Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) + Rituximab: Clinical Activity Including Survival in Patients with Recurrent/Refractory Follicular or ‘Aggressive' Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 584-584 ◽  
Author(s):  
Nam H. Dang ◽  
Mitchell R Smith ◽  
Fritz Offner ◽  
Gregor Verhoef ◽  
Peter Johnson ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Aggressive Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Time To Tumor Progression

Abstract Abstract 584 Background: CMC-544 is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. CMC-544 targets CD22, which is expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The maximum tolerated dose (MTD) for single agent CMC-544 was previously determined to be 1.8 mg/m2administered IV every 28 days, and clinical activity was shown in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Preliminary safety and efficacy data without long-term follow-up on patients with FL and non-refractory DLBCL treated with CMC-544 given in combination with rituximab was previously reported. Objectives: To assess clinical activity of CMC-544 in combination with rituximab in refractory ‘aggressive' NHL and to present long-term follow-up, including progression free survival (PFS) and overall survival (OS) of pts with relapsed FL and DLBCL. Patients and Methods: Patients were eligible if they had CD20+/CD22+ B cell NHL, which had not responded to or progressed after 1 or 2 therapies of probable clinical benefit, including at least 1 regimen containing rituximab. In patients with FL and DLBCL, subjects could have had no more than 2 prior therapies and could not be refractory to rituximab or a rituximab-containing therapy. Patients in the latter part of the study could have DLBCL, mantle cell lymphoma, transformed FL with no limit on number of prior therapies and must have had no response to, or relapse within 6 months of, the first dose of the previous rituximab-containing therapy (refractory ‘aggressive' lymphoma). After a limited dose-escalation to determine the MTD of CMC-544 in combination with rituximab, an expanded cohort at the MTD was conducted. Patients received 375 mg/m2 of rituximab IV on day 1 followed by CMC-544 on day 2 of each 28-day cycle for up to 8 cycles, provided that there was no disease progression. Results: The MTD of CMC-544 given with rituximab was confirmed as the single agent dose of 1.8 mg/m2. Enrollment is complete at 119 patients, with 110 treated with CMC-544 at the MTD of 1.8 mg/m2. Based on 112 patients, median age was 66 y (range: 20-85), 60% were male; 36% had 1 prior chemo/immunotherapy regimen, 46% had 2, and 13% had ≥3; 71% had stage III/IV disease, 38% elevated LDH, and 17% bulky disease (>7.5 cm). Patients with recurrent DLBCL were generally older, with a median age of 72 y and were thus deemed inappropriate for high-dose therapy. The most common treatment-emergent adverse events (AEs), all grades, were nausea (48%), thrombocytopenia (46%), fatigue (44%), and increased aspartate aminotransferase (AST) (34%). AEs resulting in discontinuation from treatment were most commonly hematologic AEs or elevation of ≥1 liver function test. Median follow-up is approximately 14.5 months, 10.3 months, and 2.5 months for patients with FL, recurrent DLBCL, and refractory ‘aggressive' lymphoma, respectively. The 1-year OS rate was 97% for FL and 77% for patients with recurrent DLBCL. Patients with FL (n=38) had an objective response rate (ORR) of 87%, with a median PFS of 23.6 months. Patients with relapsed DLBCL (n=40) had an ORR of 80%, with a median PFS of 15.1 months while in the rituximab-refractory pt arm (n=25) the response rate was much lower at 20%, with a median PFS of only 2 months. One year PFS was 84% for FL and 53% for recurrent DLBCL. The lower response rates and PFS in the refractory subgroup are consistent with the poor prognosis of patients with refractory 'aggressive' lymphoma. PFS in DLBCL (either de novo or from transformed follicular) with 1-2 prior therapies based on time-to-tumor progression was also analyzed. DLBCL patients with a prior time to tumor progression of less than 1 year (n=19) had an ORR of 47% (21% CR/CRu), with a median PFS of 4.3 months while DLBCL patients with a prior time to tumor progression of greater than 1 year (n=28) had an ORR of 79% (50% CR/CRu) and a median PFS of 15.1 months. Conclusion: The combination of inotuzumab ozogamicin (CMC-544) plus rituximab has a safety profile similar to that previously reported for CMC-544 alone, with hematologic, gastrointestinal, and hepatic AEs being the main toxicities. The response rates and PFS results indicate promising efficacy in patients with recurrent/refractory FL and DLBCL, These results, particularly in patients with follicular lymphoma and recurrent DLBCL, support continued clinical development of this regimen. Disclosures: Dang: Wyeth Research: Consultancy; Genentech: Consultancy, Honoraria, Speakers Bureau; Biogen: Consultancy, Speakers Bureau. Smith:Millennium: Research Funding; Genentech: Research Funding; Wyeth Research: Consultancy, Research Funding. Johnson:Wyeth Research: Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Genzyme: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding. Coiffier:Wyeth Research: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Wyeth Research: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Foran:Wyeth Research: Research Funding. Hua:Wyeth Research: Employment. Vandendries:Wyeth Research: Employment, Equity Ownership. Fayad:Wyeth Research: Consultancy, Research Funding.

Phase IIa Study of Single-Agent MOR208 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1528-1528 ◽  
Author(s):  
Wojciech Jurczak ◽  
Pier Luigi Zinzani ◽  
Gianluca Gaidano ◽  
Andre Goy ◽  
Mariano Provencio ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Hodgkin's Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Cd20 Antibody ◽  
Grade 3

Abstract Introduction: There remains a high unmet medical need for new therapies for patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is a B-lymphocyte, lineage-specific surface antigen that is highly expressed by most B-cell NHLs. CD19 expression is maintained on lymphoma cells which have CD20 expression downregulated following treatment with the CD20 antibody, rituximab. Consequently, MOR208 (XmAb5574; MOR00208), an Fc-engineered, humanized, monoclonal antibody that targets CD19, may have clinical utility as a new therapeutic approach to R-R NHL. A phase I study showed MOR208 to be safe and well-tolerated with encouraging single-agent activity in patients with chronic lymphocytic leukemia (CLL); an intravenous dose of 12 mg/kg was recommended for phase II studies. Methods: This is a non-randomized, open-label, multicenter, two-stage, phase IIa study of MOR208 in adult patients with R-R NHL whose disease had progressed after at least one prior therapy containing the CD20 antibody, rituximab. In stage 1, 10 patients were to be enrolled into each of four NHL subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent NHL (iNHL) and mantle cell lymphoma (MCL). Patients were to receive single-agent MOR208, 12 mg/kg intravenously, weekly, for 8 weeks (2 cycles). Those with at least stable disease by the 2007 International Response Criteria could continue MOR208 treatment for an additional 4 weeks (total of 12 weeks of therapy). Patients with a complete or partial response (CR or PR) after 12 weeks could then receive MOR208 as maintenance therapy, every 2 or 4 weeks depending on the investigator's decision, until progression. In stage 2, cohorts with ≥2 responses (CR or PR) were to be expanded by at least 20 additional patients. The primary endpoint was the overall response rate (ORR). Key secondary endpoints included duration of response, safety, immunogenicity of MOR208, pharmacokinetics and pharmacodynamics. Results: The DLBCL and FL cohorts were expanded (to N=35 and N=34 patients, respectively), leading to a total enrollment of 92 patients: 56 (61%) were male; median age was 66.5 (range 35-90) years; 80 (87%) had stage III-IV disease; 41 (45%) had received ≥3 prior lines of therapy and 10 (11%) had received a prior stem-cell transplant. The investigator-assessed ORR across all NHL subtypes was 23% (21/92 patients; 16 not evaluable at cutoff) with clinical activity seen in the DLBCL (26% [9/35]; 2 CR, 7 PR); FL (26% [9/34]; 3 CR, 6 PR) and iNHL (27% [3/11]; 2 CR, 1 PR) cohorts (MCL, 0/12 responses). The iNHL cohort was not expanded as the response pattern in this subgroup was heterogeneous according to lymphoma subtype. The longest durations of response recorded to date are 15.4 months for FL and 14.2 months for DLBCL (both ongoing). Grade ≥3 non-hematologic and hematologic treatment-emergent adverse events (TEAEs) were recorded in 24 (26%) and 14 (15%) of 92 patients, respectively. The most commonly reported grade ≥3 hematologic TEAEs were neutropenia (7 [8%] of 92 patients, anemia (4 [4%]), and thrombocytopenia (4 [4%]); such TEAEs were seen most frequently in the DLBCL cohort (10 [29%] of 35 patients overall; neutropenia, 5 [14%], anemia, 4 [11%], thrombocytopenia, 2 [6%]). Dyspnea was the most commonly reported grade ≥3 non-hematologic TEAE (4 [4%] of 92 patients). Infusion-related reactions were seen in 9 (10%) of 92 patients; all were grade 1-2, except for one case of dyspnea, grade 4. There were no treatment-related deaths. Clinical activity in patients with R-R DLBCL appeared to be dependent on attaining a defined cumulative exposure (AUC0-t) over 8 weeks of around 11,000 day*µg/mL; i.e., at the data cutoff date, all 8 patients with a PR after 2 cycles showed an exposure above this potential threshold level. Conclusions: MOR208 demonstrated encouraging single-agent activity with CRs observed in patients with R-R DLBCL, FL, and iNHL. MOR208 was well tolerated without significant infusional toxicity. These data support further development of MOR208 in combination with other agents (including lenalidomide and bendamustine), and protocols for studies in patients with R-R DLBCL are now being developed. Disclosures Jurczak: CELLTRION, Inc,: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gaidano:Celgene: Research Funding; MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards. Goy:Celgene: Consultancy, Research Funding, Speakers Bureau; Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Maddocks:Novartis: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Research Funding. Buske:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy. Korolkiewicz:MorphoSys AG: Employment. Striebel:MorphoSys AG: Employment. Blum:Morphosys: Research Funding; Gilead: Research Funding; Millenium: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene: Research Funding.

scholarly journals Belantamab Mafadotin in Patients with Relapsed/Refractory AL Amyloidosis with Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1670-1670
Author(s):  
Yifei Zhang ◽  
Amandeep Godara ◽  
Stacey Pan ◽  
Denis Toskic ◽  
Teresa Fogaren ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Response Rates ◽  
Cardiac Response ◽  
Clinical Activity ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Renal Response

Abstract Introduction: Daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (Dara/CyBorD) is the only FDA approved therapy for newly diagnosed systemic light-chain (AL) amyloidosis (N Engl J Med 2021;385:46). Belantamab mafodotin is a novel anti-BCMA immunoconjugate with humanized IgG1 anti-BCMA monoclonal antibody conjugated to a microtubule-disrupting agent, monomehtyl auristatin F (MMAF) via a non-cleavable linker (Blood 2014;123:3128). Phase I/II studies in heavily pre-treated multiple myeloma patients showed single agent clinical activity with overall response rates ranging from 30-60%, with majority of responses being durable at 13 months of follow-up. Toxicity profile included keratopathy, thrombocytopenia and anemia (Blood Cancer J 2019;9:37; Lancet Oncol 2020;21:207). Based on these results, belantamab mafadotin (BLM; Blenrep) was FDA approved for relapsed myeloma. A role for new agents such as BLM in AL has not been previously reported. Here we report outcomes of six patients who received BLM at different centers for relapsed refractory (RR) AL associated with myeloma. Methods: In this retrospective study we identified AL patients with RR disease who received at least one dose of BLM. In a multi-institutional collaboration we collected demographic, medical history, laboratory, pathologic and treatment/response data on patients with myeloma and biopsy-proven AL who had received BLM. Laboratory assessment including evaluations for hematologic and organ response was done as per standard criteria and toxicity assessed as per CTCAE v6.0. Results: We identified 6 patients, 3M/3F, from 4 centers; baseline characteristics and treatment data are provided in Table 1. Baseline median age was 61 years (range, 51-74) and median marrow plasmacytosis and iFLC were 40% (10-90) and 868mg/L (145-5324). Four patients had AL λ-type and 2 κ-type, and 5 of 6 had cardiac involvement while 3 had additional organ involvement (renal, GI, nervous system). Prior to initiating BLM the median number of lines of prior therapy was 6 (range, 5-10), including daratumumab, bortezomib and lenalidomide, and prior to initiating BLM marrow assessment showed a median plasmacytosis of 23%. BLM at 2.5 mg/kg was given as an intravenous infusion over the course of 30 minutes every three weeks after ophthalmologic exam clearance until discontinuation for progression or toxicity. At a median follow-up of 4.5 months, 5 patients (83%) achieved hematological responses (HR) with 3 (50%) achieving complete hematological responses (CR) by standard criteria (J Clin Oncol 2012;30:4541). Time to HR ranged from 3 to 150 days. Cardiac response was seen in all but 1 patient, with time to response ranging from 11 to 96 days. One patient had a renal response; response assessment is not yet available for 2 other patients with renal involvement. The most common toxicity was keratopathy (grade 1-2). BLM was held after the first dose in one patient who had been heavily pre-treated and had extensive cardiac and pulmonary AL and multiple sites of FDG-avid progressive myeloma bone disease. Two days after administration of the first dose of BLM, this 51-year-old man was admitted to hospital for dyspnea, developed atrial fibrillation and ventricular tachycardia, and briefly required cardiac resuscitation without intubation with return of spontaneous circulation after 6 minutes. This patient achieved a CR after one dose of BLM that has been stable for over 5 months with marked clinical improvement. A 62 year-old woman with cardiac and renal AL has achieved a CR durable for over 16 months with cardiac and renal responses. Conclusions: In this group of 6 patients with RR AL with myeloma, HR and cardiac response rates were impressive at 83% and 80%, respectively. One patient who had 24-hour urine protein evaluation also achieved a renal response. Time to response was rapid with 2 patients achieving HR within a week of starting treatment, and the rest within five months. Additionally, 3 of 6 patients achieved CR, 1 had no clonal plasma cells in the marrow and another clonal disease detectable only by MRD. In this retrospective multi-institutional cohort BLM resulted in rapid reduction of iFLC and induced critical organ responses. These data provide preliminary evidence for the clinical activity of BLM in RR AL. Results of the on-going phase 2 clinical trial in the European Myeloma Network (EMN27; NCT04617925) are awaited with great interest. Figure 1 Figure 1. Disclosures Sborov: Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; SkylineDx: Consultancy. Comenzo: Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Consultancy, Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding. Kansagra: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Cota Health: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Alynylam: Membership on an entity's Board of Directors or advisory committees.

