PRIMARY OBJECTIVES:
I. To evaluate the safety of subcutaneous rituximab and hyaluronidase human (rituximab hyaluronidase) in pediatric and adult participants with Burkitt lymphoma, diffuse large B-cell lymphoma, or Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease in Uganda when administered with standard chemotherapy and site-specific supportive care.
II. To evaluate weight-based dosing of subcutaneous rituximab hyaluronidase that minimizes extreme dose levels in pediatrics, defined as a Ctrough level below 25 ug/ml or above 400 ug/ml after the first subcutaneous dose.
SECONDARY OBJECTIVES:
I. To estimate response rates at the end of therapy.
II. To estimate overall survival, progression-free survival and disease-free survival at 1 year from initiation of therapy.
EXPLORATORY OBJECTIVES:
I. To evaluate the effect of age, weight, dose, dosing schedule and lactate dehydrogenase (LDH) on rituximab Ctrough in pediatrics and adults.
II. Evaluate gut microbiome at baseline, end of therapy, six months follow up visit and one year follow up visit, and explore associations of microbiome diversity and other characteristics with clinical parameters such as human immunodeficiency virus (HIV) infection status.
III. Evaluate KSHV and Epstein-Barr virus (EBV) viral load at baseline, end of therapy, six months follow up and one year follow up, and explore associations with clinical parameters.
IV. To compare response rate and survival to similar historical cohorts.
V. Explore the molecular characteristics of baseline tumors and their relationship to clinical parameters such as
complete response rate and overall survival.
VI. To bank blood, rectal swab and tissue specimens as well as data for future exploratory correlative studies.
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:
1) Cohort 1: Age >= 15
2) 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.
