Testing the Addition of a New Anti-Cancer Drug, Glofitamab to Usual Chemotherapy for Burkitt and Double Hit Lymphoma

Phase 3Not Yet RecruitingNCT07724457

National Cancer Institute (NCI)271 enrolled

Overview

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.

PRIMARY OBJECTIVES: I. To compare the progression free survival (PFS) of rituximab (R)-chemotherapy plus glofitamab versus R-chemotherapy alone in patients with newly diagnosed Burkitt lymphoma. II. To compare the PFS of R-chemotherapy plus glofitamab versus R-chemotherapy alone in patients with newly diagnosed high grade (double hit) B-cell lymphoma with MYC and BCL2 rearrangements. III. To determine the overall survival of obinutuzumab, rituximab, ifosfamine, carboplatin, etoposide (RICE), and glofitamab in patients with relapsed Burkitt lymphoma. SECONDARY OBJECTIVES: I. To compare the overall survival (OS) of R-chemotherapy plus glofitamab versus R-chemotherapy alone in patients with Burkitt lymphoma, and patients with high grade B-cell lymphoma with MYC and BCL2 rearrangements. II. To compare the safety and tolerability of glofitamab combined with R-chemotherapy versus R-chemotherapy alone in patients with Burkitt lymphoma, and patients with high grade B-cell lymphoma with MYC and BCL2 rearrangements. III. To determine the event free survival (EFS), complete response (CR) and overall response (OR) rates of obinutuzumab, RICE, and glofitamab in patients with relapsed Burkitt and high grade B-cell lymphoma. IV. To assess how many patients undergo transplant or chimeric antigen receptor T-cell therapy (CART) after treatment with obinutuzumab, RICE, and glofitamab for relapsed Burkitt lymphoma. EXPLORATORY OBJECTIVES: I. To assess patient reported outcomes in patients with Burkitt and double hit lymphoma at study enrollment, during treatment and at the end of therapy. II. To evaluate the completion rate of a lymphoma-specific patient assessment of life survey (PALS) for 7 patient directed questions on social determinants of health (SDH) and assess the impact of the survey collected data on outcomes for all enrolled patients. OUTLINE: Patients with newly diagnosed Burkitt lymphoma are assigned to cohort 1, patients with double hit lymphoma are assigned to cohort 2, patients with relapsed or refractory Burkitt lymphoma or high grade lymphoma are assigned to cohort 3. COHORT 1: Patients are randomized to 1 of 2 arms. Patients who received a singe cycle of anthracycline containing chemotherapy will start treatment at cycle 2 22-36 days after cycle 1. ARM 1: Patients receive either rituximab, cyclophosphamide, doxorubicin, vincristine and methotrexate (RCODOXM)/rituximab, ifosfamide, etoposide, cytarabine (RIVAC) or rituximab, etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone (DA-REPOCH) treatment per the investigators choice. Patients over the age of 60 or with other co-morbidities are assigned to DA-REPOCH. RCODOXM/RIVAC: CYCLES 1 AND 3: Patients receive rituximab intravenously (IV) or rituxan hycela subcutaneously (SC) on day 1, cyclophosphamide IV on days 1 and 2, doxorubicin IV on day 1, vincristine IV on day 1 and 15 and methotrexate IV, over 2-4 hours on day 15. CYCLES 2 AND 4: Patients receive rituximab IV or rituan hycela SC on day 1, ifosfamide IV and etoposide IV on days 1-5, and cytarabine IV every 12 hours on days 1-2. Patients without baseline central nervous system (CNS) disease also receive methotrexate intrathecally (IT) and cytarabine IT once per cycle for 4 treatments or methotrexate IT twice per cycle for 8 treatments or alternating methotrexate IT and cytarabine IT twice per cycle for 8 treatments. Patients with baseline CNS disease also receive methotrexate IT and cytarabine IT twice weekly, methotrexate IT or alternating methotrexate IT and cytarabine IT until cerebrospinal fluid (CSF) clears then weekly methotrexate IT for 4 weeks then methotrexate IT once per cycles for remaining cycles. Cycles repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. DA-REPOCH: 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 orally (PO) twice daily (BID) on days 1-5. Patients without baseline CNS disease also receive methotrexate IT and cytarabine IT once per cycle for 4 treatments or methotrexate IT twice per cycle for 8 treatments or alternating methotrexate IT and cytarabine IT twice per cycle for 8 treatments. Patients with baseline CNS disease also receive methotrexate IT and cytarabine IT twice weekly, methotrexate IT or alternating methotrexate IT and cytarabine IT 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 positron emission tomography (PET), computed tomography (CT) scan, and/or magnetic resonance imaging (MRI) and lumbar puncture with CSF sample collection throughout the study. Patients may undergo bone marrow biopsy and blood sample collection throughout the study. ARM 2: Patients receive either RCODOXM/RIVAC or DA-REPOCH with glofitamab per the investigators choice. Patients over the age of 60 or with other co-morbidities are assigned to DA-REPOCH. RCODOXM/RIVAC: CYCLES 1 AND 3: Patients receive rituximab IV or rituxan hycela SC on day 1, cyclophosphamide IV on days 1 and 2, doxorubicin IV on day 1, vincristine IV on day 1 and 15 and methotrexate IV, over 2-4 hours on day 15. Patients also receive glofitamab IV, over 2-4 hours, on day 2 of cycle 3. CYCLES 2 AND 4: Patients receive rituximab IV or rituan hycela SC on day 1, ifosfamide IV and etoposide IV on days 1-5, and cytarabine IV every 12 hours on days 1-2. Patients also receive glofitamab IV, over 2-4 hours, on day 6 and 15 of cycle 2 and day 6, 22, 43 64 and 85 of cycle 4. Patients without baseline CNS disease also receive methotrexate IT and cytarabine IT once per cycle for 4 treatments or methotrexate IT twice per cycle for 8 treatments or alternating methotrexate IT and cytarabine IT twice per cycle for 8 treatments. IT treatment can not be given on the same day as glofitamab. Patients with baseline CNS disease also receive methotrexate IT and cytarabine IT twice weekly, methotrexate IT or alternating methotrexate IT and cytarabine IT 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. 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. Cycles repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. DA-REPOCH: 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 also receive methotrexate IT and cytarabine IT once per cycle for 4 treatments or methotrexate IT twice per cycle for 8 treatments or alternating methotrexate IT and cytarabine IT twice per cycle for 8 treatments. IT treatment can not be given on the same day as glofitamab. Patients with baseline CNS disease also receive methotrexate IT and cytarabine IT twice weekly, methotrexate IT or alternating methotrexate IT and cytarabine IT 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. Patients may undergo bone marrow biopsy and blood sample collection throughout the study. COHORT 2: Patients are randomized to 1 of 2 arms. ARM 3: 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. ARM 4: 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. Patients may undergo bone marrow biopsy and blood sample collection throughout the study. COHORT 3: Patients receive obinutuzumab IV on day 1 of cycle 1, rituximab IV or rituxan hyceka SC on day 4 of cycle 1 and on day 1 of subsequent cycles, ifosfamide IV continuously on day 2, carboplatin, over 1 hour, on day 2, etoposide IV, over 2 hours, on days 1-3 and glofitamab IV, over 2-4 hours, on day 8 and 15 of cycle 1, on day 4 of cycles 2-3 and day 4 and 22 of cycle 4. 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 4 cycles in the absence of disease progression or unacceptable toxicity. Responding patients may come off study any time after cycle 3 to receive transplant or chimeric antigen receptor therapy. 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. After completion of study treatment, patients are followed up every 3 months for 2 years then every 6 months until 5 years.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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: * Stage III or IV disease * Elevated lactate dehydrogenase (LDH) greater than institutional upper limit of normal (ULN) * Tumor mass ≥ 7 cm * BL COHORT 1: No prior treatment except for pre-phase chemotherapy, pre-phase corticosteroids, or one cycle of chemotherapy as described below. * Pre-phase chemotherapy with corticosteroids or cyclophosphamide/prednisone is permitted prior to enrollment. * One cycle of prior chemotherapy (for example, cyclophosphamide, doxorubicin, vincristine and prednisone \[CHOP\], Polatuzumab-cyclophosphamide doxorubicin and prednisone \[CHP\], cyclophosphamide, vincristine, doxorubicin and methotrexate \[CODOXM\], or etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin \[EPOCH\] \[with or without rituximab\]) may be administered no more than 21 days prior to enrollment. * Patients enrolling on study after one cycle of prior anthracycline containing therapy will start the study therapy in cycle 2 and cycle 2 must occur no later than 22-36 days after the start of cycle 1. (If feasible, cycle 2 should start on day 22, but +14 days is permitted to permit recovery from toxicity in cycle 1) * 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. * Pre-phase chemotherapy with corticosteroids or cyclophosphamide/prednisone is permitted prior to enrollment. * One cycle of prior chemotherapy (for example, CHOP, Polatuzumab-CHP, or EPOCH (with or without Rituximab)) may be administered no more than 21 days prior to enrollment. * Patients enrolling on study after one cycle of prior anthracycline containing therapy will start the study therapy in cycle 2 and cycle 2 must occur no later than 22-36 days after the start of cycle 1. (If feasible, cycle 2 should start on day 22, but +14 days is permitted to permit recovery from toxicity in cycle 1) * 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. * Prior radiotherapy in addition or in conjunction with prior chemotherapy is permitted. * Patients who have previously received a bispecific antibody (BsAb) are NOT eligible. However, patients enrolled to the standard arms on cohorts 1 and 2 of this trial who did not receive glofitimab and have relapsed or refractory disease are eligible to enroll on cohort 3. * Prior treatment with systemic immunotherapeutic agents including antibody drug conjugates, radio-immunoconjugates, or immune/cytokine direct therapy must have occurred within 3 weeks or five half-lives of the drug, whichever is shorter * 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 * RELAPSED BL AND HGL COHORT 3: Patients with a history of PML are NOT eligible * RELAPSED BL AND HGL COHORT 3: Patients who have received live, attenuated vaccines within 4 weeks prior to cycle 1 D1 of study treatment are NOT eligible

Outcomes

Primary Outcomes

Progression free survival (PFS) (cohort 1) (phase II)

The median PFS will be summarized by sex with corresponding 95% confidence intervals.

Time frame: from randomization to the time of documented disease progression or death due to any cause

PFS (cohort 1) (phase III)

PFS defined as from randomization to the time of documented disease progression or death due to any cause. Will be as estimated using the methods of Kaplan and Meier. The median PFS and the 24-month PFS rates will be summarized by sex with corresponding 95% confidence intervals.

Time frame: At 24 months

PFS (cohort 2) (phase II)

The median PFS will be summarized by sex with corresponding 95% confidence intervals.

Time frame: From randomization to the time of documented disease progression or death due to any cause, up to 5 years

PFS (cohort 2) (phase III)

Time frame: At 24 months

Overall survival (cohort 3)

Time frame: At 12 months after start of treatment

Secondary Outcomes

Overall survival (OS)

Will be evaluated between the treatment arms for each of the cohorts. Kaplan Meier methods will be used to estimate key aspects of the OS distributions for each of the treatment arms, and logrank tests will be used to compare these distributions between arms.

Time frame: From randomization to the time of death due to any cause, up to 5 years

Event free survival (EFS)

Will be evaluated between the treatment arms for each of the cohorts. Kaplan Meier methods will be used to estimate key aspects of the EFS distributions for each of the treatment arms, and logrank tests will be used to compare these distributions between arms.

Time frame: From randomization date until the earlier of non-protocol lymphoma therapy, disease progression or death from any cause, up to 5 years

Overall response rate (ORR)

Defined as the number of patients achieving complete or partial response according to either the computed tomography(CT)-based or positron emission tomography (PET)-CT-based Lugano criteria, divided by the number of evaluable patients. will be estimated by treatment arm, and a 95% binomial confidence interval for the estimated ORR will be provided. Will be evaluated between the treatment arms for each of the cohorts.

Time frame: Up to 5 years

Complete response rate

Defined as the number of patients achieving complete response according to either the CT-based or PET-CT-based Lugano criteria, divided by the number of evaluable patients. The CR rate will be estimated by treatment arm, and a 95% binomial confidence interval for the estimated CR rate will be provided.

Time frame: Up to 5 years

Transplant or chimeric antigen receptor t-cell (CAR-T) rate (cohort 3)

Defined as the number of Cohort 3 patients who undergo transplant or CAR-T after treatment with Rituximab-Ifosfamide-Carboplatin-Etoposide plus Glofitamab, divided by the number of Cohort 3 patients who receive at least one dose of protocol therapy. The transplant or CAR-T rate will be estimated and the corresponding 95% binomial confidence interval will be provided.

Time frame: Up to 5 years

Incidence of adverse events (AEs)

Will be summarized per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5 and Patient Reported Outcome-CTCAE, and where toxicities will be defined as adverse events that are deemed to be at least possibly treatment-related. The maximum grade for each type of treatment-related AE will be recorded for each patient, and the frequency of each will be summarized by treatment arm. Frequency tables and graphical evaluations of AEs and treatment-related AEs will be summarized and evaluated to assess if there are any patterns or differences in the rates or types of AEs.

Time frame: Up to 5 years

Testing the Addition of a New Anti-Cancer Drug, Glofitamab to Usual Chemotherapy for Burkitt and Double Hit Lymphoma

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes