Parsaclisib in Combination with R-CHOP for Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma: Preliminary Results of a Phase 1/1b Study

Abstract Introduction: Novel genetic classifications of diffuse large B-cell lymphoma (DLBCL) highlight the molecular complexity beyond cell of origin and provide new therapeutic implications. Next generation trials may incorporate novel agents for different genetic subtypes based on the pathogenesis mechanisms. For example, with the LymphGen classification, the MCD, BN2, ST2, and EZB subtypes are predicted to be susceptive to PI3K/mTOR targeting (Wright 2020). However, PI3K inhibitors have not been tested in the frontline, although data on the mTOR inhibitor everolimus were encouraging (Alliance 1085). We launched a phase 1/1b trial (NCT04323956) to investigate the feasibility of combining a novel PI3K inhibitor parsaclisib with standard R-CHOP immunochemotherapy and to seek an efficacy signal. Methods: Adult patients with newly diagnosed DLBCL were eligible if any of the following was present: 1) non-GCB subtype per the Hans algorithm; 2) expression of either Myc (≥40%) or Bcl2 (≥50%) by immunohistochemistry; or 3) MYC rearrangement by FISH. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, regardless of morphology, was also eligible. All patients received parsaclisib plus R-CHOP. Phase 1 followed a 3+3 design and the primary endpoint was maximum tolerated dose (MTD) of parsaclisib. Dose levels tested were level 1 (20 mg QD, d1-10; starting level) and level 2 (20 mg QD, d1-14). MTD was defined as the dose level below the lowest dose that induced dose limiting toxicity (DLT) in at least one-third of patients. The primary endpoint in phase 1b is complete response (CR) rate by PET. Results: From July 2020 to June 2021, 15 patients were enrolled, 9 in phase 1 and 6 in phase 1b. The median age at diagnosis was 56 years (range 20-79), and 7 (47%) were female. One patient (7%) had ECOG PS ≥2, 7 (47%) had elevated LDH, 7 (47%) had >1 extranodal site, 13 (87%) had stage III/IV, and 7 (47%) had high-intermediate or high risk International Prognostic Index. Pathology was DLBCL in 13 patients (2 with concurrent follicular lymphoma) and high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in 2 patients. Four (27%) had non-GCB subtype, 7 (47%) had Myc or Bcl2 single expression, 8 (53%) had Myc/Bcl2 double expression, and 5 (33%) had MYC rearrangement (2 with concurrent BCL2 and/or BCL6 rearrangements). In phase 1, 3 patients were enrolled at dose level 1 and 6 patients were enrolled at dose level 2. No DLT was observed. Therefore, MTD was not reached, and dose level 2 was selected for phase 1b dose expansion. Six patients were enrolled in phase 1b to date. At the data cutoff date of 7/22/2021, 8 patients completed all 6 cycles of treatment, 1 competed 5 cycles, 3 completed 3 cycles, 2 completed 2 cycles, and 1 completed 1 cycle. Treatment-related adverse events (AE) are summarized in Table 1. The most common hematological AE included lymphopenia (60%), anemia (53%), neutropenia (53%), and thrombocytopenia (27%), and the most common non-hematological AE included nausea (67%), alopecia (40%), constipation (33%), fatigue (33%), dyspepsia (20%), and peripheral sensory neuropathy (20%). The most common grade 3 or 4 AE included lymphopenia (47%), neutropenia (33%), and anemia (13%). One 80-year-old female required parsaclisib dose reduction in cycle 3 and subsequent parsaclisib discontinuation as well as cyclophosphamide and doxorubicin dose reductions due to febrile neutropenia (no source of infection was identified). No other patients required dose reductions. The median follow-up was 3.7 months (range 0.8-10.7). Thirteen patients were evaluable for interim response by PET. The objective response rate was 92%, with 8 (62%) CR and 4 (31%) partial response (PR). One (8%) patient progressed before cycle 2 following a transient clinical response (shrinking palpable mass). Among those who achieved an objective response at interim, 7 patients were evaluable for end of treatment response and all 7 maintained a response, with 6 (86%) CR and 1 (14%) PR. Conclusions: Parsaclisib and R-CHOP combination therapy was generally well tolerated, with no DLT observed in phase 1 and no major safety concerns in both phase 1 and the ongoing phase 1b expansion. The preliminary efficacy signal of objective response appears encouraging in a small cohort of high risk patients. Parsaclisib plus R-CHOP can be an experimental arm for future frontline DLBCL trials investigating genetic subtype-driven novel therapies. Figure 1 Figure 1. Disclosures Wang: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: 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. King: Celgene/BMS: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Tun: Gossamer Bio, Acrotech: Consultancy; Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding. Habermann: Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Parsaclisib is an investigational agent used in this clinical trial.

Download Full-text

Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Blood ◽

10.1182/blood-2021-152603 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 623-623

Author(s):

Bradley M. Haverkos ◽

Onder Alpdogan ◽

Robert Baiocchi ◽

Jonathan E Brammer ◽

Tatyana A. Feldman ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

T Cell Lymphoma ◽

Phase 2 ◽

Advisory Committees ◽

Phase 1B

Abstract Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706). Methods: Patients aged ≥18 with histologically confirmed EBV + lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×10 9/L, platelet count ≥50×10 9/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8. Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from <1 to 90% in 42 tumor biopsies with central lab review. The most common treatment-emergent adverse events (TEAEs) of all grades were nausea (38%), neutropenia (34%), thrombocytopenia (34%), and constipation (31%). Grade 3/4 TEAEs in >10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation. For 43 evaluable patients (EBER-ISH + with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months. Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV + lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV + lymphomas is ongoing in the phase 2 VT3996-202 trial. Disclosures Haverkos: Viracta Therapeutics, Inc.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

Download Full-text

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 ◽

10.1182/blood-2018-99-113117 ◽

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.

Download Full-text

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 ◽

10.1182/blood-2018-99-113115 ◽

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.

Download Full-text

Preliminary Clinical Results of a Phase 1 Study Evaluating the Safety and Anti-Tumor Activity of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ B-Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-111622 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2966-2966 ◽

Cited By ~ 1

Author(s):

Ian W. Flinn ◽

Jonathon B. Cohen ◽

Luke P. Akard ◽

Samantha Jaglowski ◽

Michael Vasconcelles ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Board Of Directors ◽

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees

Abstract Background: Recent regulatory approvals of two CD19-targeted chimeric antigen receptor (CAR)-expressing autologous T lymphocyte therapies provide compelling evidence of the clinical potential of re-engineering T cells to specifically attack tumor cells, but the broader applicability of these therapies is constrained by safety considerations and target specificity. A universal approach to T cell therapy that enables flexibility in tumor target selection has been demonstrated by engineering autologous T cells to express an antibody-coupled T cell receptor (ACTR) composed of the ectodomain of the CD16 Fc receptor fused to costimulatory and CD3ζ signaling domains. Thus, the ACTR platform couples T cell anti-tumor effector functions, including cytotoxicity, cytokine production, and T cell proliferation, to target-specific therapeutic antibodies. Here we present the preliminary clinical findings of the ongoing, multicenter Phase 1 study, ATTCK-20-03 (NCT03189836), of ACTR707, a CD28-containing ACTR chimeric receptor, in combination with rituximab in subjects with relapsed or refractory CD20+ B cell lymphoma. Methods: The primary objectives of this first-in-human, dose escalation study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a maximum tolerated dose (MTD) and a proposed recommended phase 2 dose (RP2D). Other objectives include evaluation of antitumor activity, and assessment of ACTR T cell persistence, cytokine levels, and rituximab pharmacokinetics. Eligible subjects must have histologically confirmed relapsed or refractory CD20+ non-Hodgkin lymphoma and have received prior anti-CD20 mAb in combination with chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and ACTR707. Additional doses of rituximab were administered, one dose every 3 weeks in the absence of disease progression. The study is separated into 2 sequential phases, a dose escalation and a safety expansion phase. During the dose escalation phase, ACTR707 is being tested at increasing doses in combination with rituximab. Results: Six subjects were enrolled and received ACTR707 at the first dose level in combination with rituximab: 5 diagnosed with diffuse large B cell lymphoma (83%) and one with follicular lymphoma, Grade 3b (17%). Median age was 61 years (range: 57-76), 83% were male, 50% were treated with ≥3 lines of prior therapy, and 67% had no response to or relapse within 6 months from immediate prior therapy. ACTR707 was successfully manufactured for all subjects and demonstrated post-infusion expansion in the peripheral blood. ACTR+ T cells were detectable at Day 28 post-infusion for all subjects tested. No dose-limiting toxicities (DLTs) were observed at the first dose level in 4 DLT-evaluable subjects (2 subjects experienced disease progression during the DLT evaluation period). There were no cytokine release syndrome (CRS) or autoimmune adverse events (AEs), serious or severe (≥Gr3) neurotoxicity AEs, or deaths on treatment. AEs (all grades) reported in >1 subject included neutropenia (n=3), anemia, decreased appetite, febrile neutropenia, and thrombocytopenia (each in 2 subjects); the 2 events of febrile neutropenia were considered serious. Investigator-reported complete responses were observed in 3 of 6 subjects. These complete responses (duration of response range: 47+ to 81+ days) are ongoing as of the data cut-off. Enrollment into the second dose level is ongoing. Conclusions: ACTR707 in combination with rituximab induced complete responses in 3 of 6 subjects with relapsed or refractory aggressive CD20+ B cell lymphoma treated at the first dose level with ACTR707 in combination with rituximab, with no CRS, serious or severe (≥Gr3) neurotoxicity, or AEs leading to treatment discontinuation. ACTR+ T cells were detectable in all subjects and persisted. These results support the continued dose escalation of ACTR707 in combination with rituximab. Updated data, inclusive of preliminary dose level 2 and correlative biomarkers, will be presented. Disclosures Flinn: Verastem: Consultancy, Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Forty Seven: Research Funding; BeiGene: Research Funding; ArQule: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Incyte: Research Funding; Forma: Research Funding; Verastem: Research Funding; Novartis: Research Funding; Agios: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Merck: Research Funding; Calithera: Research Funding; Constellation: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Curis: Research Funding; Celgene: Research Funding. Cohen:BioInvent: Consultancy; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Akard:Gilead: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Jaglowski:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Consultancy. Vasconcelles:Unum Therapeutics: Employment. Ranger:Unum Therapeutics: Employment. Harris:Unum Therapeutics: Employment. Payumo:Unum Therapeutics: Employment. Motz:Unum Therapeutics: Employment. Bachanova:Gamida Cell: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding.

Download Full-text

A Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results In Patients With DLBCL and Other B-Cell Lymphomas

Blood ◽

10.1182/blood.v122.21.848.848 ◽

2013 ◽

Vol 122 (21) ◽

pp. 848-848 ◽

Cited By ~ 22

Author(s):

Nancy L. Bartlett ◽

Jeff P. Sharman ◽

Yasuhiro Oki ◽

Ranjana H. Advani ◽

Celeste M. Bello ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

Objective Response ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Board Membership

Abstract Background Brentuximab vedotin (ADCETRIS®) is an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Variable CD30 expression has been demonstrated in several B-cell non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBL). Methods A phase 2, open-label, single-arm study is ongoing to evaluate the antitumor activity of brentuximab vedotin in relapsed or refractory CD30-positive NHL, including B-cell neoplasms (Clinical Trials.gov NCT01421667). CD30 expression is determined by immunohistochemistry per local laboratory; any level of CD30-positive expression is permitted for enrollment. Brentuximab vedotin, 1.8 mg/kg, is administered every 3 weeks by IV infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity. The primary efficacy endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Correlation between antitumor activity and quantitative CD30 expression is also being explored. This subset analysis presents interim data for patients with relapsed/refractory Bcell neoplasms. Results Sixty-two B-cell lymphoma patients with variable CD30 expression by central review (range 0–100%) have been enrolled to date. Diagnoses include DLBCL (n=44) and other B-cell neoplasms (n=18) [grey zone lymphoma (n=6), PMBL (n=6), follicular lymphoma (n=3), and post-transplant lymphoproliferative disorder (n=3)]. The median age of all patients was 55 years (range, 16–85 years), and the majority had an ECOG performance status of 0/1 (92%). Patients had received a median of 2 prior therapies (range, 1 to 19); 11 (18%) had received prior stem cell transplant. Forty patients (65%) had primary refractory disease, and 47 patients (76%) were refractory to their most recent prior therapy. Fourteen patients (23%) had never responded to any prior therapy. At the time of this analysis, patients had received a median of 3 cycles of treatment (range, 1–17 cycles), with a median duration of treatment of 10.5 weeks (range, 2.4 to 57.1 weeks). Twelve (19%) patients remain on treatment. Of the 43 efficacy evaluable DLBCL patients, 40% achieved an objective response [7 complete remission (CR), 10 partial remission (PR)]; the median duration of objective response was 36 weeks (range, 0.1+ to 62.3+ weeks). Of the 18 efficacy evaluable patients with other Bcell neoplasms, 22% achieved an objective response: PMBL (1 CR), PTLD (1 CR), and grey zone lymphoma (2 PRs). The median duration of objective response was 21.7 weeks (range, 6.1 to 37.1 weeks). CD30 expression levels for patients with a CR or PR were variable and ranged from <1% to 90%. There was no statistical correlation between CD30 expression and response rate. Treatment-emergent adverse events (AEs) occurring in >20% of patients included fatigue (40%), nausea and neutropenia (37% each), pyrexia (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), and anemia and constipation (21% each). Peripheral neuropathy events have been primarily Grade 1 or 2. Neutropenia (29%) was the only Grade 3/4 related AE observed in >10% of patients. AEs led to treatment discontinuation in 6 patients; the most common reason was peripheral sensory neuropathy (2 patients). Conclusions In this interim analysis of 62 patients with highly refractory B-cell lymphomas, compelling antitumor activity has been observed with brentuximab vedotin. Forty percent of DLBCL patients achieved an objective response, with median remission duration of >8 months and a notable proportion of complete remissions. No correlation between CD30 expression and response rate has been observed to date. Safety data are consistent with the profile of brentuximab vedotin. This study continues to enroll patients and updated results will be presented at the meeting. Disclosures: Bartlett: Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Sharman:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Gilead: Research Funding. Oki:Seattle Genetics, Inc.: Research Funding. Advani:Millennium: Advisory/scientific board membership, Advisory/scientific board membership Other, Research Funding; Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding; Genentech: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pharmacyclics, Inc.: Research Funding; Janssen R&D: Research Funding; Allos Therapeutics: Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees; Abbott: Research Funding. Bello:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Spectrum pharmaceuticals: Speakers Bureau. Winter:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Jacobsen:Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding.

Download Full-text

Interim Results from the First-in-Human Clinical Trial of Adct-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-116081 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 398-398 ◽

Cited By ~ 7

Author(s):

John Radford ◽

Brad S. Kahl ◽

Mehdi Hamadani ◽

Carmelo Carlo-Stella ◽

Paolo Caimi ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

B Cell Lymphoma ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) represents 33% of the non-Hodgkin lymphomas (NHL) and expresses CD19, a classic B-cell marker found on B lymphocytes. ADCT-402 (loncastuximab tesirine; Lonca-T) is an antibody drug conjugate comprising a humanized antibody directed against human CD19 conjugated to a pyrrolobenzodiazepine dimer toxin. This first-in-human clinical study evaluated the safety and efficacy of Lonca-T in patients (pts) with relapsed/refractory (R/R) B-cell lineage NHL. Here we present interim results in the subgroup of pts with DLBCL. Interim efficacy and safety of Lonca-T in pts with follicular lymphoma and mantle cell lymphoma are presented in a separate abstract. Methods: Pts ≥18 years of age with R/R DLBCL who have failed or are intolerant to established therapies, or have no other treatment options available, were enrolled in this Phase 1, multicenter, open-label, single-arm study, including dose-escalation and dose-expansion parts. The primary objectives are to evaluate the safety and tolerability of Lonca-T, and determine the recommended dose(s) to use for expansion cohorts. The secondary objectives are to evaluate the clinical activity (measured by overall response rate [ORR], duration of response [DoR], progression-free survival [PFS] and overall survival [OS]), pharmacokinetics, pharmacodynamics, and anti-drug antibody activity. Pts receive 1-hour intravenous infusions of Lonca-T every 3 weeks (1 cycle), with a 3+3 dose-escalation design for the dose-escalation part of the study. No intra-pt dose escalation is allowed. Results: As of June 20, 2018, 183 pts had been enrolled on the study, including 137 with DLBCL (79 male, 58 female). Pts with DLBCL had a median age of 63 years [range 20-86], and had received a median of 3 previous therapies (range 1-10; Table). Pts received doses of Lonca-T ranging from 15 to 200 µg/kg (median cycles: 2 [range 1-13]). Treatment-emergent adverse events (TEAEs) were reported in 136/137 (99.3%) pts, and grade ≥3 TEAEs in 100/137 (73.0%) pts. The most common all-grade TEAEs (≥20% pts), regardless of relationship to study treatment, were fatigue (57 [41.6%]), nausea (44 [32.1%], peripheral edema (44 [32.1%]), anemia (39 [28.5%]), rash (35 [25.5%]), gamma-glutamyltransferase (GGT) increased (33 [24.1%]), constipation (30 [21.9%]), dyspnea (29 [21.2%]), and thrombocytopenia (28 [20.4%]). The most common grade ≥3 TEAEs (>10% pts) were GGT increased (21 [15.3%]), neutropenia (20 [14.6%]), neutrophil count decreased (19 [13.9%]), anemia (15 [10.9]), thrombocytopenia (15 [10.9%]) and platelet count decreased (14 [10.2%]. Approximately 66% and 72% of pts in the 120 and 150 µg/kg groups, respectively, tolerated at least 2 cycles before any AE leading to dose reduction/delay occurred. The figure depicts tumor response data. Out of 132 evaluable pts with DLBCL, the ORR was 40.2% (53/132 pts), comprising 29/132 (22.0%) complete responses (CRs) and 24/132 (18.2%) partial responses (PRs). Median DoR was 4.17 months and PFS was 2.79 months after a median follow-up of 5.13 months. Median DoR was not reached in pts achieving a CR and was 2.76 months in pts with a PR. In pts with non-bulky disease, the ORR was 44.2% (50/113 pts); 28/113 (24.8%) pts attained a CR and 22/113 (19.5%) pts attained a PR. The majority of pts (122/132) received doses ≥120 µg/kg; in these pts, the ORR was 41.8% (51/122 pts), with 28/122 (23.0%) pts attaining a CR and 23/122 (18.9%) pts attaining a PR. Conclusions: In this Phase 1 study, Lonca-T has demonstrated encouraging and durable single-agent antitumor activity and manageable toxicity in pts with R/R DLBCL at doses ≥120 µg/kg. Updated safety, tolerability, and efficacy results will be presented at the meeting. Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02669017. Disclosures Radford: Pfizer: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Equity Ownership; Novartis: Consultancy, Speakers Bureau; Celgene: Research Funding. Kahl:Seattle Genetics: Consultancy; Genentech: Consultancy; ADC Therapeutics: Research Funding. Hamadani:Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Research Funding; Cellerant: Consultancy; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy; Merck: Research Funding. Carlo-Stella:Boehringher Ingelheim Italia: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Sanofi: Consultancy; MSD Italia: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Genenta Science: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau. Caimi:Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference expenses, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Feingold:ADC Therapeutics: Employment, Equity Ownership. He:ADC Therapeutics: Employment, Equity Ownership. Reid:AbbVie: Research Funding; Millenium Pharmaceuticals: Research Funding; ADC Therapeutics: Research Funding. Solh:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau. Chung:ADC Therapeutics: Research Funding. Heffner:Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding. Ungar:ADC Therapeutics: Employment, Equity Ownership. O'Connor:ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding.

Download Full-text

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

Blood ◽

10.1182/blood-2019-122393 ◽

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.

Download Full-text

A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results.

Blood ◽

10.1182/blood.v120.21.2746.2746 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2746-2746 ◽

Cited By ~ 7

Author(s):

Eric D. Jacobsen ◽

Ranjana H. Advani ◽

Yasuhiro Oki ◽

Jeff Sharman ◽

Steven M. Horwitz ◽

...

Keyword(s):

Antitumor Activity ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Nk Cell ◽

Cell Lymphoma ◽

Objective Response ◽

Brentuximab Vedotin ◽

Grey Zone ◽

Advisory Committees

Abstract Abstract 2746 Background: Brentuximab vedotin (ADCETRIS®) is a CD30-directed antibody-drug conjugate approved for the treatment of relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL). Several non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphomas (PTCL) have variable quantitative and qualitative expression of CD30. As a result of the high objective response rate (86%) and durable complete remissions (CR) observed in a pivotal phase 2 study in ALCL, a study was initiated to investigate the efficacy and safety of brentuximab vedotin in other NHLs that express the CD30 antigen. Methods: A phase 2, open-label, single-arm, multicenter study is currently ongoing to evaluate the antitumor activity of brentuximab vedotin in approximately 75 patients with relapsed or refractory CD30-positive NHL (ClinicalTrials.gov NCT01421667). Brentuximab vedotin, 1.8 mg/kg, is administered every 3 weeks by IV infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity. The primary efficacy endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Efficacy variables will be analyzed by total patients, WHO NHL classification, DLBCL (excluding peripheral mediastinal large B-cell lymphoma [PMBL] due to differing treatment paradigms and outcomes for this DLBCL subtype), and by each individual disease. The correlation between antitumor activity and quantitative CD30 expression is also being explored. Results: Fifty-three patients with various CD30-positive NHLs have been enrolled to date (35 with B-cell neoplasms and 18 with mature T-/NK-cell neoplasms). Twenty-nine (55%) patients had refractory disease, 19 (36%) had relapsed since their most recent prior therapy, and 5 (9%) had primary refractory disease (did not achieve a CR with frontline therapy or relapsed within 3 months of completing frontline therapy). Diagnoses include DLBCL (assorted disease subtypes, n=22), angioimmunoblastic T-cell lymphoma (AITL, n=9), PTCL-NOS (n=8), grey zone lymphoma (n=5), PMBL (n=4), follicular lymphoma (n=3), post-transplant lymphoproliferative disorder (n=1), and cutaneous T-cell lymphoma (n=1). The median age is 64 years (range 16–83) and 30 patients (57%) are male. Patients have received a median of 3 prior systemic therapies and 6 patients have received prior stem cell transplants. Of the 36 patients who have had a response assessment to date, 12 (33%) have achieved an objective response (5 CR, 7 partial remissions [PR]). The ORR for B-cell NHLs is 36% (9/25), and 27% (3/11) for mature T-/NK-cell NHLs. Thus far, responses are particularly noteworthy in DLBCL (excluding PMBL) where 7 of 15 patients (47%) have responded (3 CR, 4 PR), in AITL where 3 of 5 patients (60%) have responded (2 CR, 1 PR), and in grey zone lymphoma where 2 of 5 patients (40%) have achieved a PR. Median duration of response has not been reached. Of the 12 responding patients, 7 remain on treatment, 3 discontinued due to a patient decision (non-adverse event), and 2 due to adverse events of neutropenia (related) and pneumocystis jiroveci pneumonia (unrelated). CD30 expression levels for patients with a CR or PR were widely variable and ranged from <1% to 90%. Treatment-emergent adverse events (TEAEs) occurring in ≥10% of patients include fatigue (26%), diarrhea (16%), nausea (16%), pyrexia (16%), neutropenia (14%), dyspnea (12%), and abdominal pain (10%), and TEAEs considered related to study drug include fatigue (16%) and neutropenia (14%). Most AEs have been Grade 1 or 2. Grade 3 dyspnea, hyponatremia, and decreased white blood cell count have occurred in 2 patients each, while Grade 3 neutropenia has occurred in 3 patients. Two patients have experienced Grade 4 neutropenia. Peripheral neuropathy events have been Grade 1 or 2. Conclusions: In this interim analysis of 53 patients (36 with response evaluations), compelling antitumor activity has been demonstrated in both B-cell and mature T-/NK-cell NHLs, in particular DLBCL, AITL, and grey zone lymphoma. Due to the range of CD30 expression in patients achieving an objective response, more data are needed to determine if there is a correlation between CD30 expression and antitumor activity. Preliminary safety data are consistent with the safety profile of brentuximab vedotin. Disclosures: Jacobsen: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with brentuximab vedotin. Advani:Seattle Genetics, Inc.: 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; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbott: Research Funding. Oki:Seattle Genetics, Inc.: Research Funding. Sharman:Seattle Genetics, Inc.: Research Funding. Horwitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Millennium: Consultancy; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Allos Therapeutics: Consultancy, Research Funding; Merck: Honoraria; Genzyme: Research Funding; Infinity Pharmaceuticals: Research Funding. Forero-Torres:Seattle Geentics, Inc.: Research Funding, Speakers Bureau. O'Connor:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Siddiqi:Seattle Genetics, Inc.: Consultancy, Research Funding. Grove:Seattle Genetics, Inc.: Employment, Equity Ownership. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other.

Download Full-text

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 ◽

10.1182/blood.v122.21.4395.4395 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4395-4395 ◽

Cited By ~ 8

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.

Download Full-text

Poor Outcomes Among Patients Failing Dose-Adjusted EPOCH in Aggressive Lymphoma: A Collaborative, Retrospective Study

Blood ◽

10.1182/blood.v126.23.1518.1518 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1518-1518 ◽

Cited By ~ 1

Author(s):

Jackie Vandermeer ◽

Allison M Winter ◽

Ajay K. Gopal ◽

Ryan D. Cassaday ◽

Brian T. Hill ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

First Line ◽

Advisory Committees ◽

First Line Therapy

Abstract Introduction Among patients with aggressive B-NHL who fail RCHOP, about half respond to standard salvage regimens and may proceed to curative-intent, transplant-based therapy. However, whether pts failing more intensive regimens such as dose-adjusted, infusional EPOCH benefit from standard salvage regimens is unclear. We hypothesized that such patients comprise a higher-risk cohort, facing inferior response rates and outcomes using standard salvage regimens. We undertook a collaborative study to assess response rates and survival among pts failing EPOCH for aggressive B-NHL, to inform patient management and design of clinical trials in this setting. Methods Pharmacy records and institutional databases were queried, identifying pts receiving EPOCH over the last 10 years at the University of Washington/SCCA and the Cleveland Clinic Foundation, for combined analysis. Under IRB approval, patient characteristics, histology, outcome with EPOCH, time to EPOCH failure, response to salvage, and overall survival were analyzed. Diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, B-cell-lymphoma unclassifiable, HIV-associated B cell lymphoma, and transformed B cell non-Hodgkin lymphoma were included. Pts receiving <2 cycles EPOCH, or who had inadequate follow-up (<3 months), were excluded. Failure of EPOCH was defined as failure to respond or progression during therapy, need for initiation of salvage therapy, or death during therapy of any cause. Adverse events or treatment change due to toxicity were not included in the definition of failure. JMP 11 was used to generate kaplan-meier survival estimates. Results 124 pts with aggressive B-NHL receiving EPOCH were identified. 54 had not relapsed, and among 70 remaining da-EPOCH failures, 37 met the above inclusion criteria. Median age was 55. 27% were female, and 23 received EPOCH as first-line therapy. All but 3 received rituximab with EPOCH. Histologies were primarily DLBCL in 22/37 (60%) and BCL-U in 12/37 (32%) carrying a MYC translocation; most of these harbored additional translocations in BCL2 and/or BCL6 (10/12). However, data regarding MYC rearrangement was not available for all pts. 2 had HIV-associated B-NHL and 3 had PMBCL. With 18 months follow up, the median time to EPOCH failure was 5 months. Only 3 EPOCH failures occurred late (>12 months). Median OS from the date of EPOCH failure was 10 months (Figure 1). Those receiving EPOCH as first-line therapy (23) had a median OS of 14 months from EPOCH failure, as opposed to 4 months for those receiving EPOCH as salvage therapy (log-rank p=.01). Salvage chemotherapy regimens after EPOCH were diverse, and generally ineffective; 6/28 (21%) regimens produced a response (Table 1). Among patients failing EPOCH within a year, platinum-containing salvage (RICE/RDHAP) was effective in only 2/13 patients (15%). 9 patients did not receive any salvage, most of whom died or proceeded to palliative measures and/or hospice care. Conclusions A relatively low overall response rate (21%) was observed in this retrospective analysis of patients failing EPOCH. Analogous to early RCHOP failure in the CORAL study, those failing EPOCH within a year may face inferior outcomes with platinum-based salvage therapy. While combined from two institutions, our data represent a modest sample size and require confirmation. If verified, examination of mechanisms of resistance to EPOCH, and selecting EPOCH failures for clinical trials of novel targeted therapies and transplant-based approaches, may prove critical. Table 1. Salvage Therapy for REPOCH failures Regimen: response/total number treated Notes Response to any salvage: 6/28 (21%) Some patients received more than 1 chemo salvage; responses were tabulated per regimen. RICE: 4/12 2/3 alive post transplant(1 auto 1 allo; 1 declined transplant and survived; 1 died) RDHAP: 1/6 Gemcitabine-based: 0/5 HyperCVAD (Part A and/or B): 1/5 Survivor had CNS only relapse, received regimen B and transplant 9- received no systemic treatmen; most died or proceeded to palliative measures and/or hospice Figure 1. Figure 1. Disclosures Gopal: Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Emergent/Abbott: Research Funding; Sanofi-Aventis: Honoraria; Seattle Genetics: Consultancy, Honoraria; BioMarin: Research Funding; Piramal: Research Funding; Janssen: Consultancy; Millenium: Honoraria, Research Funding; BMS: Research Funding; Merck: Research Funding. Hill:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Till:Roche/Genentech: Research Funding; Pfizer: Research Funding.

Download Full-text