Phase 1 Trial of ST-001 nanoFenretinide in Relapsed/Refractory T-cell Non-Hodgkin Lymphoma

2510 Background: Anti-CD19 CAR-T cell therapy is a breakthrough treatment (tx) for patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). Despite impressive outcomes, non-response and relapse with CD19 negative disease remain challenges. Through dual B-cell antigen targeting of CD20 and CD19, with a first-in-human bispecific lentiviral CAR-T cell (LV20.19CAR), we aim to improve response rates while limiting CD19 negative relapse. Methods: Pts were treated on a Phase 1 dose escalation + expansion trial (NCT03019055) to demonstrate safety of a 41BB/CD3z LV20.19CAR T cell for adults with R/R B-cell NHL. Safety was assessed by incidence of dose limiting toxicities (DLTs) within 28 days post-infusion. Starting dose was 2.5 x 10^5 cells/kg with a target dose of 2.5 x 10^6 cells/kg. All pts received fludarabine+cyclophosphamide for lymphodepletion. Results: 11 pts have completed tx to date. 9 pts in dose escalation and 2 pts in expansion phase. Median age was 54 years (46-67) and histology included DLBCL = 5 pts, MCL = 4 pts, and CLL = 2 pts. In dose escalation, 3 pts were treated at 2.5 x 10^5 cells/kg, 3 pts at 7.5 x 10^5 cells/kg, and 3 pts at 2.5 x 10^6 cells/kg with no DLTs. As a result, 2.5 x 10^6 cells/kg was selected for expansion. In terms of safety, 6 pts developed Grade 1-2 cytokine release syndrome (CRS) and 3 pts had Grade 1-2 neurotoxicity (NTX). No patient had grade 3-4 CRS or NTX and none required ICU level care. 4 pts required 1-2 doses of tocilizumab for CRS. The day 28 overall response rate (ORR) for all pts was 82% (6/11 = complete response (CR) and 3/11 = partial response). All CR pts remain in remission, the longest > 1 year. All progressing pts underwent repeat biopsy, and all retained either CD19 or CD20 positivity. Additional pts are being enrolled in the expansion phase and updated data will be presented. Conclusions: Phase 1 results from the LV20.19 CAR T clinical trial demonstrate that infusion of 2.5 x 10^6 cells/kg is safe for further investigation with no DLTs among treated pts. Down-regulation of target antigens was not identified as a mechanism of resistance in progressing pts. With limited toxicity and encouraging ORR, dual targeted LV20.19CAR T cells merits further investigation. Clinical trial information: NCT03019055.

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Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma

Blood ◽

10.1182/blood-2003-09-3284 ◽

2004 ◽

Vol 104 (1) ◽

pp. 227-236 ◽

Cited By ~ 82

Author(s):

Andres Forero ◽

Paul L. Weiden ◽

Julie M. Vose ◽

Susan J. Knox ◽

Albert F. LoBuglio ◽

...

Keyword(s):

Fusion Protein ◽

B Cell ◽

Hodgkin Lymphoma ◽

Phase 1 ◽

Whole Body ◽

Single Chain ◽

Phase 1 Trial ◽

Non Hodgkin Lymphoma ◽

Pretargeted Radioimmunotherapy ◽

Anti Cd20

Abstract Pretargeted radioimmunotherapy (PRIT) has the potential to increase the dose of radionuclide delivered to tumors while limiting radiation to normal tissues. The purpose of this phase 1 trial is to assess safety of this multistep approach using a novel tetrameric single-chain anti-CD20–streptavidin fusion protein (B9E9FP) as the targeting moiety in patients with B-cell non-Hodgkin lymphoma (NHL), and to characterize its pharmacokinetics and immunogenicity. All patients received B9E9FP (160 mg/m2 or 320 mg/m2); either 48 or 72 hours later, a synthetic clearing agent (sCA) was administered (45 mg/m2) to remove circulating unbound B9E9FP. 90Yttrium (90Y; 15 mCi/m2)/111In (5 mCi)–DOTA-biotin was injected 24 hours later. There were 15 patients enrolled in the study. B9E9FP had a mean plasma half-life (T½) of 25 ± 6 hours with a reduction in plasma level of more than 95% within 6 hours of sCA administration. 90Y/111In-DOTA-biotin infusion resulted in rapid tumor localization and urinary excretion. The ratio of average tumor to whole-body radiation dose was 49:1. No significant hematologic toxicities were noted in 12 patients. There were 2 patients who had hematologic toxicity related to progressive disease. There were 2 complete remissions (90 and 325 days) and one partial response (297 days). B9E9FP performs well as the targeting component of PRIT with encouraging dosimetry, safety, and efficacy. A dose escalation trial of 90Y-DOTA-biotin in this format is warranted.

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Biomarker characterization using mass cytometry in a phase 1 trial of urelumab (BMS-663513) in subjects with advanced solid tumors and relapsed/refractory B-cell non-Hodgkin lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.3017 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 3017-3017 ◽

Cited By ~ 5

Author(s):

Cariad Chester ◽

Serena Chang ◽

John F. Kurland ◽

Idit Sagiv-Barfi ◽

Debra Czerwinski ◽

...

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

Solid Tumors ◽

Phase 1 ◽

Advanced Solid Tumors ◽

Mass Cytometry ◽

Phase 1 Trial ◽

Non Hodgkin Lymphoma

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Molecular Profiling of Aggressive Non-Hodgkin Lymphoma - Results from a Phase 1/2 Preben Study

Blood ◽

10.1182/blood-2019-129113 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5314-5314

Author(s):

Suvi-Katri Leivonen ◽

Judit Jørgensen ◽

Thomas Stauffer Larsen ◽

Annika Pasanen ◽

Marja-Liisa Karjalainen-Lindsberg ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Advisory Committees ◽

Non Hodgkin Lymphoma ◽

Gene Expression Analyses

Background: Aggressive non-Hodgkin lymphoma (NHL) relapsing after standard first line chemotherapy represents an unmet clinical need. Currently, a phase 1/2 study with the combination of pixantrone, etoposide, bendamustine, and in CD20 positive tumors, rituximab, in patients with relapsed aggressive NHL of B- or T- cell phenotype (the PREBEN study) is ongoing. Here our aim was to molecularly characterize samples from the PREBEN trial and find clinical correlates for predicting treatment response. Methods: The profiling cohort consisted of 21 patients with pre-treatment RNA samples and clinical data. Nanostring PanCancer Pathways and PanCancer Immune profiling panels (altogether 1348 genes) were utilized for the gene expression analyses. The findings from gene expression analyses were correlated with clinical parameters. Results: Fourteen patients had diffuse large B-cell lymphoma (DLBCL), whereas seven had peripheral T-cell lymphoma (PTCL). In general, the expression of DNA replication genes distinguished DLBCL from PTCL. Additionally, gene expression analyses identified genes having differential expression based on the response to the treatment. Supervised hierarchical clustering of the ten most differentially expressed genes could separate the responding (n=4) and non-responding (n=10) DLBCL patients into two distinct subgroups (Fig. 1A). Similarly, the responding (n=3) and non-responding (n=4) PTCL patients could be separated into distinct subgroups by supervised clustering with the ten most differentially expressed genes (Fig. 1B). Conclusion: Molecular profiles of aggressive NHL are heterogeneous and may be utilized for predicting the treatment response. More detailed molecular analyses are currently ongoing. Disclosures Jørgensen: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. d'Amore:Servier: Research Funding. Leppa:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Research Funding; Bayer: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: combination of bendamustine and pixantrone for relapsed NHL

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