scholarly journals Safety and Anti-Tumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2807-2807
Author(s):  
Craig H. Moskowitz ◽  
Mariana Bastos-Oreiro ◽  
David Ungar ◽  
Ilva Dautaj ◽  
Matko Kalac
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Stock Options ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Fixed Dose ◽  
Mantle Cell ◽  
Anti Tumor Activity ◽  
Large B Cell

Introduction: Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 antibody (Ab) conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 1, first-in-human ADCT-402-101 clinical study, Lonca demonstrated single-agent anti-tumor activity with manageable toxicity in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). Durvalumab is a human monoclonal Ab of the immunoglobulin G-1 kappa subclass that blocks the interaction of programmed death-ligand 1 (PD-L1) with PD-1 on T-cells and with CD80 (B7.1) on other immune cells. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. Preclinical data, as well as early results from clinical trials combining ADCs and checkpoint inhibitors, show potentially increased effectiveness of these therapeutics when used in combination and provide the rationale for the current trial. Study Design and Methods: This is a Phase 1b, open-label, dose escalation (Part 1) and expansion (Part 2) trial of Lonca combined with durvalumab in patients with R/R DLBCL, MCL, or FL (NCT03685344). The key inclusion and exclusion criteria for the ADCT-402-104 study are reported in Table 1, and the dosing schema is presented in Figure 1. This trial will evaluate the safety and tolerability, preliminary anti-tumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of Lonca combined with durvalumab. Patients will receive Lonca once every 3 weeks for 2 doses in total, and durvalumab every 4 weeks for up to 1 year. Patients with only partial response or stable disease at the second disease evaluation may receive 2 additional doses of Lonca given once every 3 weeks. During Part 1, the dose of Lonca will be escalated using a classic 3+3 design with a fixed dose of durvalumab. Part 2 will consist of up to 3 expansion cohorts, one for each of the DLBCL, MCL, and FL populations. All patients in Part 2 will receive the dose of Lonca determined in Part 1, with a fixed dose of durvalumab. The trial opened in February 2019 and recruitment is ongoing. Study sponsored by ADC Therapeutics SA with the support of MedImmune Limited, a wholly-owned subsidiary of AstraZeneca Pharmaceuticals PLC, which supplies durvalumab (http://clinicaltrials.gov/show/NCT03685344). Disclosures Moskowitz: ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ungar:ADC Therapeutics: Employment, Other: Stock options. equity interest. Dautaj:ADC Therapeutics: Employment, Other: Stock options.

scholarly journals Protein Profiling of B-Cell Lymphomas Using Tissue Biopsies: A Potential Tool for Small Samples in Pathology

2008 ◽  
Vol 30 (1) ◽  
pp. 27-38
Author(s):  
Corine Jansen ◽  
Konnie M. Hebeda ◽  
Marianne Linkels ◽  
Johanna M. M. Grefte ◽  
John M. M. Raemaekers ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Protein Profiling ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Large B Cell

Non-Hodgkin’s lymphoma comprises many related but distinct diseases and diagnosis and classification is complex. Protein profiling of lymphoma biopsies may be of potential value for use in this lymphoma classification and the discovery of novel markers. In this study, we have optimized a method for SELDI-TOF MS based protein profiling of frozen tissue sections, without dissection of tumour cells. First we have compared chip surfaces and lysis buffers. Also, we have determined the minimal input using laser dissection microscopy. Subsequently, we have analyzed and compared protein profiles of diffuse large B-cell lymphoma (n=8), follicular lymphoma (n=8) and mantle cell lymphoma (n=8). Benign, reactive lymph nodes (n=14) were used as a reference group.CM10 chip surface in combination with urea lysis buffer and an input of approximately 50,000 lymphocytes allowed the detection of many differential peaks. Identification of the diffuse large B-cell lymphoma cases was reliably made in the supervised classification. Unsupervised clustering showed segregation into a benign/indolent cluster predominantly formed by benign, reactive lymph nodes and follicular lymphoma cases and into a more aggressive cluster formed by diffuse large B-cell lymphoma and mantle cell lymphoma cases. In conclusion, our protocol enables protein profiling of protein lysates derived from small histological samples and the subsequent detection of many differentially expressed proteins, without the need of tumour cell dissection. These results support further evaluation of protein profiling of small lymphoma biopsies as an additional tool in pathology.

scholarly journals An Open-Label Phase II Study of Buparlisib (BKM120) in Patients with Relapsed and Refractory Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma or Follicular Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1718-1718 ◽  
Author(s):  
Anas Younes ◽  
Gilles Salles ◽  
R. Gregory Bociek ◽  
Giovanni Martinelli ◽  
Dolores Caballero ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: Non-Hodgkin's lymphoma (NHL), which includes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL), is associated with a high unmet need in the relapsed and refractory setting. The PI3K/AKT/mTOR pathway has been shown to play a key role in the pathogenesis of NHL. Overexpression of PIK3CD (encoding the PI3Kd isoform) is common in B-cell malignancies and is therefore widely viewed as a therapeutic target in NHL. PIK3CA and PIK3CB are also expressed in B-cell malignancies, with PIK3CA overexpression seen particularly at relapse, thereby justifying exploration of pan-PI3K inhibitors in the relapsed or refractory setting. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor which has demonstrated activity in patients with solid tumors as well as in in vitro and in vivo models of hematologic malignancies. Methods: The primary objective of this Phase II study (NCT01693614) was to evaluate the efficacy of buparlisib in three parallel cohorts of adult patients with relapsed or refractory DLBCL, FL, or MCL. Secondary objectives were to evaluate safety and tolerability, progression-free survival, duration of response, and overall survival. Inclusion criteria were: patients with relapsed or refractory disease who have received at least one prior line of therapy; at least one measurable nodal lesion (≥2 cm); ECOG performance status ≤2; and adequate bone marrow and organ function. Patients with DLBCL must have received, or be ineligible for, autologous or allogeneic stem cell transplant. All patients received single-agent buparlisib 100 mg orally QD continuously until progression, intolerance, or patient withdrawal. Tumor response was evaluated by investigators per standard criteria (Cheson, 2007). Results: At data cut-off (June 19, 2014), 64 patients had been enrolled; 26 DLBCL, 24 FL, and 14 MCL. Here, results are presented for the DLBCL cohort only. Updated results from the DLBCL cohort including biomarker analyses and results for the FL cohort will be presented at the meeting. The MCL cohort is currently enrolling. For the DLBCL cohort, median age (range) was 63.5 (28–81) years and 69% were male. The median (range) number of prior therapy regimens was 3 (1–12). Specific prior therapies included: rituximab (n=25, 96%) and bendamustine/carmustine (n=8, 31%); all patients had received prior anthracycline and an alkylating agent (e.g. cyclophosphamide), and 6 (23%) patients had undergone prior stem cell transplantation. The most common (≥15%) AEs (all grades) regardless of causality were hyperglycemia and nausea (39% each), depression (31%), anxiety and fatigue (23% each), vomiting and diarrhea (19% each), and abdominal pain (15%). Alanine transaminase or aspartate transaminase elevations were rare (4% each, with no Grade 3/4 AEs). The most common (>5%) Grade 3/4 AEs regardless of causality were hyperglycemia (23%), and nausea, depression, anxiety, urinary tract infection, and neutropenia (8% each). Six (23%) patients discontinued therapy due to AEs (potentially treatment-related). Seven on-treatment deaths were reported: 6 were disease-related and 1 was suspected to be treatment-related (unexplained death following a gastrointestinal [GI] bleed in a patient with massive GI lymphoma involvement). Overall response rate was 12% (95% CI = 2.4, 30.2) with 3 responses: 1 complete response (4%) and 2 partial responses (8%). Five patients had stable disease (19%). Eight patients (31%) experienced some decrease in tumor burden (Figure 1). At data cut-off, 2 patients demonstrated durable responses, as they were still on study treatment after 9.2 and 7.4 months, respectively. Figure 1 Figure 1. Conclusions: Early results from this Phase II study of the pan-PI3K inhibitor, buparlisib, demonstrate encouraging clinical activity, and a favorable safety profile in heavily pretreated patients with relapsed or refractory DLBCL. These data suggest that targeting all 4 PI3K isoforms in DLBCL is a viable strategy and worthy of further exploration in patients with NHL. Future combination studies with buparlisib will take a mechanism-based approach. Disclosures Younes: Novartis, Curis, J&J: Research Funding; Bayer, BMS, Celgene, Incyte, Janssen R&D: Honoraria; Sanofi, Seattle Genetics, Takeda Millenium: Honoraria. Mukherjee:Novartis Healthcare Pvt. Ltd. India: Employment. Williams:Novartis: Employment. Herbst:Novartis: Employment. Tavorath:Novartis: Employment. Kim:Novartis, Celgene, Takeda: Research Funding.

Phase 2 Study of Daratumumab in Relapsed/Refractory Mantle-Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma

2019 ◽  
Vol 19 (5) ◽  
pp. 275-284 ◽  
Author(s):  
Gilles Salles ◽  
Ajay K. Gopal ◽  
Monique C. Minnema ◽  
Karen Wakamiya ◽  
Huaibao Feng ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Large B Cell Lymphoma ◽  
Phase 2 Study ◽  
Mantle Cell ◽  
Large B Cell

Safety and Efficacy of Bendamustine with or without Rituximab for the Treatment of Heavily Pretreated CLL and Lymphoma Patients. A Multicenter Retrospective Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1662-1662 ◽  
Author(s):  
Luigi Rigacci ◽  
Benedetta Puccini ◽  
Enrico Orciuolo ◽  
Alfonso D'Arco ◽  
Sergio Storti ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Large B Cell

Abstract Abstract 1662 Poster Board I-688 Introduction Bendamustine is an alkylating agent with a nitrogen mustard group and a purine like benzimidazol group. Recently this drug was introduced in Italy. We analized all pts treated in sixteen haematological Italian centers with Bendamustine alone or in combination with anti-CD20 antibody. Patients and methods On an intention to treat basis pts who have received at least one complete cycle were evaluable for response and toxicity. The treatments consisted of: Bendamustine 60-90 mg/m2 days 1,2 alone or in combination with Rituximab 375 mg/m2 day 0, every 21 or 28 days. 173 pts were analized, median age was 67 (range 31-87), 114 were male, 63 chronic lymphatic leukaemia 41 indolent non-follicular lymphoma, 26 diffuse large B cell lymphoma, 26 follicular lymphoma, 15 mantle cell lymphoma, 2 Peripheral T cell lymphoma. Pts were heavily pretreated, the median number of previous treatments was 3,5 (range 1-8), 121 pts have experienced more than three chemotherapy schemes. One hundred and twenty-seven pts were previously treated with Rituximab and 24 performed an autologous peripheral blood stem cell transplantation. The Bendamustine pre-treatment condition was: 70 relapsed pts, 40 with refractory disease and 63 with a progressive disease after partial response. The median number of Bendamustine cycles was 4.3 (range 1-11). Results All patients were evaluable for response: 48 pts (28%) obtained a complete remission, 78 (45%) a partial response or stable disease with an overall response rate of 73% and 47 were non responders. According to histotype we observed that 10/15 pts (67%) with mantle cell lymphoma obtained a response (6 CR;4 PR), 37/41 (9 CR; 28 PR) indolent non follicular lymphoma and 25/26 (96%) follicular lymphoma obtained a response (12 CR;13 PR), 46/63 CLL obtained a response and 8/26 (31%) DLBCL obtained a response to therapy (4 CR;4 PR), none of the two T lymphoma pts responded to therapy. With a median period of observation of 12 months (1-46) 121 (70%) pts are alive and 83 pts are in complete remission or with stable disease without any other treatment. The overall survival was 82%, 72%, 68% and 27% respectively for indolent, CLL, mantle cell and diffuse large B cell lymphoma. The progression free survival was 31%, 27%, 15% and 10% respectively for indolent, CLL, mantle cell and diffuse large B cell lymphoma. Fifthy-two pts died, 47 for progressive disease, 11 due to infection and sepsis (6%) and 2 due to other causes not related with therapy or disease. In this group of heavily pretreated pts 760 cycles were performed. The extrahematological toxicity was mild the most important problem were infections (Herpes Zooster, pneumonia, enteritis) reported in 16 pts, hepatic in 4 and cardiologic in 2 pts. The hematological toxicity was trombocytopenia grade 3-4 in 20 pts (12%), neutropenia grade 3-4 in 40 pts (23%) and anemia grade 3-4 in 19 pts (11%). Discussion In conclusion this retrospective study shows that treatment with Bendamustine alone or in combination with Rituximab is a safe and efficacy regimen in a subset of pluriresistent patients. This data shows also that the best results could be obtained in indolent lymphoma and CLL incouraging data in mantle cell lymphoma are reported. Disclosures No relevant conflicts of interest to declare.

Phase I/II clinical trial of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 7520-7520 ◽  
Author(s):  
Connie Lee Batlevi ◽  
Stephanie De Frank ◽  
Caitlin Stewart ◽  
Paul A. Hamlin ◽  
Matthew J. Matasar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Large B Cell

scholarly journals PAK4 and NAMPT as Novel Therapeutic Targets in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 160
Author(s):  
Husain Yar Khan ◽  
Md. Hafiz Uddin ◽  
Suresh Kumar Balasubramanian ◽  
Noor Sulaiman ◽  
Marium Iqbal ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Hodgkin's Lymphomas ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL), grade 3b follicular lymphoma (FL), and mantle cell lymphoma (MCL) are aggressive non-Hodgkin’s lymphomas (NHL). Cure rates are suboptimal and novel treatment strategies are needed to improve outcomes. Here, we show that p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) is critical for lymphoma subsistence. Dual targeting of PAK4-NAMPT by the Phase I small molecule KPT-9274 suppressed cell proliferation in DLBCL, FL, and MCL. Growth inhibition was concurrent with apoptosis induction alongside activation of pro-apoptotic proteins and reduced pro-survival markers. We observed NAD suppression, ATP reduction, and consequent cellular metabolic collapse in lymphoma cells due to KPT-9274 treatment. KPT-9274 in combination with standard-of-care chemotherapeutics led to superior inhibition of cell proliferation. In vivo, KPT-9274 could markedly suppress the growth of WSU-DLCL2 (DLBCL), Z-138, and JeKo-1 (MCL) sub-cutaneous xenografts, and a remarkable increase in host life span was shown, with a 50% cure of a systemic WSU-FSCCL (FL) model. Residual tumor analysis confirmed a reduction in total and phosphorylated PAK4 and activation of the pro-apoptotic cascade. This study, using various preclinical experimental models, demonstrates the therapeutic potential of targeting PAK4-NAMPT in DLBCL, FL, and MCL. The orally bioavailable, safe, and efficacious PAK4-NAMPT dual inhibitor KPT-9274 warrants further clinical investigation.

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