Results from ongoing studies show the potential of an investigational anti-CD19 chimeric antigen receptor T-cell therapy in patients with previously treated blood cancers, including patients with high-risk disease.

Lisocabtagene maraleucel, also known as liso-cel or JCAR017, is an investigational defined composition CD19-directed chimeric antigen receptor (CAR) T-cell product candidate using a 4-1BB costimulatory domain.

Celgene’s lead CAR T trial, TRANSCEND NHL-001, is studying liso-cel in adult patients with relapsed or refractory diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B and mantle cell lymphoma.

ASCOClinical trial
The data presented at the annual ASCO meeting comes from the TRANSCEND CLL 004 and TRANSCEND NHL 001 trials studying the investigational anti-CD19 CAR T-cell therapy with lisocabtagene maraleucel in patients with B-cell blood cancers were presented at the annual meeting of the American Society of Clinical Oncology – ASCO, held June 1 – 4, 2019 in Chicago, Illinois.

The latest results from the ongoing, open-label multicenter phase I/II TRANSCEND CLL 004 study (Abstract #7501) of liso-cel in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) were presented in an oral presentation today.[1]

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The data included safety and efficacy findings from 23 patients who received liso-cel infusion at one of two dose levels: 50 × 106 or 100 × 106 total CAR-positive T cells following lymphodepleting chemotherapy. All participating patients had been previously treated with ibrutinib, and more than half had received prior venetoclax. The median number of lines of prior therapy was five and 83% of patients had high-risk cytogenetic features.

In the study, 22 of 23 patients were evaluable for response. The best overall response rate was 82% (18/22), with 46% (10/22) of patients achieving complete remission with or without complete blood count recovery (CR/CRi). Of 20 patients evaluable for minimal residual disease (MRD), 75% (15/20) achieved undetectable MRD (uMRD) by blood measures (sensitivity, 10-4) and 65% (13/20) achieved uMRD by bone marrow measures (sensitivity, 10-4). Responses have been durable, with 83% of patients (5/6) who were in CR/CRi at six months post liso-cel infusion showing ongoing response.

“For patients who have failed the current standard of care treatments for CLL, such as ibrutinib and venetoclax, there is a need for additional treatment options,” said lead study investigator Tanya Siddiqi, MD, City of Hope National Medical Center.

“I am highly encouraged by this early data showing manageable toxicity and promising clinical activity in a heavily pretreated patient population with high-risk CLL. In this preliminary analysis, clinical responses are rapid, deep and durable when assessed by clinical and MRD criteria. We look forward to further investigation of liso-cel in CLL patients who have relapsed from or have become refractory to currently available treatment options,” Siddiqi said.

Adverse events
The most common treatment-emergent adverse events (TEAEs) of any grade were anemia (83%), cytokine release syndrome (CRS; 74%), thrombocytopenia (74%), neutropenia (57%), and leukopenia (48%).

There were two patients with dose-limiting toxicities among the 14 patients treated at 100 × 106 total CAR-positive T cells: grade 4 hypertension in one patient; and grade 3 encephalopathy, grade 3 muscle weakness and grade 4 tumor lysis syndrome in the other patient.

Across 23 patients evaluable for safety, TEAEs of note included grade 3 CRS (2/23), grade ≥ 3 neurological events (5/23), and grade ≥ 3 tumor lysis syndrome (4/23). No grade 5 CRS or neurological events occurred.

Subgroup analyses
In addition to these findings from TRANSCEND CLL 004, preliminary safety and efficacy data were presented from two subgroup analyses from the ongoing, open-label multicenter phase 1 TRANSCEND NHL 001 trial evaluating liso-cel in patients with R/R B-cell non-Hodgkin’s lymphoma at one of two dose levels: 50 × 106 or 100 × 106 total CAR-positive T cells following lymphodepleting chemotherapy. The data included results from a subgroup of patients with secondary central nervous system (CNS) lymphoma (n=9) (Poster Presentation/Abstract #7515) and from patients with R/R mantle cell lymphoma (MCL; n=17) (Abstract #7516). These were highlighted in a poster discussion session on Monday, June 3.[2][3]

Patients had secondary CNS lymphoma at the time of first treatment (n=7; 6 DLBCL, 1 MCL) or retreatment with liso-cel (n=2 DLBCL), and neurological events and CRS were observed in only one patient. Of the 6 DLBCL patients with CNS lymphoma at the time of first retreatment with liso-cel, 4 achieved complete responses, 2 of whom are in sustained remission at more than 8 and 17 months, respectively.

The data in patients with MCL included safety and preliminary efficacy findings for 17 treated patients. The most common grade ≥ 3 TEAEs were thrombocytopenia (41%), anemia (35%) and neutropenia (35%). Grade ≥ 3 CRS and neurological events occurred in 6% and 12% of patients, respectively. One fatal event of tumor lysis syndrome was observed. The best overall response rate across dose levels was 71% (12/17); the best complete response rate was 53% (9/17).

These results are consistent with those seen in all patients treated with liso-cel in the TRANSCEND NHL 001 study.

“We are pleased to share these new data, which continue to demonstrate the potential of liso-cel in a range of B-cell cancers, at this year’s ASCO,” said Alise Reicin, MD, President, Global Clinical Development at Celgene.

“These results support our continued commitment to broadly develop CAR T-cell therapies to address the clinical needs of patients living with blood cancers,” Reicin concluded.

Clinical trials
Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) – NCT03331198

Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-cell Non-Hodgkin Lymphoma (TRANSCEND-NHL-001) – NCT02631044

[1] Siddiqi T, Dorritie KA, Soumerai JD, Stephens DM, Dubovsky JA, Gillenwater HH, Gong L. et al. TRANSCEND CLL 004: Minimal residual disease (MRD) negative responses after lisocabtagene maraleucel (Liso-Cel; JCAR017), a CD19-directed CAR T cell product, in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). J Clin Oncol 37, 2019 (suppl; abstract 7501).
[2] Abramson JS, Palomba ML, Arnason JE, Lunning MA, Solomon SR, Farazi T, Garcia J, Xie B, et al. Lisocabtagene maraleucel (liso-cel) treatment of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) and secondary CNS lymphoma: Initial results from TRANSCEND NHL 001. J Clin Oncol 37, 2019 (suppl; abstract 7515).
[3] Wang M, Gordon LI, Palomba ML, Abramson JS, Andreadis C, Ghosh N, Lunning MA, Maloney DG, et al. Safety and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) receiving lisocabtagene maraleucel (Liso-cel) in TRANSCEND NHL 001. Poster Discussion Session (Board #270). J Clin Oncol 37, 2019 (suppl; abstract 7516)

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