EA4231: A Phase II Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (ViPOR) in Relapsed or Refractory CD10-Negative Diffuse-Large B-Cell Lymphoma (DLBCL) and High-Grade B-Cell Lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2)

The study chair for this trial is Christopher Melani, MD (National Cancer Institute). The study co-chairs are Wyndham H. Wilson, MD, PhD (National Cancer Institute) and Craig Portell, MD (University of Virginia/UVA Comprehensive Cancer Center).

Approximately 80,000 new cases of non-Hodgkin lymphoma occur in the United States per year, of which about 85% are B-cell lymphomas. B-cell lymphomas are cancers that start in early forms of B lymphocytes (B cells), a type of white blood cell that produces antibodies and is an important part of the immune system.  The current standard of care for this type of cancer depends on the specific subtype and stage, but usually involves a combination of chemotherapy, radiation, and/or immunotherapy, including one or more of the targeted therapies being used in this study.

Standard initial treatments can lead to long-lasting remission in about 60% of patients with B-cell lymphoma. Unfortunately, about 40% of patients will either have their cancer relapse after a period of remission or stop responding to treatment and become refractory. Relapsed or refractory cancers are difficult to treat, and outcomes for these patients are generally poor. These patients need new, more effective treatments that can improve their survival.

In recent years, researchers have developed targeted therapies that can disrupt key survival pathways in cancer cells, such as venetoclax and ibrutinib. However, targeted drugs rarely produce lasting responses because the tumors may become resistant by developing alternative survival pathways. Combining targeted drugs that block multiple pathways has the potential to overcome mechanisms of resistance and eradicate the tumor cells.

An early phase study at the National Cancer Institute tested a five-drug non-chemotherapy combination containing venetoclax, ibrutinib, the steroid prednisone, obinutuzumab (also a targeted therapy), and Revlimid (lenalidomide), an immunotherapy drug. The trial showed that this regimen, known as ViPOR, was safe and potentially effective, especially for patients with the following lymphoma subtypes: CD10-negative diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 rearrangements (Melani C. Blood. November 2020).

The EA4231 study is a single-arm phase 2 trial that aims to confirm these early findings. Researchers plan to enroll 120 participants who will all receive ViPOR for up to 6 cycles of treatment. To better understand the treatment's impact across the subtypes mentioned above, they plan to enroll 80 patients with CD10-negative DLBCL and 40 patients with HGBCL. 

The study’s primary objective is to measure the complete response rate after receiving ViPOR. After treatment is completed, all patients will be monitored for up to 10 years.

To be eligible for the study, patients must have a diagnosis of either CD10-negative DLBCL or CD10-positive or negative HGBCL with MYC and BCL2 rearrangements. They must have relapsed and/or refractory disease after at least one prior anthracycline and anti-CD20 antibody-containing treatment regimen. Patients with confirmed or suspected primary mediastinal large B-cell lymphoma are not eligible.

Learn more about EA4231 at ecog-acrin.org.