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

Sponsor

Fred Hutchinson Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT03864419

Collaborator

(none)

Enrollment

Location

Arms

42.3

Anticipated Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Burkitt Lymphoma KSHV-associated Multicentric Castleman Disease Diffuse Large B-Cell Lymphoma	Biological: Rituximab and Hyaluronidase Human Drug: Cyclophosphamide Drug: Vincristine Drug: Methotrexate Drug: Doxorubicin Drug: Doxorubicin Hydrochloride Drug: Prednisone Drug: Etoposide Biological: Rituximab	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 24, 2019

Anticipated Primary Completion Date :

May 4, 2023

Anticipated Study Completion Date :

May 4, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Biological: Rituximab and Hyaluronidase Human Given SC Other Names: Rituxan Hycela Rituximab Plus Hyaluronidase Rituximab/Hyaluronidase Rituximab/Hyaluronidase Human Drug: Cyclophosphamide Given IV Other Names: Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Drug: Vincristine Given IV Other Names: LEUROCRISTINE VCR Vincrystine Drug: Methotrexate Given IV Other Names: Abitrexate Alpha-Methopterin Amethopterin Brimexate Emthexat Emtexate Methotrexate LPF Methylaminopterin Methotrexatum Biological: Rituximab Given IV Other Names: BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 Rituxan Rituximab ABBS Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar JHL1101 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SIBP-02 rituximab biosimilar TQB2303 RTXM83 Truxima
Experimental: 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.	Biological: Rituximab and Hyaluronidase Human Given SC Other Names: Rituxan Hycela Rituximab Plus Hyaluronidase Rituximab/Hyaluronidase Rituximab/Hyaluronidase Human Drug: Cyclophosphamide Given IV Other Names: Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Drug: Vincristine Given IV Other Names: LEUROCRISTINE VCR Vincrystine Drug: Doxorubicin Given IV Other Names: Hydroxyl Daunorubicin Hydroxyldaunorubicin Drug: Doxorubicin Hydrochloride Given IV Other Names: Adriamycine Adriblastina Doxolem Doxorubicin.HCl Drug: Prednisone Given PO Other Names: Deltacortene Decorton Decortisyl DeCortin Deltacortisone Econosone Drug: Etoposide Given IV Other Names: Demethyl Epipodophyllotoxin Ethylidine Glucoside EPEG Vepesid Biological: Rituximab Given IV Other Names: BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 Rituxan Rituximab ABBS Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar JHL1101 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SIBP-02 rituximab biosimilar TQB2303 RTXM83 Truxima
Experimental: 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.	Biological: Rituximab and Hyaluronidase Human Given SC Other Names: Rituxan Hycela Rituximab Plus Hyaluronidase Rituximab/Hyaluronidase Rituximab/Hyaluronidase Human Drug: Cyclophosphamide Given IV Other Names: Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Drug: Vincristine Given IV Other Names: LEUROCRISTINE VCR Vincrystine Drug: Doxorubicin Given IV Other Names: Hydroxyl Daunorubicin Hydroxyldaunorubicin Drug: Doxorubicin Hydrochloride Given IV Other Names: Adriamycine Adriblastina Doxolem Doxorubicin.HCl Drug: Prednisone Given PO Other Names: Deltacortene Decorton Decortisyl DeCortin Deltacortisone Econosone Biological: Rituximab Given IV Other Names: BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 Rituxan Rituximab ABBS Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar JHL1101 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SIBP-02 rituximab biosimilar TQB2303 RTXM83 Truxima
Experimental: 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.	Biological: Rituximab and Hyaluronidase Human Given SC Other Names: Rituxan Hycela Rituximab Plus Hyaluronidase Rituximab/Hyaluronidase Rituximab/Hyaluronidase Human Biological: Rituximab Given IV Other Names: BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 Rituxan Rituximab ABBS Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar JHL1101 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SIBP-02 rituximab biosimilar TQB2303 RTXM83 Truxima

Outcome Measures

Primary Outcome Measures

Incidence of treatment-emergent adverse events [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 [Up to 12 months]
Pharmacodynamic criteria is a Ctrough level above 25 ug/ml in children and adolescents after the first subcutaneous dose.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)