Brentuximab Vedotin, Bendamustine, and Rituximab in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This phase II trial studies how well brentuximab vedotin, bendamustine, and rituximab work in treating patients with B-cell non-Hodgkin lymphoma that has returned after a period of improvement or has not responded to previous treatment. Monoclonal antibody-drug conjugates, such as brentuximab vedotin, use antibody to target chemotherapy in cancer cells. Drugs used in chemotherapy, such as bendamustine, work in different ways to kill cancer cells. Monoclonal antibodies, such as rituximab, kill the cancer cells directly, but also harness the immune system to kill the cancer cells. Adding brentuximab to rituximab may improve response rates in CD30 positive, CD20 positive Relapsed Refactory NHL.

Detailed Description
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PRIMARY OBJECTIVES: I. Complete response (CR) rate and overall response rate (ORR) for patients with relapsed aggressive high-risk non-Hodgkin lymphoma (NHL) treated with brentuximab vedotin, bendamustine and rituximab (S-BR). SECONDARY OBJECTIVES: I. To estimate 2-year progression-free survival (PFS). II. To evaluate rate of positron emission tomography (PET)-CR and correlation to 2 year PFS. III. To evaluate the toxicity of six cycles of S-BR. IV. To evaluate mobilization, stem cell collection, engraftment in patients that proceed to salvage autologous stem cell transplant (ASCT). SCIENTIFIC OBJECTIVES: I. To evaluate percentage of tumor cells that are positive or negative for cluster of differentiation (CD)30 by immunohistochemistry (IHC), the subcellular location of CD30 (membrane or cytoplasmic only with absence of membrane expression), intensity of scoring, and correlating with clinical outcomes. II. To evaluate gene expression profiling (GEP) by Nanostring Technology and comparing expression levels of target genes in CD30 membrane positive, CD30 cytoplasmic only positive or CD30 negative tumor cells. III. To evaluate correlation between mutations identified through next generation sequencing (NGS) including ribonucleic acid (RNA) sequencing of the tumor transcriptome, and correlating to GEP and CD30 IHC, and correlating to clinical outcomes. IV. To evaluate the levels of soluble CD30 at baseline and in response to treatment. SCHEDULE: Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1, bendamustine IV over 30-60 minutes on days 1-2, and rituximab IV on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years.

Official Title
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Phase II Study of Brentuximab Vedotin in Combination With Bendamustine and Rituximab, in Patients With CD30 Positive, Relapsed or Refractory B Cell Non-Hodgkin Lymphoma (NHL)

Conditions
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Diffuse Large B Cell Lymphoma, Mediastinal Large B-cell Lymphoma, Grey Zone Lymphoma, High Grade B Cell Lymphoma, Follicular Lymphoma, Marginal Zone Lymphoma, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Brentuximab
* Drug: Bendamustine
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CD30 detectable B lineage relapsed refractory NHL including the following histologies: Aggressive lymphomas: diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, grey zone lymphomas, high grade B cell lymphomas, and transformed indolent lymphomas Indolent lymphoma: follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma; indolent lymphoma patients eligible for this trial should have high tumor burden and high risk disease, as defined by: The Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria Intermediate or high risk by Follicular Lymphoma International Prognostic Index (FLIPI) score or elevated lactose dehydrogenase (LDH)/ beta-2 microglobulin (B2M) Subjects between 18 and 75 years old. Subjects older than 75 years old to be discussed with PI prior to subject consent; consensus between PI and treating physician is required. Karnofsky performance status (KPS) >= 70%, Eastern Cooperative Oncology Group (ECOG) =< 2 At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma Patients must have received at least one but no more than 4 prior lines of systemic therapy American Heart Association (AHA) class 1 without significant limitation of physical activity Ejection fraction (EF) of at least >= 40% by multigated acquisition (MUGA) or echocardiography (ECHO) Total bilirubin =< 1.5 mg/dl Alanine aminotransferase (ALT), aspartate aminotransferase (AST) less than 2.5 times the upper limit of normal without evidence of active infectious hepatitis Creatinine clearance >= 40 ml/min Platelets > 75,000 cells/ul Absolute neutrophil count (ANC) > 1,000 cells/ul Ability to provide informed consent Females of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (HCG) pregnancy test at screening; pregnancy testing is not required for: (a) women who have been post-menopausal for at least 2 years without menses; or (b) women who are surgically sterile (e.g. by means of hysterectomy, tubal ligation, etc.) Males and females of childbearing potential must be able and willing to use an effective contraceptive method during treatment and for three months after completing treatment Exclusion Criteria: Active infections (bacterial, fungal, or viral) Evidence of sanctuary site involvement by disease, e.g., central nervous system, ocular, testicular involvement Evidence of second malignancy, abnormal cytogenetics, or morphologic evidence of myelodysplastic syndromes (MDS) Recent chemotherapy within 3 weeks of screening Major surgery within 4 weeks of screening Diagnosed or treated for malignancy other than NHL for which patient will be treated, except: malignancy treated with curative intent and with no known active disease present for >= 3 years before subject registration; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma in situ without evidence of disease History of stroke or intracranial hemorrhage within 6 months prior to registration Requires anticoagulation with warfarin or equivalent vitamin K antagonists Requires treatment with strong cytochrome (CYP3A4/5) inhibitors Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification Known history of human immunodeficiency virus or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous antibiotics Women who are pregnant or breastfeeding Prior use of brentuximab vedotin Prior use of bendamustine for indolent lymphoma allowed if > 2 years, CR to bendamustine and well tolerated with no residual > grade 1 toxicity; no prior use of bendamustine for aggressive lymphoma allowed Prior allogeneic transplant Patients with Child-Pugh B or C hepatic impairment

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brentuximab, Bendamustine, Rituximab<br>Brentuximab Vedotin in Combination with Bendamustine and Rituximab | Drug: Brentuximab<br>* Brentuximab vedotin IV over 30 minutes on day 1.Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.<br>* Other names: Adcetris;Drug: Bendamustine<br>* Bendamustine IV over 30-60 minutes on days 1-2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.<br>* Other names: Treanda;Drug: Rituximab<br>* Rituximab IV on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR rate | The complete response rate will be estimated as the proportion of patients with response, with a 95% exact confidence interval. | Up to 2 years after completion of study treatment | 
| Percentage of patients obtaining a CR + PR using Cheson criteria | The overall response rate will be estimated as the proportion of patients with response, with a 95% exact confidence interval. | Up to 2 years after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median time to progression |  | At 2 years | 
| PFS | PFS will be estimated using the Kaplan-Meier estimate, with stratification by allogeneic stem cell transplantation status. | At 2 years | 
| Complete response rate assessed by PET/CT | The complete response rate by PET/CT will be estimated with the 95% exact confidence interval. | Up to 2 years after the completion of study treatment | 
| Frequency of adverse events (AEs) and serious AEs assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | The proportion of patients with treatment-emergent AEs will be tabulated, including by causality, seriousness, severity/grade, and whether the AE resulted in death or discontinuation of treatment. | Up to 2 years after completion of study treatment | 
| CD34+ peripheral blood stem cells assessed by flow cytometry | Only for subjects receiving transplant | Up to 2 years after completion of study treatment | 
| Median time to engraftment | Only for subjects receiving transplant | Up to 2 years after completion of study treatment | 
| Soluble CD30 levels in blood by biochemical assay | Brentuximab vedotin pharmacokinetics in combination therapy will be measured and correlated to single agent data. | 48-72 hours after brentuximab vedotin treatment |