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)
Overview
- Phase
- Phase 2
- Intervention
- Brentuximab
- Conditions
- Diffuse Large B Cell Lymphoma
- Sponsor
- University of Arizona
- Locations
- 1
- Primary Endpoint
- CR rate
- Status
- Withdrawn
- Last Updated
- 8 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Brentuximab, Bendamustine, Rituximab
Brentuximab Vedotin in Combination with Bendamustine and Rituximab
Intervention: Brentuximab
Brentuximab, Bendamustine, Rituximab
Brentuximab Vedotin in Combination with Bendamustine and Rituximab
Intervention: Bendamustine
Brentuximab, Bendamustine, Rituximab
Brentuximab Vedotin in Combination with Bendamustine and Rituximab
Intervention: Rituximab
Outcomes
Primary Outcomes
CR rate
Time Frame: Up to 2 years after completion of study treatment
The complete response rate will be estimated as the proportion of patients with response, with a 95% exact confidence interval.
Percentage of patients obtaining a CR + PR using Cheson criteria
Time Frame: Up to 2 years after completion of study treatment
The overall response rate will be estimated as the proportion of patients with response, with a 95% exact confidence interval.
Secondary Outcomes
- Median time to progression(At 2 years)
- PFS(At 2 years)
- Complete response rate assessed by PET/CT(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(Up to 2 years after completion of study treatment)
- CD34+ peripheral blood stem cells assessed by flow cytometry(Up to 2 years after completion of study treatment)
- Median time to engraftment(Up to 2 years after completion of study treatment)
- Soluble CD30 levels in blood by biochemical assay(48-72 hours after brentuximab vedotin treatment)