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Clinical Trials Offer New Approaches to CAR T-Cell Therapy and Oral, Time-Limited Treatment for Patients with CLL or Lymphoma


Could new combination allow time-limited treatment without infusion?

Investigators at Roswell Park Comprehensive Cancer Center hope a new clinical trial will pave the way for a new time-limited, oral-delivery treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not been treated previously.

In the past these patients received continual treatment with Bruton tyrosine kinase inhibitors (BTKi) until the disease progressed or side effects became problematic— a strategy that negatively affected quality of life and increased the financial burden of care.  More recent combination studies have shown that the oral targeted therapy venetoclax (brand name Venclexta) can be combined with BTKi to achieve significant undetectable minimal residual disease (MRD) in a majority of patients, offering a pill-only treatment with a definite end date.

As studied in the CLL14 trial, the current time-limited standard of care combines venetoclax with the anti-CD20 drug obinutuzumab (brand name Gazyva), which is delivered by infusion in combination with chemotherapy, requiring patients to travel to a treatment center. The MAJIC clinical trial, now open at Roswell Park, will evaluate a new strategy that could eliminate the need for infusion by replacing obinutuzumab with acalabrutinib (brand name Calquence), a BTKi taken orally that is already FDA-approved for the treatment of CLL and SLL.

Matthew Cortese, MD, MPH, Assistant Professor of Oncology with the Departments of Medicine and Cancer Genetics & Genomics at Roswell Park, serves as site PI for MAJIC, which will directly compare the safety and efficacy of the current standard of care with the novel all-oral treatment combination in a large international clinical trial. “We are excited to open the MAJIC trial here at Roswell Park, because it offers an exciting new and convenient treatment option for our patients,” says Dr. Cortese. “This study also will incorporate sensitive MRD testing, which is increasingly recognized as important in predicting remission length and time off treatment.”

The randomized, open-label, phase 3 study, "A Study of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (MAJIC)” (NCT05057494), is sponsored by AstraZeneca. It has a projected enrollment of 600 patients.


Strategy aims to overcome previous challenges of CAR T-cell therapy

Dr. Cortese also serves as site principal investigator of a phase 1 clinical trial that takes a new approach to CAR T-cell therapy for patients with relapsed or refractory hematological malignancies, including chronic lymphocytic leukemia (CLL) and several subtypes of non-Hodgkin B-cell lymphomas that currently do not have approved cellular therapy options.  Roswell Park is one of a handful of sites for the Synthekine-sponsored study, “Autologous CD19 CAR T-Cell Therapy (SYNCAR-001) + Orthogonal IL-2 (STK-009) in Subjects with CD19+ Hematologic Malignancies” (NCT05666062). It aims to enroll 36 patients with CLL, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphomas.

“Synthekine is a new CAR T-cell platform that uses a well-proven target — CD19 on B-cells, used by FDA-approved CAR T-cell products for lymphomas — for relapsed B-cell lymphomas and CLL but allows us to push along those cancer-fighting cells in the hope of preventing significant toxicities while allowing for a persistent attack on cancer cells,” says Dr. Cortese.

“It uses an orthogonal interleukin-2 and correspondingly engineered receptor on the CAR T cells to give them a targeted boost that otherwise should not affect patients directly. This may allow the CAR T cells to work in patients with more advanced lymphoma or CLL, who we know generally don’t respond as well with currently approved CAR T-cell products, usually due to T-cell exhaustion. We hope this strategy will improve the effectiveness of these so-called ‘living drugs.’”

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