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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Incidence of treatment-emergent adverse events
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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)
研究组 & 干预措施
Cohort I (pediatric BL)
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.
干预措施: Rituximab and Hyaluronidase Human (Biological)
Cohort I (pediatric BL)
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.
干预措施: Cyclophosphamide (Drug)
Cohort I (pediatric BL)
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.
干预措施: Vincristine (Drug)
Cohort I (pediatric BL)
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.
干预措施: Methotrexate (Drug)
Cohort I (pediatric BL)
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.
干预措施: Rituximab (Biological)
Cohort II (DLBCL)
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.
干预措施: Rituximab and Hyaluronidase Human (Biological)
Cohort II (DLBCL)
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.
干预措施: Cyclophosphamide (Drug)
Cohort II (DLBCL)
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.
干预措施: Vincristine (Drug)
Cohort II (DLBCL)
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.
干预措施: Doxorubicin (Drug)
Cohort II (DLBCL)
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.
干预措施: Doxorubicin Hydrochloride (Drug)
Cohort II (DLBCL)
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.
干预措施: Prednisone (Drug)
Cohort II (DLBCL)
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.
干预措施: Etoposide (Drug)
Cohort II (DLBCL)
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.
干预措施: Rituximab (Biological)
Cohort III (Adult BL)
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.
干预措施: Cyclophosphamide (Drug)
Cohort III (Adult BL)
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.
干预措施: Rituximab and Hyaluronidase Human (Biological)
Cohort III (Adult BL)
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.
干预措施: Vincristine (Drug)
Cohort III (Adult BL)
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.
干预措施: Doxorubicin (Drug)
Cohort III (Adult BL)
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.
干预措施: Doxorubicin Hydrochloride (Drug)
Cohort III (Adult BL)
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.
干预措施: Prednisone (Drug)
Cohort III (Adult BL)
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.
干预措施: Rituximab (Biological)
Cohort IV (MCD)
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.
干预措施: Rituximab and Hyaluronidase Human (Biological)
Cohort IV (MCD)
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.
干预措施: Rituximab (Biological)
结局指标
主要结局
Incidence of treatment-emergent adverse events
时间窗: Up to 12 months
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.
Number of participants that result in sufficient pharmacodynamic criteria
时间窗: Up to 12 months
Pharmacodynamic criteria is a Ctrough level above 25 ug/ml in children and adolescents after the first subcutaneous dose.
次要结局
- Progression-free survival(1 year)
- Number of participants achieving a repose of complete response (CR)(1 year)
- Overall survival(1 year)
- Disease-free survival(1 year)