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.

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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1518-1518 ◽  
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.

Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 233-233 ◽  
Author(s):  
Susan M. O'Brien ◽  
Richard R. Furman ◽  
Steven E. Coutre ◽  
Ian W. Flinn ◽  
Jan Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Over Time

Abstract Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton's tyrosine kinase inhibitor, is approved by the US FDA for treatment of patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including pts with del17p. The phase 1b/2 PCYC-1102 trial showed single-agent efficacy and tolerability in treatment-naïve (TN; O'Brien, Lancet Oncol 2014) and relapsed/refractory (R/R) CLL/SLL (Byrd, N Engl J Med 2013). We report efficacy and safety results of the longest follow-up to date for ibr-treated pts. Methods: Pts received 420 or 840 mg ibr QD until disease progression (PD) or unacceptable toxicity. Overall response rate (ORR) including partial response (PR) with lymphocytosis (PR-L) was assessed using updated iwCLL criteria. Responses were assessed by risk groups: unmutated IGVH, complex karyotype (CK; ≥3 unrelated chromosomal abnormalities by stimulated cytogenetics assessed by a reference lab), and in hierarchical order for del17p, then del11q. In the long-term extension study PCYC-1103, grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation were collected. Results: Median age of the 132 pts with CLL/SLL (31 TN, 101 R/R) was 68 y (range, 37-84) with 43% ≥70 y. Baseline CK was observed in 41/112 (37%) of pts. Among R/R pts, 34 (34%) had del17p, 35 (35%) del11q, and 79 (78%) unmutated IGVH. R/R pts had a median of 4 prior therapies (range, 1-12). Median time on study was 46 m (range, 0-67) for all-treated pts, 60 m (range, 0-67.4) for TN pts, and 39 m (range, 0-67) for R/R pts. The ORR (per investigator) was 86% (complete response [CR], 14%) for all-treated pts (TN: 84% [CR, 29%], R/R: 86% [CR, 10%]). Median progression-free survival (PFS) was not reached (NR) for TN and 52 m for R/R pts with 60 m estimated PFS rates of 92% and 43%, respectively (Figure 1). In R/R pts, median PFS was 55 m (95% confidence intervals [CI], 31-not estimable [NE]) for pts with del11q, 26 m (95% CI,18-37) for pts with del17p, and NR (95% CI, 40-NE) for pts without del17p, del11q, trisomy 12, or del13q. Median PFS was 33 m (95% CI, 22-NE) and NR for pts with and without CK, and 43 m (95% CI, 32-NE) and 63 m (95% CI, 7-NE) for pts with unmutated and mutated IGVH, respectively(Figure 2). Among R/R pts, median PFS was 63 m (95% CI, 37-NE) for pts with 1-2 prior regimens (n=27, 3 pts with 1 prior therapy) and 59 m (95% CI, 22-NE) and 39 m (95% CI, 26-NE) for pts with 3 and ≥4 prior regimens, respectively. Median duration of response was NR for TN pts and 45 m for R/R pts. Pts estimated to be alive at 60 m were: TN, 92%; all R/R, 57%; R/R del17p, 32%; R/R del 11q, 61%; R/R unmutated IGVH, 55%. Among all treated pts, onset of grade ≥3 treatment-emergent AEs was highest in the first year and decreased during subsequent years. With about 5 years of follow-up, the most frequent grade ≥3 AEs were hypertension (26%), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%). Study treatment was discontinued due to AEs in 27 pts (20%) and disease progression in 34 pts (26%). Of all treated pts, 38% remain on ibr treatment on study including 65% of TN pts and 30% of R/R pts. Conclusions: Single-agent ibrutinib continues to show durable responses in pts with TN or R/R CLL/SLL including those with del17p, del11q, or unmutated IGVH. With extended treatment, CRs were observed in 29% of TN and 10% of R/R pts, having evolved over time. Ibrutinib provided better PFS outcomes if administered earlier in therapy than in the third-line or beyond. Those without CK experienced more favorable PFS and OS than those with CK. Ibrutinib was well tolerated with the onset of AEs decreasing over time, allowing for extended dosing for 65% of TN and 30% of R/R pts who continue treatment. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Coutre:Janssen: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Burger:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses. Sharman:Gilead: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Wierda:Abbvie: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Jones:Janssen: 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; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luan:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Chu:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership.

