Rituximab Hyaluronidase in Combination With Chemotherapy in Treating Aggressive B-cell Lymphoma in Uganda

Study Overview
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Brief Summary
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This phase I trial studies how well rituximab hyaluronidase and combination chemotherapy work in treating patients in Uganda with Burkitt lymphoma, diffuse large B-cell lymphoma, or Kaposi sarcoma herpesvirus associated multicentric Castleman disease. Rituximab hyaluronidase is a combination of rituximab and hyaluronidase. Rituximab binds to a molecule 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. Hyaluronidase allows rituximab to be given by injection under the skin. Giving rituximab and hyaluronidase by injection under the skin is faster than giving rituximab alone by infusion into the blood. Drugs used in chemotherapy, such as cyclophosphamide, vincristine, methotrexate, etoposide, doxorubicin, and prednisone work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. While rituximab has a clear survival benefit in patients within developed countries, differences in supportive care and infectious co-morbidities require special attention. Giving rituximab hyaluronidase alone or in combination with chemotherapy may work better in treating patients with Burkitt lymphoma, diffuse large B-cell lymphoma, or Kaposi sarcoma herpesvirus associated multicentric Castleman disease compared to chemotherapy alone in Uganda.

Detailed Description
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OUTLINE: Open-label Phase I study characterizing the safety, tolerability, and activity of subcutaneous rituximab hyaluronidase (sqR) alone (KSHV-MCD), or combined with local standard of care chemotherapy (BL or DLBCL), in 2 age-based cohorts of patients: Cohort 1: Age >= 15 Cohort 2: Age: 2-14 sqR dose for Cohort 1 (adults) will be 1400 mg (flat dose); sqR dose for Cohort 2 (pediatrics) will depend on patient weight: >= 35 kg: 1400 mg, < 35 kg: 700 mg. For all participants, sqR will be administered with local standard of care chemotherapy (BL, DLBCL) or alone (KSHV-MCD), and supportive care. Each cohort comprises two Therapy Groups. Therapy Group 1: up to 6 participants and will receive the first cycle of rituximab IV, and subsequent cycles as flat-dose sqR. Therapy Group 2: up to 12 participants and will receive flat-dose sqR for all cycles. Disease-specific chemotherapy to be administered with rituximab hyaluronidase include: PEDIATRIC BURKITT LYMPHOMA (BL): cyclophosphamide, vincristine and prednisone followed by 6 cycles of cyclophosphamide, vincristine, and methotrexate (COP-COM). DLBCL: 6 cycles of cyclophosphamide, doxorubicin, vincristine and prednisone PO on days 1-5 of cycle 1 (CHOP). ADULT BL: 6 cycles modified dose: etoposide, doxorubicin, vincristine, cyclophosphamide and prednisone PO on days 1-5 (adjusted EPOCH). KSHV-MCD: Rituximab or rituximab hyaluronidase SC on days 1, 8, 15, and 22. After completion of study treatment, patients are followed up at 30 days, 3, 6, 9 and 12 months.

Official Title
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A Phase I Study of Subcutaneous Rituximab Hyaluronidase Combined With Local Standard-of-Care Chemotherapy for the Treatment of Burkitt Lymphoma, Diffuse Large B-Cell Lymphoma or as Monotherapy for Kaposi Sarcoma Herpesvirus Associated Multicentric Castleman Disease in Pediatrics and Adults in Uganda

Conditions
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Burkitt Lymphoma, KSHV-associated Multicentric Castleman Disease, Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Biological: Rituximab and Hyaluronidase Human
* Drug: Cyclophosphamide
* Drug: Vincristine
* Drug: Methotrexate
* Drug: Doxorubicin
* Drug: Doxorubicin Hydrochloride
* Drug: Prednisone
* Drug: Etoposide
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histology and immunohistochemistry (CD20+) confirmed Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), or histology confirmed KSHV-associated multicentric Castleman disease with elevated blood KSHV viral load Cohort 1: Age should be equal to or greater than 15 Cohort 2: Age: 2-15 Measurable disease Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Able to provide informed consent (adults) or assent (children < 18 years) in English or Luganda Human immunodeficiency virus (HIV)-infected patients eligible if meet the following criteria: CD4+ T-cell count > 200 cells/uL HIV treatable with effective antiretroviral therapy that does not include agents with known significant drug-drug interactions with accompanying chemotherapy (ritonavir and cobicistat contraindicated) Exclusion Criteria: Previous therapy for lymphoma or KSHV-multicentric Castleman disease (MCD) History of hypersensitivity to rituximab Pregnant or nursing women. Men or women may not participate unless they have agreed to use effective contraception during treatment and for 12 months following completion of therapy Inadequate organ function, unless attributed to lymphoma or KSHV-MCD Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 times upper limit of normal Creatinine > 2 times upper limit than normal or calculated creatinine clearance < 60 mL/min New York Heart Association (NYHA) cardiac failure class III or IV Patients with clinically significant anemia-hemoglobin less than 10 g/dL Central nervous system (CNS) masses consistent with lymphoma or untreated infection; leptomeningeal disease will not be excluded Patients with malignancy within 5 years, other than resected local skin cancer or limited Kaposi sarcoma (KS) (no known pulmonary KS) Patients with evidence of active infections including malaria and hepatitis B (participants with hepatitis B virus [HBV] controlled on antivirals will not be excluded)

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort I (pediatric BL)<br>Patients receive cyclophosphamide IV and vincristine IV on day 1, and prednisone IV or PO on days 1-7 in the absence of disease progression or unacceptable toxicity. Patients then receive rituximab IV or rituximab hyaluronidase SC, cyclophosphamide IV, vincristine IV, and methotrexate IV on day 1. Cycles repeat every 14 days for 6 cycles in the absence of disease progression or unacceptable toxicity. | Biological: Rituximab and Hyaluronidase Human<br>* Given SC<br>* Other names: Rituximab/Hyaluronidase Human;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Cicloxal;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;Drug: Methotrexate<br>* Given IV<br>* Other names: Methotrexatum;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|
| Experimental: Cohort II (DLBCL)<br>Patients receive rituximab IV or rituximab and hyaluronidase human SC, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, and prednisone PO on days 1-5 of cycle 1. Cycles repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. | Biological: Rituximab and Hyaluronidase Human<br>* Given SC<br>* Other names: Rituximab/Hyaluronidase Human;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Cicloxal;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Doxorubicin.HCl;Drug: Prednisone<br>* Given PO<br>* Other names: Econosone;Drug: Etoposide<br>* Given IV<br>* Other names: Vepesid;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|
| Experimental: Cohort III (Adult BL)<br>Patients receive rituximab IV or rituximab and hyaluronidase human SC in day 1, etoposide IV, doxorubicin IV, and vincristine IV on days 1-4. Patients also receive cyclophosphamide IV on day 5 and prednisone PO on days 1-5. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. | Biological: Rituximab and Hyaluronidase Human<br>* Given SC<br>* Other names: Rituximab/Hyaluronidase Human;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Cicloxal;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Doxorubicin.HCl;Drug: Prednisone<br>* Given PO<br>* Other names: Econosone;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|
| Experimental: Cohort IV (MCD)<br>Patients receive rituximab IV or rituximab and hyaluronidase human SC on days 1, 8, 15, and 22 in the absence of disease progression or unacceptable toxicity. | Biological: Rituximab and Hyaluronidase Human<br>* Given SC<br>* Other names: Rituximab/Hyaluronidase Human;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events | Common Terminology Criteria for Adverse Events version 5.0 including unanticipated problems and grade 3-5 adverse events (AEs) at least probably related to subcutaneous rituximab hyaluronidase (sqR) administration. | Up to 12 months | 
| Number of participants that result in sufficient pharmacodynamic criteria | Pharmacodynamic criteria is a Ctrough level above 25 ug/ml in children and adolescents after the first subcutaneous dose. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants achieving a repose of complete response (CR) | Response Evaluation Criteria in Solid Tumors (RECIST) criteria CR: complete disappearance of all target lesions. | 1 year | 
| Overall survival | Kaplan-Meier estimate | 1 year | 
| Progression-free survival | Kaplan-Meier estimate | 1 year | 
| Disease-free survival | Kaplan-Meier estimate | 1 year |