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

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

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.

Study Overview

• Status: Terminated
• Conditions: Diffuse Large B-Cell Lymphoma; Burkitt Lymphoma; KSHV-associated Multicentric Castleman Disease
• Intervention / Treatment: Drug: Etoposide; Drug: Cyclophosphamide; Drug: Prednisone; Drug: Doxorubicin Hydrochloride; Drug: Vincristine; Drug: Methotrexate; Biological: Rituximab; Biological: Rituximab and Hyaluronidase Human; Drug: Doxorubicin

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:

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda
    • UCI-Fred Hutch Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Investigators: Principal Investigator: Manoj Menon, MD, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2019
• Primary Completion (Actual): July 26, 2023
• Study Completion (Actual): July 26, 2023

Study Registration Dates

• First Submitted: March 1, 2019
• First Submitted That Met QC Criteria: March 4, 2019
• First Posted (Actual): March 6, 2019

Study Record Updates

• Last Update Posted (Estimated): January 3, 2024
• Last Update Submitted That Met QC Criteria: December 27, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Virus Diseases; Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; DNA Virus Infections; Tumor Virus Infections; Epstein-Barr Virus Infections; Herpesviridae Infections; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Castleman Disease; Burkitt Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Keratolytic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cyclophosphamide; Etoposide; Antibodies; Podophyllotoxin; Immunoglobulins; Rituximab; Prednisone; Doxorubicin; Liposomal doxorubicin; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Methotrexate; Vincristine; Daunorubicin
• Other Study ID Numbers: RG1001799; 10040 (Registry Identifier: DAIDS ES); U028 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2019-01493 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes