scholarly journals Results of a First in Human, Dose Ascending, Phase I Study Examining the Safety and Tolerability of KA2237, an Oral PI3K p110β/δ Inhibitor in Patients with Relapsed/Refractory (R/R) B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4099-4099 ◽  
Author(s):  
Loretta J. Nastoupil ◽  
Sattva S Neelapu ◽  
Eric Davis ◽  
Felipe Samaniego ◽  
Nathan H Fowler ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Advisory Committees ◽  
Once Daily ◽  
Anti Tumor Activity

Introduction: Despite therapeutic advances, there remains a considerable need for novel therapies for B-cell lymphomas. Although a high proportion of patients (pts) show response to initial therapy, many fail to achieve durable remissions and experience recurrent disease. Agents that target molecular pathways associated with the development and progression of lymphoma are likely to be highly effective and are desirable. The p110δ isoform of the PI3K enzyme is mainly expressed in lymphocytes and has been an attractive therapeutic target, with several PI3Kδ inhibitors demonstrating meaningful efficacy in B-cell lymphomas. Targeting the p110β isoform may further overcome tumor growth and escape mechanisms by mitigating the upregulation of the PI3K/AKT pathway, particularly in PTEN-deficient lymphomas. KA2237 is an oral, potent and selective inhibitor of the PI3K β and δ isoforms. The aim of this first in human, phase I, open-label, single arm study (NCT02679196) was to investigate the safety, tolerability, pharmacokinetic properties and pharmacodynamic effects of KA2237, in order to determine the maximum tolerated dose based on dose limiting toxicity and assess preliminary anti-tumor activity in pts with R/R B-cell lymphoma. Methods: Pts ≥ 18 years (yrs) of age, ECOG ≤ 2, with B-cell lymphoma R/R or intolerant of established therapies (including rituximab) were enrolled using a 3+3 dose escalation (50-400mg) design. KA2237 was given orally on a once daily continuous schedule until progression or unacceptable toxicity. Anti-tumor activity was evaluated by computed tomography and, when available, integrating 18F-FDG positron emission tomography response assessment, at 8, 16 and 24 weeks. Response was assessed according to Lugano 2014 criteria. Pts received PJP prophylaxis. Results: 21 pts with B-cell lymphoma were enrolled (8 DLBCL [diffuse large B-cell], 5 FL [follicular], 3 MCL [mantle cell], 3 CLL/SLL [chronic lymphocytic leukemia/small lymphocytic lymphoma], 1 MZL [marginal zone], 1 WM [Waldenstrom]). Pts received KA2237 at 4 dose levels: 50mg (n=6), 100mg (n=3), 200mg (n=7) and 400mg (n=5) daily; 21 pts were evaluable for safety assessment. Pharmacokinetic profiles were favorable with mean plasma half-life of 17-33 hours, compatible with once daily oral dosing. Median age was 69 yrs (range 48-84) with 76% males; median number of prior therapies was 3 (range 1-6). Median follow up duration was 8.5 months (range 6.9-24.6). Median duration of drug exposure was 82 days (range 10-714 days). 86% of pts experienced treatment-related adverse events (TRAE). 43% of pts experienced a grade ≥ 3 TRAE, with rash (n=3), transaminitis (n=2) and pneumonitis (n=2) occurring in more than 1 pt. 29% discontinued treatment due to a TRAE with pneumonitis (n=2) occurring in more than 1 pt. One grade 5 TEAE (multifocal pneumonia) was observed. 19/21 pts were evaluable for response, ORR was 37% (4 CR, 3 PR). Responses were observed across lymphoma subtypes including DLBCL, FL, CLL and MCL. Responses were often durable (see Figure) and in 2 pts with DLBCL who achieved CR permitted consolidation by autologous stem cell transplantation. Conclusions: KA2237 is an oral, once a day, selective dual inhibitor of PI3K β/δ with a manageable toxicity profile and promising single-agent clinical activity in heavily pretreated R/R B-cell lymphoma. The recommended phase II dose is 200mg daily. The findings of this study support the further evaluation of KA2237. Figure. Disclosures Nastoupil: Novartis: Honoraria; Spectrum: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding. Neelapu:Acerta: Research Funding; Merck: Consultancy, Research Funding; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Karus: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Precision Biosciences: Consultancy; BMS: Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Cell Medica: Consultancy. Fowler:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Janssen: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Unum: Research Funding; Kite: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board. Wang:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta Pharma: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; BioInvent: Consultancy, Research Funding; Aviara: Research Funding; BeiGene: Research Funding; Loxo Oncology: Research Funding; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Juno Therapeutics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Dava Oncology: Honoraria; Kite Pharma: Consultancy, Research Funding. Beer:Karus therapeutics Ltd.: Employment. Cecil:Karus Therapeutics: Employment. Dow:Karus Therapeutics: Employment. McHale:Karus Therapeutics: Employment. Silva:Karus Therapeutics: Employment. Ward:Karus Therapeutics: Employment. Yavari:Karus Therapeutics: Employment. Shuttleworth:Karus Therapeutics: Employment.

scholarly journals Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4082-4082
Author(s):  
Beth A. Christian ◽  
Ying Huang ◽  
Sabarish Ayyappan ◽  
Robert A Baiocchi ◽  
Jonathan E Brammer ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Advisory Committees ◽  
Oral Agents ◽  
Grade 3 ◽  
Aggressive B Cell Lymphoma

Introduction: Venetoclax, a BCL2 inhibitor, has demonstrated efficacy both as a single agent and in combination with rituximabin several subtypes of B-cell non-Hodgkin lymphoma (NHL). The combination of obinutuzumab and lenalidomide has demonstrated safety and preliminary efficacy in follicular lymphoma (Fowler et al., JCO 2015; 35: 7531). We conducted a phase I study of obinutuzumab, venetoclax, and lenalidomide to determine the safety, maximum tolerated dose, and preliminary efficacy of the combination. Methods: Patients with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell (HGBCL), marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous (ASCT) but not allogeneic stem cell transplant were permitted. Prior lenalidomide or BCL2 family inhibitors, CNS involvement, and active hepatitis or HIV infection were not permitted. ANC > 1000/mm3, platelets > 75,000/mm3, creatinine clearance ≥50 ml/min, ALT/AST ≤ 3 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required. Treatment consisted of obinutuzumab 1000 mg on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6 with escalating doses of lenalidomide days 1-21 and venetoclax days 1-28 of a 28 day cycle (Table 1). A 3+3 dose escalation schema was followed. The DLT period was 1 cycle and patients had to receive 80% of the doses of the oral agents and all doses of obinutuzumab to be considered evaluable for DLT. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection; grade 3 infection that fails to resolve within 7 days; and grade 3 or 4 non-hematologic toxicity. Patients without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed by CT or PET/CT every 3 months for 12 months and then every 6 months until disease progression. Results: 22 patients were treated. Median age was 61 years (range 31-78 years) with 16 males. Median prior therapies was 2 (range 1-10) and included 5 patients who had relapsed after chimeric antigen receptor T-cell therapy and 2 patients relapsed after ASCT. Median baseline lactate dehydrogenase was 259.5 U/L (range 147-5133, ULN 190 U/L). 16 patients had aggressive B-cell lymphoma including DLBCL, HGBCL, primary mediastinal and transformed FL, 5 patients had FL and 1 patient had marginal zone lymphoma. At dose level (DL) 1, one patient experienced a DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. No further DLTs occurred at DL 2-4. DL 4 was expanded and was determined to be the MTD. Four patients, 1 in each dose level, were not evaluable for DLT and were replaced including 3 who did not receiving 80% of the oral agents due to required dose reductions and 1 patient for disease progression. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n=20, 90.9%), thrombocytopenia (n=5, 22.7%), and anemia (n=3, 13.6%). Grade 3-4 infections (n=6, 27%) included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. Other grade 3-4 AEs occurring once each included dysgeusia, dyspnea, nausea, vomiting, and hyperhidrosis. No clinically significant tumor lysis has occurred. Patients have received a median of 3 cycles (range 1-12) of treatment. Three patients remain on therapy and 5 patients are on follow up. Dose reductions of lenalidomide occurred for 17 patients (77%) and of venetoclax for 11 patients (50%). Nine patients have achieved a response (41%), including 8 complete (CR) and 1 partial responses (PR). Responses have occurred at each DL and include 4 patients with FL (2 CR, 2 PR), 4 patients with aggressive lymphoma (4 CR) and 1 patient with MZL (CR). 14 patients are off of the study, 9 with progression, 2 for alternative therapy, and 1 each for DLT, physician preference, and a diagnosis of MDS in a patient with 3 prior lines of chemotherapy. Conclusions: Combined treatment with obinutuzumab, venetoclax, and lenalidomide administered up to 12 cycles is feasible with activity in multiple subtypes of relapsed NHL. Enrollment in expansion cohorts of FL and aggressive B-cell lymphoma is ongoing. Disclosures Christian: Celgene: Research Funding; Janssen: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Research Funding; Bristol-Myers Squibb: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Triphase: Research Funding; Immunomedics: Research Funding; Acerta: Research Funding. Baiocchi:Prelude: Consultancy. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. William:Guidepoint Global: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy; Techspert: Consultancy. Awan:Gilead: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Sunesis: Consultancy; Janssen: Consultancy; Genentech: Consultancy. Maddocks:BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Obinutuzumab - off label use in relapsed aggressive B-cell lymphoma and indolent B-cell lymphoma Venetoclax - off label use in relapsed B-cell lymphoma

scholarly journals Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination with Idelalisib in Patients with B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5345-5345
Author(s):  
Franck Morschhauser ◽  
John Radford ◽  
Loic Ysebaert ◽  
Stephen E Spurgeon ◽  
Ebenezer A Kio ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Advisory Board ◽  
Duration Of Treatment ◽  
Advisory Committees ◽  
Phase 1B

Abstract Introduction: Tirabrutinib (TIRA; GS/ONO-4059) is a selective Bruton's tyrosine kinase (BTK) inhibitor. Idelalisib (IDELA), a first-in-class phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor, is approved for the treatment of CLL and follicular lymphoma (FL). Both have single agent activity in lymphoma and updated results from the combination of TIRA+IDELA from this ongoing phase 1b study (NCT02457598) are reported here. Methods: Patients with previously treated non-germinal-center B-cell type (non-GCB) diffuse large B-cell lymphoma (DLBCL) or two prior lines of therapy for FL, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Waldenstrom's macroglobulinemia (WM) and no prior exposure to targeted inhibitors were eligible for enrollment. Patients were enrolled using a 3+3 dose escalation design with a fixed dose of IDELA at either 50 mg BID or 100mg QD and TIRA ranging from 20mg to 160mg QD. Cohorts were subsequently enrolled at multiple dose levels to evaluate disease-specific safety and efficacy. Results: As of March 5, 2018, 40 patients were enrolled on the combination. The median age was 65 (32-89) years and the disease subtypes were non-GCB DLBCL (n=17), FL (10), MZL (5), WM (5), SLL (2), and MCL (1). No maximum tolerated dose and no dose-response relationship was observed with daily dosing of both agents at the dose levels evaluated. For patients with non-GCB DLBCL (n=17), the median number of prior therapies is 3 (range 1-4). The median duration of treatment is 8 weeks (range 0.9, 44.1) with 2 patients still on treatment. 4/15 (27%) evaluable patients achieved a response; best overall response is shown in table 1. For the patients with indolent NHL (n=23), the median number of prior therapies is 3 (range 2-6). The median duration of treatment is 28 weeks (range 2.1, 120.0), with 5 patients still on treatment. 10/20 (50%) of the evaluable patients achieved a response with best overall response by indication shown in table 1. The most common treatment-emergent adverse events (AEs) are listed in table 2. Of the 40 patients who received treatment on study, AEs led to treatment interruption or discontinuation of both study drugs in 22 and 3 patients, respectively. There have been 7 deaths on study, 6 due to disease progression and 1 from an unknown cause. Conclusion: Once-daily dosing of GS-4059 up to 160 mg in combination with idelalisib 50 mg BID or 100 mg QD was generally safe and well tolerated. Early results show activity across all indications studied. Disclosures Morschhauser: Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Radford:GlaxoSmithKline: Equity Ownership; BMS: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership; Celgene: Research Funding; ADC Therapeutics: Consultancy, Research Funding. Ysebaert:Gilead Sciences, Inc.: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Spurgeon:Bristol Myers Squibb: Research Funding; MEI Pharma: Consultancy; Oncternal: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding. Salles:Merck: Honoraria; BMS: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Servier: Honoraria; Janssen: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Abbvie: Honoraria; Acerta: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Amgen: Honoraria; Epizyme: Honoraria; Novartis: Consultancy, Honoraria. Huang:Gilead Sciences, Inc.: Employment. Mitra:Gilead Sciences, Inc.: Employment. Rule:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees. Dyer:Gilead Sciences, Inc.: Honoraria, Research Funding.

scholarly journals Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination with Entospletinib in Patients with B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5344-5344
Author(s):  
Gilles Salles ◽  
Martin J.S. Dyer ◽  
Daniel James Hodson ◽  
Krimo Bouabdallah ◽  
Loic Ysebaert ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Advisory Board ◽  
Duration Of Treatment ◽  
Advisory Committees ◽  
Phase 1B

Abstract Introduction: Tirabrutinib (TIRA; GS/ONO-4059) is a selective Bruton's tyrosine kinase (BTK) inhibitor. Entospletinib is a selective inhibitor of spleen tyrosine kinase (SYK). Both have single agent activity in lymphoma and updated results from the combination of TIRA+ENTO from this ongoing phase 1b study (NCT02457598) are reported here. Methods: Patients with previously treated non-germinal-center B-cell type (non-GCB) diffuse large B-cell lymphoma (DLBCL) or two prior lines of therapy for follicular lymphoma (FL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Waldenstrom's macroglobulinemia (WM) and no prior exposure to targeted inhibitors were eligible for enrollment. Patients were enrolled using a 3+3 dose escalation design with either ENTO 200mg or 400mg QD and doses of TIRA ranging from 20mg to 160mg QD. Cohorts were subsequently enrolled at multiple dose levels to evaluate disease-specific safety and efficacy. Results: As of March 5, 2018, 72 patients have enrolled on the combination. The median age was 67.5 years (range: 30-90) and the disease subtypes for patients enrolled were non-GCB DLBCL (n=32), FL (18), MZL (5), WM (7), SLL (2), MCL (8). No maximum tolerated dose and no dose-response relationship was observed with daily dosing of both agents at the dose levels evaluated. For patients with non-GCB DLBCL (n=32), the median number of prior therapies is 3 (range 1-7). The median duration of treatment is 8 weeks (range 2-98.1) with 6 patients still on treatment. 6/27 (22%) of the evaluable patients achieved a response; best overall response is shown in table 1. For patients with indolent NHL (n=40), the median number of prior therapies is 3 (range 1-6). The median duration of treatment is 36 weeks (range 0.1-116), with 29 patients still on treatment. 19/31 (61%) of the evaluable patients achieved a response with best overall response by indication shown in table 1. The most common treatment-emergent adverse events (AEs) are listed in table 2. Of the 71 patients who have received treatment on study, AEs led to treatment interruption or discontinuation of both study drugs in 10 and 1 patients, respectively. There have been 4 deaths on study, all due to disease progression. Conclusion: Once-daily dosing of TIRA up to 160 mg in combination with ENTO up to 400 mg QD was safe and well tolerated. Early results show activity in combination across all indications treated. Disclosures Salles: Novartis: Consultancy, Honoraria; Epizyme: Honoraria; Abbvie: Honoraria; Servier: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Pfizer: Honoraria; Merck: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Servier: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Dyer:Gilead Sciences, Inc.: Honoraria, Research Funding. Hodson:Gilead Sciences, Inc.: Research Funding. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cartron:Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Honoraria. Davies:Acerta Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; ADC-Therapeutics: Research Funding; Janssen: Honoraria; Karyopharma: Membership on an entity's Board of Directors or advisory committees. Danilov:Aptose Biosciences: Research Funding; Gilead Sciences: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy; Astra Zeneca: Consultancy. Fegan:Roche: Honoraria; Abbvie: Honoraria; Gilead Sciences, Inc.: Honoraria; Napp: Honoraria; Janssen: Honoraria. Huang:Gilead Sciences, Inc.: Employment. Mitra:Gilead Sciences, Inc.: Employment. Rule:Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Morschhauser:Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase I Study of Nivolumab and Lenalidomide in Relapsed/ Refractory B Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4091-4091 ◽  
Author(s):  
David A. Bond ◽  
Vedat Yildiz ◽  
Lai Wei ◽  
Lapo Alinari ◽  
Basem M. William ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Board Of Directors ◽  
Immune Checkpoint ◽  
Research Funding ◽  
Phase I Study ◽  
Progressive Disease ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees

Introduction: Both lenalidomide and monoclonal antibodies targeting the immune checkpoint PD-1, including nivolumab, have single agent activity in subsets of patients with Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL). Lenalidomide mediates increased T cell IL-2 production and may enhance T and NK cell response to immune checkpoint blockade resulting in synergistic activity, but with potential for overlapping immune related toxicities. We conducted a phase I study to determine the safety, tolerability, and maximum tolerated dose (MTD) of nivolumab and lenalidomide in patients with relapsed/ refractory (R/R) HL and NHL. Methods: Patients (age ≥18 years) with R/R B-cell NHL who were transplant ineligible or patients with R/R HL with ≥ 2 prior lines of treatment were eligible (NCT03015896). Inclusion criteria included ECOG performance status ≤ 2, creatinine clearance ≥ 40 mL/min, platelets ≥ 100,000/mm3, absolute neutrophil count (ANC) ≥ 1,500/mm3, and bilirubin ≤ 1.5 times the upper limit of normal. The primary objective was to determine the MTD of lenalidomide when combined with nivolumab given at standard fixed dosing. Nivolumab was administered as 240 mg IV every 2 weeks; lenalidomide was administered orally on days 1-21 of 28-day cycles. Aspirin 81 mg daily was required for thromboprophylaxis in patients not already receiving therapeutic anticoagulation. Dose escalation of lenalidomide was performed using a 3+3 design, with dose levels (DL): 10 mg (DL -1), 15 mg (DL 1), and 20 mg (DL 2). Dose limiting toxicity (DLT) was defined within cycle 1 as grade Gr 3 or 4 non-hematologic toxicity, Gr 3/4 febrile neutropenia, any Gr 5 toxicity, or either ANC ≤ 500/mm3 or platelets < 25,000/mm3 persisting > seven days. Adverse events (AEs) were reported using CTCAE Version 4.0. Responses were investigator assessed according to the 2014 Lugano criteria. Results: Ten patients were enrolled. The median age was 68.5 (range 23-80), 5 were male, and the histologic diagnoses included diffuse large B cell lymphoma (DLBCL) in 5 patients (1 GCB, 4 non-GCB including 2 double expressor), high grade B cell lymphoma (HGBCL) in 1 patient, HL in 3 patients, and lymphoplasmacytic lymphoma in 1 patient. Two DLTs occurred at DL 1: Gr 3 rash requiring dose interruption and subsequent dose reduction in one patient and Gr 3 generalized weakness in a patient with rapidly progressive disease, considered possibly related to therapy. Six patients were treated at DL -1 with no DLTs. Gr ≥ 3 AEs occurred in 9/10 patients (Table 1). Neutropenia occurred in 7/10 patients: Gr 4 in two patients (both DL1), Gr 3 in four patients, and Gr 2 in one patient. Gr 3 rash occurred in two patients, and Gr 3 lung infection (pneumonia), Gr 3 fatigue, and Gr 3 duodenal hemorrhage (at site of DLBCL involvement) all occurred once respectively. Thromboembolic events occurred in two patients, one Gr 3 and one Gr 2. One Gr 4 non-hematologic AE occurred, Gr 4 respiratory disorder (COPD exacerbation) considered unrelated to treatment. One patient with rapidly progressive HGBCL prior to study entry died on study due to disease progression. Immune related AEs included Gr 1 hypothyroidism and Gr 1 fever in one patient. Common non-hematologic AEs of any grade are summarized in Table 2. Therapy related AEs lead to treatment discontinuation in one patient (Gr 3 rash and Gr 3 neutropenia); three additional patients required dose reductions of lenalidomide due to therapy related AEs. As of July 1, 2019, one patient remains on treatment. Therapy was discontinued for disease progression in five patients, including one patient who died on study from progressive disease. Three patients discontinued treatment without progression in order to pursue definitive therapy (axicabtagene ciloleucel, autologous transplant, and allogeneic transplant respectively). Three patients achieved an objective response, one complete response and two partial responses, with an additional three patients with best response of stable disease, two of whom discontinued for alternative therapies without progression of disease. Conclusions: We determined the MTD in R/R HL and NHL to be 10 mg lenalidomide in combination with 240 mg nivolumab. Treatment discontinuation due to toxicity was uncommon as were immune related AEs. A pre-planned phase 2 study in DLBCL and dose expansion study in HL is underway to evaluate preliminary efficacy of this combination at the MTD. Disclosures William: Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Christian:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Triphase: Research Funding; Merck: Research Funding; Janssen: Research Funding; Cephalon: Research Funding; Bristol-Myers Squibb: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Millennium Pharmaceuticals Inc: Research Funding. Maddocks:Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Short Diagnosis-to-Treatment Interval Is Associated with Higher Levels of Circulating Tumor DNA in Aggressive B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 491-491
Author(s):  
Stefan Alig ◽  
Charles Macaulay ◽  
David M. Kurtz ◽  
Ulrich Dührsen ◽  
Andreas Hüttmann ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Circulating Tumor Dna ◽  
Advisory Board ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Scientific Advisory

BACKGROUND Selection biases can impair the generalizability of clinical trials. Studies investigating aggressive diseases such as Diffuse Large B-cell Lymphoma (DLBCL) can be particularly affected by such biases since clinical urgency and need for therapy may not allow the requisite extensive screening and consent processes for trials. Diagnosis-to-Treatment Interval (DTI) has recently been proposed as a novel metric to capture this phenomenon (Maurer et al, JCO, 2018), and short DTI is associated with both adverse clinical factors and adverse clinical outcomes. Intriguingly, DTI was independent of clinical risk factors like the International Prognostic Index (IPI) suggesting that widely applied prognostic scores do not adequately reflect risk factors considered for clinical decision making. In this study, we aim to assess whether pretreatment levels of circulating tumor DNA (ctDNA) are associated with shorter DTI and may constitute an objective measure of clinical urgency. METHODS We quantified pretreatment ctDNA levels in plasma samples from 178 patients treated in 5 US and European centers for large cell lymphoma (DLBCL, Follicular lymphoma grade 3b, or High-grade-B-cell-lymphoma) using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) as previously described (Kurtz, JCO 2018; Scherer, STM 2016). Pretreatment ctDNA levels were correlated with DTI, clinical factors and treatment outcome. RESULTS Pretreatment ctDNA was detectable in 175/178 cases. Median number of single nucleotide variants (SNV) detected per patient was 129 (range 0-628). Pretreatment ctDNA levels ranged from 0 - 1.4 x105 haploid genome equivalents per milliliter of plasma (hGE/ml, median 239). Median DTI was 19 days (range 0-141, Figure 1A) and was similar in distribution to 2 previously described cohorts from the US and Europe (Maurer et al, JCO 2018). Shorter DTI was associated with higher ctDNA levels (RS=-0.39, P= 1.4 x10-7, Figure 1B). Patients with longer DTI had improved Event-Free Survival (EFS, Hazard Ratio (HR) for DTI: 0.9/week, P= 0.03). However, this association was lost when adjusting for pretreatment ctDNA levels (HR for DTI: 0.95/week, P= 0.39; HR for log10(ctDNA): 1.7, P= 5.8 x10-5). In a multivariate analysis including DTI, ctDNA and IPI, only ctDNA levels were significantly associated with EFS (HR for log10(ctDNA): 1.6, P= 0.002, n=178, Figure 1C). Pretreatment ctDNA levels remained the only prognostic factor for EFS in a second multivariate analysis also considering pretreatment metabolic tumor volume (MTV, HR for log10(ctDNA): 1.8, P= 0.01, n=93, Figure 1D). DISCUSSION Shorter DTI is associated with higher pretreatment ctDNA levels in patients with aggressive B-cell lymphomas. When comparing to established factors (DTI, IPI, MTV), pretreatment ctDNA levels appear to best predict clinical outcomes. This suggests that quantification of ctDNA better reflects disease burden and treatment urgency than existing clinical biomarkers. Pretreatment ctDNA level may therefore be a valuable metric for disease aggressiveness of patients included in clinical trials, and may help identify studies suffering from selection bias. This may be particularly useful for noncontrolled Phase I/II single arm trials, but also for stratification in randomized trials. Disclosures Kurtz: Roche: Consultancy. Dührsen:Alexion: Honoraria; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria; Takeda: Consultancy, Honoraria; Celgene: Research Funding; CPT: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Teva: Honoraria; Roche: Honoraria, Research Funding. Hüttmann:Takeda: Honoraria; Gilead: Honoraria; University Hospital Essen: Employment. Westin:Juno: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria. Rossi:Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Diehn:Novartis: Consultancy; BioNTech: Consultancy; AstraZeneca: Consultancy; Quanticell: Consultancy; Roche: Consultancy. Alizadeh:Pfizer: Research Funding; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Roche: Consultancy.

scholarly journals Response to Bridging Therapy As a Predictor of Outcomes for Chimeric Antigen Receptor Therapy in Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3841-3841
Author(s):  
Arushi Khurana ◽  
Matthew Hathcock ◽  
Radhika Bansal ◽  
Yucai Wang ◽  
Jonas Paludo ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Bridging Therapy ◽  
Advisory Committees ◽  
Pet Ct ◽  
Car T

Abstract Background: Bridging therapy (BT) was not allowed in the ZUMA-1 pivotal trial for axicabtagene ciloleucel (axi-cel) chimeric antigen receptor T-cell therapy (CAR-T) . Since then, several real-world studies have shown the use of bridging therapy to be associated with worse overall survival, duration of response, and complete remission rates. In addition, patients requiring BT during CAR-T manufacturing have a more aggressive and higher tumor burden of disease, also factors associated with poor outcomes. Therefore, factors that can predict outcomes in this high-risk patient cohort are required. We herein examine the impact of response to BT on CAR-T outcomes in large B-cell lymphoma (LBCL). Methods: A retrospective review of patients who received axi-cel for NHL from June 2016 - July 2020 at Mayo Clinic, Rochester, was performed. BT was defined as any lymphoma-directed therapy given between leukapheresis and CAR-T infusion. Patients received BT if there were concerns for symptomatic progression of disease during CAR-T manufacturing, reducing the likelihood of eligibility to receive CAR-T. The decision and choice of BT were at the discretion of the treating physician. Response to all lymphoma-directed therapy was evaluated using the 2014 Lugano criteria. Response to BT included patients with a partial response (PR) or stable disease (SD) on PET-CT before initiating lymphodepletion chemotherapy. Event-free survival (EFS) was defined as the time from axi-cel infusion to progression, next treatment, or death. Overall survival (OS) was defined as the time from axi-cel infusion to death. Survival curves were calculated using Kaplan-Meier estimates and were compared between subgroups using the log-rank test. Cox regression was used for univariate and multivariate analysis (MVA). Results: A total of 73 patients underwent car T therapy during this period. Of these, 67% (49/73) received BT therapy. Table 1 shows baseline characteristics of the total BT cohort (n = 49). The median age at CAR-T infusion was 59 years (IQR 46-64); 57% were males and comprised of 47% (23/49) DLBCL followed by 31% (15/49) high-grade B-cell lymphoma types. Based on the Lugano criteria on PET-CT, 22/49 (45%) patients responded to BT. The baseline characteristics were comparable between the responders and non-responders to BT except for a higher proportion (73%) of patients receiving systemic chemotherapy as BT in the responders (Table 1). At a median follow-up of 24 months, 75% had either progressed, died, or started the next treatment (event), and 59% (29/49) had died. The median EFS was significantly longer in the responders as compared to the non-responders to BT, figure 1 (13.04 months (95%CI, 3.54-not reached [NR]) vs. 2.56 months (95%CI, 1.18-3.02), p = 0.002). The OS also trended in favor of the responders (median OS 18.4 months (95% CI, 13.44-NR) vs. 11.84 months (95% CI, 5.05-NR), p = 0.092). The responder group also had a higher 6-month CR rate of 50% than 11.1% in the non-responder group (p = 0.004). There were no differences in any grade or grade ≥ 3 cytokine release syndrome and neurotoxicity rates in the two groups. On univariate analysis within the bridging group (n = 49), type of bridge (non-chemo) and response to bridge (PR+SD) were associated with a better EFS. In the MVA, only response to BT maintained significance for EFS (HR 0.34, p = 0.025). Conclusions: Having some control of lymphoma after BT was associated with better EFS and 6-month CR rate. Future studies need to prospectively evaluate the type and response to BT as a prognostic factor for improving outcomes in patients receiving CAR-T. Figure 1 Figure 1. Disclosures Wang: InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; MorphoSys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend: Consultancy; Sorrento: Consultancy; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Takeda: Research Funding.

scholarly journals Initial Clinical Activity of FT596, a First-in-Class, Multi-Antigen Targeted, Off-the-Shelf, iPSC-Derived CD19 CAR NK Cell Therapy in Relapsed/Refractory B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-8
Author(s):  
Veronika Bachanova ◽  
Zuzan Cayci ◽  
Dixie Lewis ◽  
Joseph E. Maakaron ◽  
Murali Janakiram ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Phase I ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Publicly Traded ◽  
Advisory Committees

Induced pluripotent stem cell (iPSC)-derived immune effector cells offer distinct advantages over existing patient- and donor-derived therapeutic approaches, including the use of a clonal master engineered iPSC line as a renewable source for the mass production of immune cells, which are available off-the-shelf for broad patient access. FT596 is an investigational, off-the-shelf, multi-antigen targeting, chimeric antigen receptor (CAR) natural killer (NK) cell therapy derived from a human clonal master iPSC line engineered with three anti-tumor modalities: (1) a proprietary CD19-targeting CAR; (2) a novel high-affinity, non-cleavable CD16 Fc receptor that enables tumor targeting and enhanced antibody-dependent cell cytotoxicity in combination with a therapeutic monoclonal antibody (mAb); and (3) interleukin (IL)-15/IL-15 receptor fusion promoting cytokine-autonomous persistence. Preclinical in vivo models demonstrate potent multi-antigen targeting activity of FT596 against both CD19+ and CD19- tumor cell lines when combined with the anti-CD20 agent rituximab (Goodridge et al. 2019). FT596 is currently being investigated as a monotherapy and in combination with the anti-CD20 mAbs rituximab and obinutuzumab in a multicenter, Phase I clinical trial for the treatment of relapsed/refractory B-cell lymphoma and chronic lymphocytic leukemia. The trial will test up to four FT596 dose levels ranging from 30 to 900 million cells. We describe the demonstration of early clinical benefit of FT596 in a patient who received a single administration of FT596 as a monotherapy at the first dose level in the Phase I trial. The patient is a 76-year-old female with diffuse large B-cell lymphoma, germinal center B-cell subtype, who was initially diagnosed in January 2014. The patient received eight prior treatment regimens, including autologous stem cell transplant, rituximab in combination with engineered autologous T cells expressing antibody-coupled T-cell receptor, and, most recently, was refractory to an experimental combination therapy comprised of lymphodepleting chemotherapy followed by ex vivo expanded allogeneic NK cells, IL-2, and rituximab. The patient received fludarabine and cyclophosphamide lympho-conditioning followed by a single administration of 30 million cells of FT596 as monotherapy. During the 28-day follow-up period for safety, no dose-limiting toxicities were observed. No cytokine release syndrome, neurologic toxicity, or graft-versus-host disease of any grade was observed. Grade ≥3 treatment-emergent adverse events (AEs) included decreased white blood cell count, decreased neutrophil count, anemia, urinary tract infection with neutropenic fever, and hypertension. Notably, none of these AEs were considered related to FT596 by the treating investigator physician, except for decreased neutrophil count, which was considered possibly related to FT596 and resolved. Evidence of hematologic recovery was observed by the end of the 28-day follow-up safety period. On Study Day 29, the patient's tumor response assessment showed partial response by Lugano 2014 criteria, with a greater than 70% decrease in 18F-fluorodeoxyglucose uptake and greater than 50% reduction in tumor size. The patient remains on study and, per protocol and in collaboration with the U.S. Food and Drug Administration, is being considered for retreatment with a second cycle of FT596 monotherapy. This is the first-ever demonstration of clinical activity following treatment with an off-the-shelf, iPSC-derived CAR immune cell therapy and provides direct evidence that low doses of FT596 can induce short-term responses, opening the opportunity for multi-dosing strategies to deepen response and duration. Additional clinical, pharmacokinetic, and pharmacodynamic data from this patient will be provided at the time of the meeting. The Phase I trial is ongoing and is registered on clinicaltrials.gov: NCT04245722. Disclosures Bachanova: FATE: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding. Janakiram:Takeda, Fate, Nektar: Research Funding. Payne:Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wong:Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cooley:Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Valamehr:Fate Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company. Chu:Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Roche Holding AG: Current equity holder in publicly-traded company. Miller:GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; Onkimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding. OffLabel Disclosure: Cyclophosphamide and fludarabine will be used as lympho-conditioning therapy prior to FT596 administration.

scholarly journals Preliminary Results of a Phase I Study of Nivolumab (BMS-936558) in Patients with Relapsed or Refractory Lymphoid Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 291-291 ◽  
Author(s):  
Alexander M. Lesokhin ◽  
Stephen M. Ansell ◽  
Philippe Armand ◽  
Emma C. Scott ◽  
Ahmad Halwani ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
T Cell Lymphoma ◽  
Advisory Committees ◽  
Lymphoid Malignancies

Abstract Introduction Programmed cell death-1 (PD-1) is an immune checkpoint receptor that inhibits T cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported in various lymphoid malignancies, and may allow these tumors to circumvent host anti-tumor immunity. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, potentiates T cell activity, and has clinical efficacy in various solid tumors. We hypothesized that nivolumab might also have clinically important anti-tumor activity in patients with lymphoid malignancies. Methods This open-label study enrolled patients with relapsed or refractory lymphoid malignancies including B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), multiple myeloma (MM), and classical Hodgkin lymphoma (cHL). Patients were treated using a dose escalation design (1 mg/kg and 3 mg/kg) of nivolumab administered every two weeks for up to two years. Responses were assessed using standard criteria. The primary endpoint was safety; key secondary endpoints included anti-tumor activity and expression of immunomodulatory proteins in tumor biopsies. The preliminary results for the cHL patients will be reported separately. Results Twenty-nine patients with B-NHL, 2 patients with primary mediastinal B-cell lymphoma; 23 patients with T-NHL; 27 patients with MM; and 1 with chronic myelogenous leukemia were enrolled. Patients were heavily pretreated with 67%, 69%, and 78% of MM, B-NHL, and T-NHL patients, respectively, having received ≥ 3 prior treatment regimens. Previous autologous stem cell transplantation was reported for 56% of MM, 14% of B-NHL, and 9% of T-NHL patients. Prior brentuximab treatment was reported in 7% of B-NHL and 26% of T-NHL patients. When this pre-planned interim analysis was performed, six patients had been treated at the 1 mg/kg dose with 2 dose-limiting toxicities (DLTs) occurring in the same patient: grade 3 pneumonia and pneumonitis. At the 3mg/kg dose, seven patients were treated with one patient experiencing two DLTs: grade 3 eosinophilia and diplopia. Additional patients were enrolled in the cohort expansion at 3 mg/kg. Drug-related adverse events (AEs) occurred in 72%, 65%, and 52% of B-NHL, T-NHL, and MM patients, respectively. Serious AEs in B-NHL patients were pneumonitis (7%), acute respiratory distress syndrome, dermatitis, diplopia, enteritis, eosinophilia, mucosal inflammation, pyrexia and vomiting, each occurring in 3%. In the T-NHL patients, serious AEs were pneumonitis, rash, and sepsis, each occurring in 4%, and in MM patients, serious AEs were pneumonitis, myositis, and increased creatine phosphokinase, each occurring in 4%. The incidence and severity of drug related AEs were similar across tumor types. Efficacy results are shown for each tumor type in the table. The overall response rate (ORR) and complete response (CR) rate in patients with B-NHL were 28% and 7%, respectively, including an ORR of 36% in patients with diffuse large B-cell lymphoma (DLBCL), and 40% in patients with follicular lymphoma (FL). In patients with T-NHL, ORR was 17% (no CR), including an ORR of 40% in the 5 patients with peripheral T cell lymphoma. No objective responses were observed in MM. Analysis of PD-L1 expression and correlation to clinical outcome is being performed and will be presented. Conclusions Nivolumab administered at a dose of 3 mg/kg every two weeks was tolerable and the safety profile was similar to that of the agent in solid tumors. Objective responses were observed in DLBCL, FL, mycosis fungoides (MF), and peripheral T cell lymphoma (PTCL). Durable stable disease was observed in relapsed MM. The results of this phase 1 study have led to phase 2 studies in DLBCL and FL, which are ongoing. Table: Efficacy Results Tumor N Complete Response n (%) Partial Response n (%) Stable Disease (SD) n (%) Progression Free Survival Rate at 24 Weeks (%) Diffuse Large B Cell Lymphoma (DLBCL) 11 1 (9) 3 (27) 3 (27) (24) Follicular Lymphoma (FL) 10 1 (10) 3 (30) 6 (60) (68) Other B Cell Lymphoma 8 0 0 5 (63) (38) Primary Mediastinal B Cell Lymphoma 2 0 0 2 (100) (0) Mycosis Fungoides (MF) 13 0 2 (15) 9 (69) (39) Peripheral T Cell Lymphoma (PTCL) 5 0 2 (40) 0 (30) Other T Cell Lymphoma 5 0 0 1 (20) (0) Multiple Myeloma (MM) 27 0 0 18 (67) (15) Chronic Myelogenous Leukemia 1 0 0 1 (100) (100) Disclosures Lesokhin: Bristol-Myers Squibb: Consultancy, Research Funding. Ansell:Bristol-Myers Sqibb: Research Funding. Armand:Merck: Consultancy. Cohen:Celgene: Member, Independent Response Adjudication Committee Other; Onyx: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Janssen: Advisory Board, Advisory Board Other. Lebovic:Genentech, Allos, Celgene, Onyx, Millennium: Consultancy, Research Funding, Speakers Bureau. Rodig:Bristol-Myers Squibb: Research Funding. Zhu:Bristol-Myers Squibb: Employment. Grosso:Bristol-Myers Squibb: Employment, Equity Ownership. Kim:Bristol-Myers Squibb: Employment. Shipp:Merck: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Borrello:Bristol-Myers Squibb: Research Funding. Timmerman:Bristol-Myers Squibb: Research Funding.

scholarly journals Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2898-2898
Author(s):  
Vania Phuoc ◽  
Leidy Isenalumhe ◽  
Hayder Saeed ◽  
Celeste Bello ◽  
Bijal Shah ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Fdg Pet ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Phase II Study Of Anti-CD19 Antibody Drug Conjugate (SAR3419) In Combination With Rituximab: Clinical Activity and Safety In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (NCT01470456)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4395-4395 ◽  
Author(s):  
Bertrand Coiffier ◽  
Catherine Thieblemont ◽  
Sophie de Guibert ◽  
Jehan Dupuis ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Grade 3

Abstract Background SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a potent cytotoxic agent. SAR3419 targets CD19, an antigen expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The recommended dose for single agent SAR3419 was previously determined to be 55 mg/m2 administered IV every week for 4 weeks, then bi-weekly. In phase I, clinical activity was shown mainly in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Trial funded by Sanofi). Methods Patients (pts) with a CD20+ and CD19+ DLBCL relapsing or refractory (R/R) after at least 1 standard treatment including rituximab and not candidate for or who already underwent transplantation, were eligible. Refractory disease was defined as unresponsive to or progressing within 6 months of regimen completion. Fresh (or recent formalin-fixed, paraffin-embedded) biopsy was required before SAR3419 start. Pts received 375 mg/m2 of rituximab (R) IV and 55 mg/m² of SAR3419 on day 1, 8, 15, 22 (35-day cycle 1), followed by bi-weekly R and SAR3419 at the same doses for 2 additional 28-day cycles, provided there was no disease progression or other study discontinuation criteria met. The primary objective was the overall response rate (ORR) following Cheson 2007 criteria, with the first tumor assessment being done 42 days after the last study treatment administration. Secondary objectives were: safety, pharmacokinetics (PK), duration of response (DOR), progression free survival (PFS), overall survival (OS) and correlation of the antitumor and biological activity of the combination with tumor biomarker status. Results Fifty-three pts were enrolled, 52 treated. Median age was 66.5 years (range 38-85), 50% were male; 23%, 33% and 40% of patients had received 1, 2 or ≥3 prior chemo/immunotherapy regimens for DLBCL, respectively. Of the enrolled patients, 3.8% had received no prior regimen for DLBCL and therefore were excluded from primary analysis for efficacy. Seventy-three percent had stage III/IV disease, 59% had elevated lactate dehydrogenase (LDH), and 63% had bulky disease. Sixty percent were refractory to first regimen (primary refractory), 16% were refractory to last regimen and 24% were relapsed pts. The ORR in the per-protocol population (n=45) was 31.1% (80% confidence interval (CI): 22.0% to 41.6%). Among the 14 responders, 5 had progressed at the time of analysis, with duration of response beyond 6 months for 3 of them. The ORR was 58.3% (80% CI: 36.2% to 78.1%) for patients with relapsed DLBCL (n=12), 42.9% (80% CI: 17.0% to 72.1%) for pts refractory to last regimen (n=7) and 15.4% (80% CI: 6.9% to 28.4%) for primary refractory pts (n=26). Overall survival and PFS data are not yet mature. Biomarkers and PK data will be presented at the meeting. The most common (≥10%) all grades non-hematologic treatment-emergent adverse events (TEAEs) were asthenia (25.0%), nausea (21.2%), cough (19.2%), diarrhea (17.3%), weight decrease (17.3%), vomiting (15.4%), dyspnea (15.4%), abdominal pain (13.5%), back pain (13.5%), pyrexia (13.5%) and constipation (11.5%). Related grade 3-4 TEAEs were: 1 syncope, 1 bronchospasm, 2 neutropenia and 1 anemia. No TEAEs led to treatment discontinuation, no grade 3-4 peripheral neuropathy or grade 3-4 ocular events were observed. Two pts experienced grade 2 keratitis, both rapidly recovered with local treatment. Hematological toxicity was moderate, with grade 3-4 neutropenia and thrombocytopenia in 15.7% and 9.8% pts, respectively. No complications related to neutropenia were reported. Grade 3 transaminase increase was observed in 1 patient. Conclusions The combination of SAR3419 plus R showed moderate ORR in R/R DLBCL; however the study population was of poor prognosis (60% refractory to first line therapy). In the relapsed DLBCL patients a higher ORR was observed. SAR3419 plus R presented with a favorable safety profile. Further investigations on biomarker expression are ongoing to identify a sub-group of pts who could have better benefited from this combination. Disclosures: Coiffier: Sanofi: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Phase II of SAR3419. Ribrag:Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cartron:LFB: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Casasnovas:Roche: Consultancy, Honoraria, Research Funding. Hatteville:Sanofi: Employment. Zilocchi:Sanofi: Employment. Oprea:Sanofi: Employment. Tilly:Amgen: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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