This phase II/III trial tests adding glofitamab to standard of care chemoimmunotherapy in patients with Burkitt and high grade (double hit) B- cell lymphomas that are newly diagnosed, that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Glofitamab 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. Obinutuzumab and rituximab are also monoclonal antibodies. They bind 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. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill cancer cells. It also blocks a certain enzyme needed for cell division and DNA repair. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. 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. Methotrexate is in a class of medications called antimetabolites. It is also a type of antifolate. Methotrexate stops cells from using folic acid to make DNA and may kill cancer cells. Chemotherapy drugs, such as cytarabine and ifosfamide, 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. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Giving glofitamab with standard of care chemotherapy may work well for the treatment of newly diagnosed, relapsed or refractory Burkitt and high grade (double hit) B- cell lymphomas.
Inclusion Criteria:
BURKITT LYMPHOMA (BL) COHORT 1: Histologically confirmed Burkitt lymphoma by International Consensus Classification criteria. Patients with Burkitt lymphoma must have one or more of the following adverse risk factors at diagnosis:
BL COHORT 1: No prior treatment except for pre-phase chemotherapy, pre-phase corticosteroids, or one cycle of chemotherapy as described below.
BL COHORT 1: Age ≥ 18 years
BL COHORT 1: Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. ECOG performance status of 3 is permitted if related to lymphoma
BL COHORT 1: Absolute neutrophil count (ANC) ≥ 1,000/mm^3 (unless attributable to lymphoma)
BL COHORT 1: Platelet count ≥ 75,000/mm^3 (unless attributable to lymphoma)
BL COHORT 1: Calculated (Calc.) creatinine clearance ≥ 50 mL/min (unless attributable to lymphoma)
BL COHORT 1: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN (unless attributable to lymphoma)
BL COHORT 1: Total bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome) (unless attributable to lymphoma)
BL COHORT 1: International normalization ratio (INR) OR prothrombin time (PT) > 1.5 x institutional ULN (unless attributable to lymphoma)
BL COHORT 1: Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) > 1.5 x institutional ULN (unless attributable to lymphoma)
BL COHORT 1: Not pregnant and not nursing, because this study involves agents that have known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 28 days prior to registration is required
BL COHORT 1: Patients with prior malignancy or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen (i.e. anthracycline dosing that will exceed recommended lifetime maximum dosing) are eligible for this trial
BL COHORT 1: Patients with HIV are eligible but must be on effective anti-retroviral therapy, with undetectable viral load within 6 months of enrollment
BL COHORT 1: Patients with a history of hepatitis B who are hepatitis B (HepB) surface antigen (Ag) positive and/or HepB core antibody (Ab) positive with undetectable Hep B viral load who start suppressive antiviral therapy prior to chemotherapy are eligible
BL COHORT 1: Patients with a history of hepatitis C infection that have been treated for hepatitis C virus (HCV) and have an undetectable HCV viral load are eligible
BL COHORT 1: No active ischemic heart disease or congestive heart failure, AND adequate cardiac function defined as ejection fraction of ≥ 45%
BL COHORT 1: Patients with CSF/leptomeningeal involvement at diagnosis are eligible. Patients with parenchymal brain involvement at diagnosis are NOT eligible
BL COHORT 1: Patients requiring > 10 mg/day of prednisone or equivalent, for the treatment of conditions other than the control of lymphoma related symptoms, are NOT eligible
BL COHORT 1: Patients with major surgery within 4 weeks other than for diagnosis of lymphoma are NOT eligible
BL COHORT 1: Patients with known active infections, or reactivation of a latent infection (excluding fungal infections of nail bed, hepatitis B on suppressive therapy or treated hepatitis C) requiring hospitalization or treatment with IV antibiotics within 4 weeks of study treatment are NOT eligible
BL COHORT 1: Patients with a prior history of hemophagocytic lymphohistocytosis (HLH) are NOT eligible
BL COHORT 1: Patients with a history of autoimmune disease (including but not limited to myasthenia gravis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Guillain-Barre syndrome, or multiple sclerosis) are NOT eligible.
However, patients with autoimmune related hypothyroidism on a stable dose of thyroid replacement hormone, patients with a history of lymphoma related immune thrombocytopenic purpura or hemolytic anemia, and patients with type 1 or type 2 diabetes on a stable insulin regimen are eligible to enroll. In addition, patients with eczema, lichen simplex chronicus, or vitiligo with dermatologic manifestations only may also enroll if the rash covers < 10% of body surface area and the disease is well controlled and requires only topical corticosteroids.
Lastly, patients treated with prior immunotherapeutic agents with a history of any grade 3 events (except for grade 3 endocrinopathy managed with replacement therapy) or grade 1-2 events that did not resolve to baseline with treatment discontinuation are NOT eligible.
BL COHORT 1: Patients with a history of progressive multifocal leukoencephalopathy (PML) are NOT eligible
BL COHORT 1: Patients who have received live, attenuated vaccines within 4 weeks prior to cycle 1 day (D) 1 of study treatment are NOT eligible
DOUBLE HIT LYMPHOMA (DHL) COHORT 2: Histologically confirmed high grade/double hit B-cell lymphoma with MYC and BCL2 translocations by International Consensus Classification (ICC) or World Health Organization (WHO) criteria. Fluorescence in situ hybridization (FISH) For MYC and BCL2 translocations must be performed by the referring site and must be positive for translocations of BOTH MYC and BCL2. Patients found to have BCL6 translocations in addition to BOTH MYC and BCL2 (so called "triple hit lymphoma") are eligible
DHL COHORT 2: Stage II-IV disease per Lugano staging classification
DHL COHORT 2: No prior treatment except for pre-phase chemotherapy, pre-phase corticosteroids, or one cycle of chemotherapy as described below.
DHL COHORT 2: Age ≥ 18 years
DHL COHORT 2: ECOG performance status ≤ 2. ECOG performance status of 3 is permitted if related to lymphoma
DHL COHORT 2: Absolute neutrophil count (ANC) ≥ 1,000/mm^ 3 (unless attributable to lymphoma)
DHL COHORT 2: Platelet Count ≥ 75,000/mm^3 (unless attributable to lymphoma)
DHL COHORT 2: Calc. Creatinine Clearance ≥ 50 mL/min (unless attributable to lymphoma)
DHL COHORT 2: AST(SGOT)/ALT(SGPT) ≤ 3 x institutional ULN (unless attributable to lymphoma)
DHL COHORT 2: Total Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's Syndrome) (unless attributable to lymphoma)
DHL COHORT 2: INR OR PT > 1.5 x institutional ULN (unless attributable to lymphoma)
DHL COHORT 2: PTT or aPTT > 1.5 x institutional ULN (unless attributable to lymphoma)
DHL COHORT 2: Not pregnant and not nursing, because this study involves agents that have known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 28 days prior to registration is required
DHL COHORT 2: Patients with prior malignancy or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen (i.e. anthracycline dosing that will exceed recommended lifetime maximum dosing) are eligible for this trial
DHL COHORT 2: Patients with HIV are eligible but must be on effective anti-retroviral therapy, with undetectable viral load within 6 months of enrollment
DHL COHORT 2: Patients with a history of hepatitis B who are HepB surface Ag positive and/or HepB core Ab positive with undetectable Hep B viral load who who start suppressive antiviral therapy prior to chemotherapy are eligible
DHL COHORT 2: Patients with a history of hepatitis C infection that have been treated for HCV and have an undetectable HCV viral load are eligible
DHL COHORT 2: No active ischemic heart disease or congestive heart failure, AND adequate cardiac function defined as ejection fraction of ≥ 45%
DHL COHORT 2: Patients with CSF/leptomeningeal involvement at diagnosis are eligible. Patients with parenchymal brain involvement at diagnosis are NOT eligible
DHL COHORT 2: Corticosteroid use: Patients requiring > 10 mg/day of prednisone or equivalent, for the treatment of conditions other than the control of lymphoma related symptoms, are NOT eligible
DHL COHORT 2: Patients with major surgery within 4 weeks other than for diagnosis of lymphoma are NOT eligible
DHL COHORT 2: Patients with known active infections, or reactivation of a latent infection (excluding fungal infections of nail bed, hepatitis B on suppressive therapy, or treated hepatitis C) requiring hospitalization or treatment with IV antibiotics within 4 weeks of study treatment are NOT eligible
DHL COHORT 2: Patients with a prior history of HLH are NOT eligible
DHL COHORT 2: Patients with a history of autoimmune disease (including but not limited to myasthenia gravis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Guillain-Barre syndrome, or multiple sclerosis) are NOT eligible.
However, patients with autoimmune related hypothyroidism on a stable dose of thyroid replacement hormone, patients with a history of lymphoma related immune thrombocytopenic purpura or hemolytic anemia, and patients with type 1 or type 2 diabetes on a stable insulin regimen are eligible to enroll. In addition, patients with eczema, lichen simplex chronicus, or vitiligo with dermatologic manifestations only may also enroll if the rash covers < 10% of body surface area and the disease is well controlled and requires only topical corticosteroids.
Lastly, patients treated with prior immunotherapeutic agents with a history of any grade 3 events (except for grade 3 endocrinopathy managed with replacement therapy) or grade 1-2 events that did not resolve to baseline with treatment discontinuation are NOT eligible
DHL COHORT 2: Patients with a history of PML are NOT eligible
DHL COHORT 2: Patients who have received live, attenuated vaccines within 4 weeks prior to cycle 1 D1 of study treatment are NOT eligible
RELAPSED BL AND HGL COHORT 3: Histologically confirmed Burkitt lymphoma by International Consensus Classification criteria
RELAPSED BL AND HGL COHORT 3: Patients must have relapsed or refractory disease after at least one prior treatment with chemotherapy or chemoimmunotherapy.
RELAPSED BL AND HGL COHORT 3: Age ≥ 18 years
RELAPSED BL AND HGL COHORT 3: ECOG Performance Status ≤ 2. ECOG performance status of 3 is permitted if related to lymphoma
RELAPSED BL AND HGL COHORT 3: Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3 (unless attributable to lymphoma)
RELAPSED BL AND HGL COHORT 3: Platelet Count ≥ 75,000/mm^3 (unless attributable to lymphoma)
RELAPSED BL AND HGL COHORT 3: Calc. Creatinine Clearance ≥ 50 mL/min (unless attributable to lymphoma)
RELAPSED BL AND HGL COHORT 3: AST(SGOT)/ALT(SGPT) ≤ 3 x institutional ULN (unless attributable to lymphoma)
RELAPSED BL AND HGL COHORT 3: Total bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's Syndrome) (unless attributable to lymphoma)
RELAPSED BL AND HGL COHORT 3: INR OR PT > 1.5 x institutional ULN (unless due to Gilbert's Syndrome) (unless attributable to lymphoma)
RELAPSED BL AND HGL COHORT 3: PTT or aPTT > 1.5 x institutional ULN (unless due to Gilbert's Syndrome) (unless attributable to lymphoma)
RELAPSED BL AND HGL COHORT 3: Not pregnant and not nursing, because this study involves agents that have known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 28 days prior to registration is required
RELAPSED BL AND HGL COHORT 3: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen (i.e. anthracycline dosing that will exceed recommended lifetime maximum dosing) are eligible for this trial
RELAPSED BL AND HGL COHORT 3: Patients with HIV are eligible but must be on effective anti-retroviral therapy, with undetectable viral load within 6 months of enrollment
RELAPSED BL AND HGL COHORT 3: Patients with a history of hepatitis B who are HepB surface Ag positive and/or HepB core Ab positive with undetectable Hep B viral load who are taking suppressive antiviral therapy are eligible
RELAPSED BL AND HGL COHORT 3: Patients with a history of hepatitis C infection that have been treated for HCV and have an undetectable HCV viral load are eligible
RELAPSED BL AND HGL COHORT 3: No active ischemic heart disease or congestive heart failure, AND adequate cardiac function defined as ejection fraction of ≥ 45%
RELAPSED BL AND HGL COHORT 3: Patients with CSF/leptomeningeal involvement at diagnosis are eligible. Patients with parenchymal brain involvement at diagnosis are NOT eligible
RELAPSED BL AND HGL COHORT 3: Corticosteroid use: Patients requiring > 10 mg/day of prednisone or equivalent, for the treatment of conditions other than the control of lymphoma related symptoms, are NOT eligible
RELAPSED BL AND HGL COHORT 3: Patients with major surgery within 4 weeks other than for diagnosis of lymphoma are NOT eligible
RELAPSED BL AND HGL COHORT 3: Patients with known active infections, or reactivation of a latent infection (excluding fungal infections of nail bed, hepatitis B on suppressive therapy, or treated hepatitis C) requiring hospitalization or treatment with IV antibiotics within 4 weeks of study treatment are NOT eligible
RELAPSED BL AND HGL COHORT 3: Patients with a prior history of HLH are NOT eligible
RELAPSED BL AND HGL COHORT 3: Patients with a history of autoimmune disease (including but not limited to myasthenia gravis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Guillain-Barre syndrome, or multiple sclerosis) are NOT eligible.
However, patients with autoimmune related hypothyroidism on a stable dose of thyroid replacement hormone, patients with a history of lymphoma related immune thrombocytopenic purpura or hemolytic anemia, and patients with type 1 diabetes on a stable insulin regimen are eligible to enroll. In addition, patients with eczema, lichen simplex chronicus, or vitiligo with dermatologic manifestations only may also enroll if the rash covers < 10% of body surface area and the disease is well controlled and requires only topical corticosteroids.
Lastly, patients treated with prior immunotherapeutic agents with a history of any grade 3 events (except for grade 3 endocrinopathy managed with replacement therapy) or grade 1-2 events that did not resolve to baseline with treatment discontinuation are NOT eligible
See Detailed Description
See Detailed Description.
Patients receive rituximab IV or rituxan hycela SC on day 1, etoposide IV continuously, doxorubicin IV continuously and vincristine IV continuously on days 1-4, cyclophosphamide IV on day 5, and prednisone PO BID on days 1-5. Patients without baseline CNS disease may also receive methotrexate IT once per cycle for 4-6 treatments. Patients with baseline CNS disease also receive methotrexate IT twice weekly until CSF clears then weekly methotrexate IT for 4 weeks then methotrexate IT once per cycles for remaining cycles. Cycles repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET, CT scan, and/or MRI and lumbar puncture with CSF sample collection throughout the study. Patients may undergo bone marrow biopsy and blood sample collection throughout the study.
Patients receive rituximab IV or rituxan hycela SC on day 1, etoposide IV continuously, doxorubicin IV continuously and vincristine IV continuously on days 1-4, cyclophosphamide IV on day 5, and prednisone PO BID on days 1-5. Patients also receive glofitamab IV, over 2-4 hours, on day 6 and 15 of cycle 2, day 6 of cycle 3-5 and days 6, 22 and 43 of cycle 6. Patients without baseline CNS disease may also receive methotrexate IT once per cycle for 4-6 treatments. IT treatment can not be given on the same day as glofitamab. Patients with baseline CNS disease also receive methotrexate IT twice weekly until CSF clears then weekly methotrexate IT for 4 weeks then methotrexate IT once per cycles for remaining cycles. IT treatment can not be given on the same day as glofitamab. Cycles repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET, CT scan, and/or MRI and lumbar puncture with CSF sample collection throughout the study.
See Detailed Description
AMC 120, Glofitamab Plus Chemoimmunotherapy in Newly Diagnosed HIV-Associated Large B-Cell Lymphoma (The "Glofit-RCHOP Study")
Testing the Addition of an Anti-Cancer Drug, Glofitamab, to the Usual Chemotherapy Treatment (Alternating R-CHOP/R-DHAP) for Previously Untreated Mantle Cell Lymphoma