refractory Transformed Diffuse Large B-Cell Lymphoma

Official Title

A Pilot Phase I Study of Atezolizumab (MPDL3280A) in Combination With Immunogenic Chemotherapy (Gemcitabine-Oxaliplatin) and Rituximab for Transformed Diffuse Large B-Cell Lymphoma

Brief Summary

      This pilot phase I trial studies the side effects of atezolizumab, gemcitabine, oxaliplatin,
      and rituximab and to see how well they work in treating patients with transformed diffuse
      large B-cell lymphoma that has come back or does not respond to treatment. Immunotherapy with
      monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the
      cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in
      chemotherapy, such as gemcitabine and oxaliplatin, 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 that may interfere with the ability
      of cancer cells to grow and spread. Giving atezolizumab, gemcitabine, oxaliplatin, and
      rituximab may work better in treating patients with transformed diffuse large B-cell
      lymphoma.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. Assess the safety and toxicity of atezolizumab in combination with immunogenic
      chemotherapy (gemcitabine plus oxaliplatin) with rituximab (R-GEMOX-ATEZO) in patients with
      relapsed or refractory (rel/ref) transformed diffuse large B-cell lymphoma (DLBCL), including
      determination of the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of
      R-GEMOX-ATEZO.

      II. Evaluate on-treatment changes in density of and proximity between immune cell subsets in
      the tumor microenvironment after immunogenic chemotherapy alone and R-GEMOX-ATEZO by
      multispectral immunofluorescence, including density of CD8+ cells and cytotoxic lymphocyte
      (CTL):regulatory T cell (Treg) ratio.

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity. II. Evaluate genomic (e.g. gene expression
      profiles, whole exome sequencing) characteristics of patients with rel/ref transformed DLBCL
      treated with R-GEMOX-ATEZO.

      OUTLINE:

      INDUCTION PHASE: Patients receive rituximab intravenously (IV), gemcitabine IV, and
      oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over
      30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for
      up to 4 cycles in the absence of disease progression or unaccepted toxicity.

      MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab over 30-60 minutes IV on
      day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted
      toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 6
      months for up to 1 year.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Incidence of adverse events

Secondary Outcome

 Complete response rate

Condition

Recurrent Diffuse Large B-Cell Lymphoma

Intervention

Atezolizumab

Study Arms / Comparison Groups

 Treatment (rituximab, gemcitabine, oxaliplatin, atezolizumab)
Description:  INDUCTION PHASE: Patients receive rituximab IV, gemcitabine IV, and oxaliplatin IV every 2 weeks. Starting cycle 2, patients also receive atezolizumab IV over 30-60 minutes every 2 weeks. Treatment repeats every 14 days of cycle 1 and every 28 days for up to 4 cycles in the absence of disease progression or unaccepted toxicity.
MAINTENANCE PHASE: Patients receive rituximab IV and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unaccepted toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

24

Start Date

March 7, 2018

Completion Date

June 30, 2022

Primary Completion Date

June 30, 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed transformed diffuse large B-cell lymphoma
             (DLBCL), including histologic transformation from any indolent lymphoma (e.g.
             follicular or marginal zone lymphoma) or Richter transformation of chronic lymphocytic
             leukemia/small lymphocytic lymphoma (CLL/SLL)

          -  Patients must have measurable disease by computed tomography (CT) or positron emission
             tomography (PET) scan, with one or more sites of disease >= 1.5 cm in longest
             dimension

          -  Relapsed or refractory disease after at least 1 prior regimen, defined using the 2014
             Lugano classification

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Life expectancy of greater than 3 months

          -  Leukocytes >= 2,500/mcL, unless documented bone marrow involvement by lymphoma

          -  Absolute neutrophil count >= 1,000/mcL, unless documented bone marrow involvement by
             lymphoma

          -  Platelets >= 75,000/mcL, unless documented bone marrow involvement by lymphoma

          -  Hemoglobin >= 8 g/dL, unless documented bone marrow involvement by lymphoma

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients
             with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x ULN (AST and/or ALT =< 5 x ULN for patients with liver involvement)

          -  Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver
             involvement or bone metastases)

          -  Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault

          -  International normalized ratio (INR) and partial thromboplastin time (aPTT) =< 1.5 x
             ULN (this applies only to patients who do not receive therapeutic anticoagulation;
             patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin
             or warfarin, should be on a stable dose)

          -  Administration of atezolizumab may have an adverse effect on pregnancy and poses a
             risk to the human fetus, including embryo-lethality; 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, for the duration of study participation,
             and for 5 months (150 days) after the last dose of study agent; 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

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

          -  Patients positive for human immunodeficiency virus (HIV) are allowed on study, but
             HIV-positive patients must have:

               -  A stable regimen of highly active anti-retroviral therapy (HAART)

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                  polymerase chain reaction (PCR)-based tests

        Exclusion Criteria:

          -  Patients with prior allogeneic bone marrow transplantation or prior solid organ
             transplantation

          -  Patients who have previously received gemcitabine plus oxaliplatin therapy

          -  Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events (other than alopecia) due to agents administered more
             than 2 weeks earlier; however, the following therapies are allowed:

               -  Hormone-replacement therapy or oral contraceptives

               -  Herbal therapy > 1 week prior to cycle 1, day 1 (herbal therapy intended as
                  anticancer therapy must be discontinued at least 1 week prior to cycle 1, day 1)

          -  Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or
             pathway-targeting agents

               -  Patients who have received prior treatment with anti-CTLA-4 may be enrolled,
                  provided the following requirements are met:

                    -  Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from
                       the last dose

                    -  No history of severe immune-related adverse effects from anti-CTLA-4
                       (National Cancer Institute [NCI] Common Terminology Criteria for Adverse
                       Events [CTCAE] version 5.0)

          -  Treatment with any other investigational agent within 3 weeks prior to cycle 1, day 1

          -  Treatment with systemic immunostimulatory agents (including, but not limited to,
             interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks prior to cycle 1, day 1

          -  Treatment with systemic immunosuppressive medications (including, but not limited to,
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1

               -  Patients who have received acute, low dose, systemic immunosuppressant
                  medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled

               -  The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
                  for patients with orthostatic hypotension or adrenocortical insufficiency is
                  allowed

          -  Patients taking bisphosphonate therapy for symptomatic hypercalcemia; use of
             bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is
             allowed

          -  Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) who cannot
             discontinue it before treatment with atezolizumab

          -  Patients with known active central nervous system (CNS) involvement by lymphoma,
             including leptomeningeal involvement

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to other agents used in study

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease

               -  Patients with past or resolved hepatitis B infection (defined as having a
                  negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
                  [antibody to hepatitis B core antigen] antibody test) are eligible

               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

          -  History or risk of autoimmune disease, including, but not limited to, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
             syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
             thyroid disease, vasculitis, or glomerulonephritis

               -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
                  replacement hormone may be eligible

               -  Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
                  be eligible

               -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis would
                  be excluded) are permitted provided that they meet the following conditions:

                    -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out
                       ocular manifestations

                    -  Rash must cover less than 10% of body surface area (BSA)

                    -  Disease is well controlled at baseline and only requiring low potency
                       topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
                       fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

                    -  No acute exacerbations of underlying condition within the last 12 months
                       (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
                       retinoids, biologic agents, oral calcineurin inhibitors; high potency or
                       oral steroids)

          -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan; history of radiation pneumonitis in the radiation field
             (fibrosis) is permitted

          -  Patients with active tuberculosis (TB) are excluded

          -  Severe infections within 4 weeks prior to cycle 1, day 1, including, but not limited
             to, hospitalization for complications of infection, bacteremia, or severe pneumonia

          -  Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1

          -  Received oral or intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1;
             patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
             infection or chronic obstructive pulmonary disease) are eligible

          -  Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of
             need for a major surgical procedure during the course of the study

          -  Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or
             anticipation that such a live, attenuated vaccine will be required during the study
             and up to 5 months after the last dose of atezolizumab

               -  Influenza vaccination should be given during influenza season only (approximately
                  October to March); patients must not receive live, attenuated influenza vaccine
                  within 4 weeks prior to cycle 1, day 1 or at any time during the study

          -  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

          -  Pregnant women are excluded from this study because atezolizumab, gemcitabine, and
             oxaliplatin are agents with the potential for teratogenic or abortifacient effects;
             because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with atezolizumab, gemcitabine, and oxaliplatin,
             breastfeeding should be discontinued if the mother is treated with atezolizumab,
             gemcitabine, and oxaliplatin; these potential risks may also apply to other agents
             used in this study
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Alex F Herrera, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03321643

Organization ID

NCI-2017-01957

Secondary IDs

NCI-2017-01957

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Alex F Herrera, Principal Investigator, City of Hope Comprehensive Cancer Center LAO


Verification Date

February 2022