scholarly journals A Phase II Trial of Nivolumab and Ibrutinib for Patients with Relapsed or Refractory Central Nervous System Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4086-4086
Author(s):  
Jason R. Westin ◽  
Nathan H. Fowler ◽  
Loretta J. Nastoupil ◽  
Sattva S Neelapu ◽  
Hun Ju Lee ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Advisory Board ◽  
Cns Lymphoma ◽  
Advisory Committees

Background: Central Nervous System (CNS) lymphoma is a rare and distinct subtype of diffuse large B-cell lymphoma (DLBCL). CNS lymphoma has a unique genomic profile which has similarities to the activated B-cell (ABC) subtype of DLBCL, which may speak to potential targets for therapy. These aberrancies include near uniform reliance on Toll-Like Receptor signaling, mutations of MYD88, and frequent translocation or copy number alterations of 9p24 which codes for programmed death receptor ligand 1 (PD-L1). Mutations of MYD88 may predict for response to Bruton's tyrosine kinase (BTK) inhibitors in patients with systemic DLBCL. Expression of PD1 or PD-L1, which corresponds to response with PD-targeted therapy in solid tumors, has been found on up to 90% of CNS lymphoma cases, and 60% of specimens had tumor infiltrating lymphocytes which were PD1+ (Berghoff, Clin Neuropath 2014). In addition, the majority of CNS lymphoma cases have a copy gain of 9p24.1, associated with increased expression of PD-L1 (Chapuy, Blood 2016). This suggests a potential ongoing immune reaction against CNS lymphoma, but the microenvironment and tumor conspire to render the immune response ineffective. Ibrutinib is a BTK inhibitor which is FDA approved for multiple B-cell malignancies and is known to achieve therapeutic concentration in the cerebral spinal fluid (CSF), with activity in CNS lymphoma as a single agent and in combination with other agents. Nivolumab is a PD1 inhibitor which is FDA approved for multiple malignancies, with impressive anecdotal evidence of single agent activity in CNS lymphoma. Ibrutinib and nivolumab have been combined in other studies with modest toxicities. Study Design and Methods: We are conducting a phase II, open label, single center clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Patients are eligible if they have CNS lymphoma relapsed after or were refractory to at least 1 prior line of therapy with adequate organ and bone marrow function, are aged 18y or greater, have not received prior ibrutinib or PD1 inhibitor, and do not require persistent high dose steroids. The trial has two cohorts which will be sequentially enrolled. Cohort A begins with ibrutinib 560mg oral daily for a single 28-day cycle, followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B begins with the ibrutinib and nivolumab combination during the first cycle. Patients who have at least a partial response at the conclusion of the planned 6 cycles of combined ibrutinib and nivolumab may continue therapy for up to 2 years total or until progression of disease or unacceptable toxicity occurs. Neurocognitive assays and patient reported outcome instruments are being utilized. The primary objective is to determine the best overall response rate during the first 24 weeks of therapy. Secondary objectives will include the response rate of ibrutinib as a lead in prior to the combination, the complete response rate, landmark survival outcomes, and the safety of the combination. Exploratory analyses include assays of the blood and CSF for ctDNA and immune profiling. The first patient was treated in February 2019, with a planned total of 40 patients to be enrolled. Disclosures Westin: MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Bayer: Honoraria. Neelapu:Allogene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Karus: Research Funding; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Poseida: Research Funding; Merck: Consultancy, Research Funding; Cellectis: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: ibrutinib and nivolumab are not yet indicated for CNS lymphoma

scholarly journals First-in-Human, Phase 1/2 Trial to Assess the Safety and Clinical Activity of Subcutaneous GEN3013 (DuoBody®-CD3×CD20) in B-Cell Non-Hodgkin Lymphomas

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 758-758 ◽  
Author(s):  
Pieternella Lugtenburg ◽  
Rogier Mous ◽  
Michael Roost Clausen ◽  
Martine E.D. Chamuleau ◽  
Peter Johnson ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Clinical Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Introduction: CD20-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the treatment of B-cell non-Hodgkin lymphomas (B-NHL); however, a significant proportion of patients (pts) present with refractory disease or will experience relapse. GEN3013 (DuoBody®-CD3×CD20) is the first subcutaneously administered IgG1 bispecific antibody (bsAb) that targets the T-cell surface antigen CD3 and the B-cell surface antigen CD20, triggering T-cell-mediated killing of B cells. In vitro, GEN3013 efficiently activates and induces cytotoxic activity of CD4+ and CD8+ T cells in the presence of B cells (Hiemstra et al. Blood 2018), and results in long-lasting depletion of B cells in cynomolgus monkeys. Subcutaneous (SC) GEN3013 in cynomolgus monkeys resulted in lower plasma cytokine levels, and similar bioavailability and B-cell depletion, compared with intravenous administration. GEN3013 has higher potency in vitro than most other CD3×CD20 bsAbs in clinical development (Hiemstra et al. HemaSphere 2019). SC GEN3013 in pts with B-NHL is being evaluated in a first-in-human, Phase 1/2 trial (NCT03625037), which comprises a dose-escalation part and a dose-expansion part. Here we report preliminary dose-escalation data. Methods: Pts with CD20+ B-NHL with relapsed, progressive, or refractory disease following anti-CD20 mAb treatment, and ECOG PS 0-2 were included. During dose escalation, pts received SC GEN3013 flat dose in 28-day cycles (q1w: cycle 1-2; q2w: cycle 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Risk of cytokine release syndrome (CRS) was mitigated with the use of a priming dose and premedication with corticosteroids, antihistamines, and antipyretics. Primary endpoints were adverse events (AEs) and dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics (PK), immunogenicity (anti-drug antibodies [ADA]), pharmacodynamics (PD) (cytokine measures; laboratory parameters), and anti-tumor activity (tumor size reduction; objective and best response). Results: At data cut-off (June 28, 2019), 18 pts were enrolled into the dose-escalation part of the trial, with safety data available for pts receiving doses starting at 4 µg. Most pts had diffuse large B-cell lymphoma (DLBCL; n=14) and were heavily pre-treated; 10 pts had received ≥3 prior lines of therapy (overall median [range]: 3 [1-11]). The median age was 58.5 years (range: 21-80), and 13 pts were male. At a median follow-up of 1.9 months, pts received a median of 5 doses (range: 1-14); treatment is ongoing in 6 pts. Twelve pts discontinued treatment due to progressive disease. Six pts died (2 during treatment, 4 during survival follow-up), all due to disease progression and unrelated to treatment. The most common (n≥5) treatment-emergent AEs were pyrexia (n=8), local injection-site reactions (n=7), diarrhea (n=5), fatigue (n=5), and increased aspartate aminotransferase (n=5). The most common Grade (G) 3/4 AEs were anemia (n=3) and neutropenia (n=3). Despite increasing GEN3013 doses, all CRS events were non-severe (initial observation: 3/8 pts, G1: n=1, G2: n=2; following modification of premedication plan [corticosteroids for 3 days]: 6/10 pts, G1: n=4, G2: n=2). Increases in peripheral cytokine (IL6, IL8, IL10, IFNγ, TNFα) concentrations after GEN3013 dosing correlated with clinical symptoms of CRS in most pts. No pts had tumor lysis syndrome or neurological symptoms. No DLTs were observed. GEN3013 PK profiles reflect SC dosing; Cmax occurred 2-4 days after dosing. No ADAs were detected. PD effects following GEN3013 dosing were observed at dose levels as low as 40 µg and included rapid, complete depletion of circulating B cells (if present after prior anti-CD20 therapy) and peripheral T-cell activation and expansion. The first evidence of clinical activity was observed at a dose level of 120 µg, with complete metabolic response observed in a pt with DLBCL. Conclusions: Subcutaneously administered GEN3013, a potent CD3×CD20 bsAb, shows good tolerability and early evidence of clinical activity at low dose levels in heavily pretreated pts with relapsed or refractory B-NHL. All CRS events were non-severe and did not lead to discontinuation. No DLTs were observed. Dose escalation is ongoing; updated data will be presented. Dose expansion will begin upon determining the recommended Phase 2 dose (RP2D) (NCT03625037). Disclosures Lugtenburg: Janssen Cilag: Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria, Research Funding. Mous:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; MSD: Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Clausen:Abbvie: Other: Travel grant to attend ASH 2019. Johnson:Boehringer Ingelheim: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Epizyme: Honoraria, Research Funding; Incyte: Honoraria; Takeda: Honoraria; Genmab: Honoraria; Bristol-Myers Squibb: Honoraria; Kite: Honoraria; Novartis: Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy. Oliveri:Genmab: Employment, Equity Ownership. DeMarco:Genmab: Employment, Equity Ownership. Hiemstra:Genmab: Employment, Equity Ownership, Other: Warrants. Chen:Genmab: Employment. Azaryan:Genmab: Employment. Gupta:Genmab: Employment, Equity Ownership. Ahmadi:Genmab Inc: Employment, Other: stock and/or warrants. Hutchings:Incyte: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Research Funding; Pfizer: Research Funding.

scholarly journals Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4457-4457 ◽  
Author(s):  
Franck Morschhauser ◽  
Ian Flinn ◽  
Ranjana H Advani ◽  
Catherine S. Diefenbach ◽  
Kathryn Kolibaba ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Grade 5 ◽  
Grade 3

Abstract Background: Previously reported results from an ongoing study of polatuzumab vedotin (PoV) and pinatuzumab vedotin (PiV), antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in combination with rituximab (R) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Here we report updated results of ADC + R at the RP2D of 2.4 mg/kg and initial results of PoV + R in r/r FL at the PoV dose of 1.8 mg/kg. Methods: Pts were randomized to receive PoV or PiV + R (ADC 2.4 mg/kg + R 375 mg/m2). In a separate non-randomized cohort (Cohort C), r/r FL pts were treated with PoV (1.8 mg/kg) + R. ADC + R was given every 21 days. Tumor assessments were performed every 3 months. Results: As of 21 February 2014, 59 pts received PoV + R (39 DLBCL; 20 FL), 63 PiV + R (42 DLBCL; 21 FL); 20 r/r FL pts were treated in Cohort C. Median time of follow-up was 10 mo. for PoV + R, 9 mo. for PiV + R, and 5 mo. for Cohort C. Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced among the randomized treatment (tx) arms, median prior therapies in Cohort C was 2 (1-13); overall 44% were R refractory. Median tx cycles in DLBCL: 6 PoV (range 1-16) and 7 PiV (1-15); FL: 10 PoV (3-17), 7 PiV (1-14), and 6 Cohort C (2-10). