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Glofitamab-based Treatment in Older Adults with Diffuse Large B-cell Lymphoma, High-Grade B-cell Lymphoma or Transformed Lymphoma, GLORY Trial
Trial Status: active
This phase II trial tests how well glofitamab, polatuzumab vedotin, and obinutuzumab in combination with standard chemotherapy treatment, rituximab, cyclophosphamide, doxorubicin, and prednisone, works in treating patients with diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL) or transformed lymphoma. This clinical trial also evaluates how well adding glofitamab, polatuzumab vedotin, and obinutuzumab early to treatment with rituximab, cyclophosphamide, doxorubicin and prednisone works in reducing the amount of chemotherapy needed to treat these types of lymphoma. Glofitamab is a bispecific monoclonal antibody that can bind to two different proteins at the same time. Glofitamab binds to a protein CD3, which is found on T cells (a type of white blood cell). It also binds to a protein called CD20, which is found on B cells (another type of white blood cell) and some lymphoma cells and may interfere with the ability of cancer cells to grow and spread. Polatuzumab vedotin is a monoclonal antibody, called polatuzumab, linked to a chemotherapy drug, called monomethylauristatin E (MMAE). Polatuzumab vedotin is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD79B receptors, and delivers MMAE to kill them. Obinutuzumab and rituximab are monoclonal antibodies that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Chemotherapy drugs, such as cyclophosphamide and doxorubicin, 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. Prednisone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Chemotherapy often causes many short- and long-term side effects, especially in people over 65 years of age with other medical problems. Lowering the dose of chemotherapy may cause fewer and more mild side effects than standard doses. Giving glofitamab, polatuzumab vedotin, and obinutuzumab early in the treatment plan with rituximab, cyclophosphamide, doxorubicin and prednisone may kill more cancer cells and reduce the amount of chemotherapy needed to treat patients with DLBCL, HGBCL or transformed lymphoma.
Inclusion Criteria
Age 65-79 years with a fitness assessment of unfit or frail per simplified geriatric assessment (GA)
Age ≥ 80 years with any fitness level
Pathologically confirmed DLBCL, HGBCL or transformed lymphoma
No prior systemic anti-lymphoma therapy (prednisone/equivalent up to 100 mg daily x 7 days is permissible)
Ann Arbor stage 2 bulky, 3 or 4 disease
Any International Prognostic Index (IPI) score
Anthracycline eligible: Left ventricular ejection fraction (LVEF) ≥ 45% by echocardiogram or MUGA scan
Must have at least one bi-dimensionally measurable lesion (> 1.5 cm in its largest dimension for nodal lesions, or > 1.0 cm in its largest dimension for extranodal lesions by computerized tomography [CT] scan or MRI)
Eastern Cooperative Oncology Group performance status ≤ 2
Absolute neutrophil count (ANC) ≥ 1,000/mm^3 or ≥ 500/mm^3 if due to disease involvement in the bone marrow
Platelet count ≥ 50,000 cells/mm^3 or ≥ 25,000/mm^3 if due to disease involvement in the bone marrow
Patients who do not meet criteria for bone marrow function due to marrow involvement of lymphoma and/or other disease-related cytopenias (e.g., immune thrombocytopenia) may be enrolled into the study after discussion with, and confirmation by the principal investigator (PI)
Serum creatinine ≤ upper limit of normal (ULN) OR estimated creatinine clearance (CrCl) ≥ 30 mL/min (Cockcroft-Gault formula or other institutional standard methods)
Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3 x upper limit of normal (ULN)
Total bilirubin ≤ 1.5 x ULN (≤ 3 if due to Gilbert's syndrome or liver involvement by the lymphoma)
Patients who do not meet criteria for liver function due to liver involvement of lymphoma may be enrolled into the study after discussion with, and confirmation by the PI
Negative HIV test at screening, with the following exception: Individuals with a positive HIV test at screening are eligible provided, prior to enrollment, they are stable on antiretroviral therapy, have a CD4 count ≥ 200/uL, and have an undetectable viral load
Signed informed consent form(s)
Ability to comply with all the study-related procedures, in the investigator’s judgement
Female patients who are not of child bearing potential (i.e., who are postmenopausal or surgically sterile). For male participants: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agree to refrain from donating sperm, as defined below: With a female partner of childbearing potential or pregnant female partners, male participants must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after pretreatment with obinutuzumab, 6 months after the last dose of polatuzumab, 160 days after the last dose of rituximab, 2 months after the final dose of glofitamab or 2 months after the last dose of tocilizumab (as applicable), whichever is longer. Male participants must refrain from donating sperm during this same period.
* The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local informed consent form
Exclusion Criteria
Prior systemic anti-lymphoma therapy (localized radiation, steroids and antibiotics are permitted)
Prior solid organ transplantation
Prior allogeneic stem cell transplantation
Active central nervous system (CNS) involvement
Uncontrolled HIV or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (controlled HIV with undetectable viral load and previously treated HBV and HCV are allowed)
* Participants with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative hepatitis B surface antigen [HBsAg]) may be included if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is undetectable at the time of screening. Such participants must be willing to undergo HBV DNA testing on day 1 of every cycle and every 3 months for at least 12 months after the final cycle of study treatment and appropriate antiviral therapy as indicated.
* Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
Uncontrolled active systemic infection
Major surgery within 4 weeks of the first dose of study drug (exceptions may be allowed after discussion with PI if patient has fully recovered from procedure and anti-lymphoma therapy is urgently needed)
Significant or extensive history of cardiovascular disease such as New York Heart Association class III or IV cardiac disease or objective assessment class C or D, myocardial infarction within the last 3 months prior to the start of cycle 1, unstable arrhythmias, or unstable angina
Uncontrolled autoimmune disorder
A history of confirmed progressive multifocal leukoencephalopathy
Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or risk study outcomes
Inability to comply with all the study-related procedures, in the investigator’s judgement
Contraindication to any of the individual components of polatuzumab, R-miniCHP and glofitamab or history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
Prior treatment with systemic immunotherapeutic agents, including but not limited to, radio-immuno-conjugates, antibody-drug conjugates, immune/cytokines and monoclonal antibodies (mAbs) (e.g., anti-cytotoxic T lymphocyte associated protein 4, anti-PD-1, and anti-PD-L1) within 4 weeks or five half-lives of the drug, whichever is shorter
Prior use of any monoclonal antibody for the purposes of treating cancer within 3 months of the start of cycle 1
Any investigational therapy for the purposes of treating cancer within 28 days prior to the start of cycle 1
Prior radiotherapy to the mediastinal/pericardial region. Radiotherapy to non-target lesion sites will be permitted
Corticosteroid use > 50 mg/day of prednisone or equivalent, for purposes other than lymphoma symptom control
* Participants receiving corticosteroid treatment with ≤ 50 mg/day of prednisone or equivalent for reasons other than lymphoma symptom control (e.g., rheumatoid arthritis) must be documented to be on a stable dose of at least 4 weeks duration prior to the start of cycle
* Corticosteroid therapy for control of cancer symptoms or side effects of prior treatment (e.g., nausea or B-symptoms) is permitted
* The use of inhaled corticosteroids is permitted
* The use of mineralocorticoids for management of orthostatic hypotension is permitted
* The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted
History of other malignancy that could affect compliance with the protocol or interpretation of results:
* Participants with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible
* Participants with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment are eligible
* Participants with low-grade, early-stage prostate cancer (Gleason score 6 or below, stage 1 or 2) with no requirement for therapy at any time prior to study are eligible
* Patients with other concomitant malignancies may be eligible after discussion with, and confirmation by the PI
Live, attenuated vaccine within 4 weeks before study treatment infusion on day 1 of cycle 1 or anticipation that such a live, attenuated vaccine will be required during the study. Live vaccines during the study and until participants B cells recover, are prohibited
* Influenza vaccination should be given during influenza season only. Participants must not receive live, attenuated influenza vaccine at any time during the study treatment period
Additional locations may be listed on ClinicalTrials.gov for NCT06765317.
I. To determine the complete response rate (CRR) of glofitamab+polatuzumab (glofit-pola) after 2 cycles.
II. To determine the CRR of all patients treated with glofitamab+polatuzumab-rituximab-mini-cyclophosphamide, doxorubicin, and prednisone (CHP) (glofit-pola-R-mini-CHP) at the end of therapy.
SECONDARY OBJECTIVES:
I. To evaluate other measures of efficacy including overall response rate, progression free survival, overall survival, duration of response and duration of complete response.
II. To evaluate tolerability by tabulating adverse events and analyzing the number of patients who were able to complete therapy per protocol.
EXPLORATORY OBJECTIVES:
I. To characterize the response to doublet window regimen based on cell of origin and DLBCL subtypes by gene expression profiling (GEP).
2. To understand treatment-induced changes in the tumor immune microenvironment and/or peripheral blood immune cell populations.
III. To evaluate dynamic changes in aging biomarkers (epigenetic aging clock, senescence associated secretory phenotype [SASP]) and correlation with disease response and treatment toxicity.
IV. To perform serial health-related quality of life (HRQoL) assessment and understand the correlation of HRQoL with aging biomarkers, toxicity and response.
V. To understand the kinetics of circulating tumor-derived deoxyribonucleic acid (ctDNA) reduction and its correlation with outcomes.
OUTLINE:
Patients receive obinutuzumab intravenously (IV) on day 1 of cycle 1 only, glofitamab IV over 2-4 hours on days 8 and 15 of cycle 1 then on day 1 of remaining cycles, and polatuzumab vedotin IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Starting with cycle 3, all patients also receive rituximab IV, cyclophosphamide IV, and doxorubicin IV on day 2 of cycle 3 and on day 1 of remaining cycles and prednisone orally (PO) on days 2-6 of each cycle. Cycles repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with a partial response or stable disease after cycle 2, receive an additional 2 cycles of glofitamab and rituximab, cyclophosphamide, doxorubicin and prednisone. Patients undergo echocardiography or multigated acquisition scan (MUGA) at screening and tumor tissue biopsy at screening and optionally throughout the study. Additionally, patients undergo blood sample collection, and computed tomography (CT), fludeoxyglucose F-18 (FDG) positron emission tomography (PET)/CT and/or magnetic resonance imaging (MRI) and optional bone marrow aspiration and/or biopsy throughout the study.
After completion of study treatment, patients are followed up at 28 days, then every 3 months for 2 years then every 6 months for up to 3 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center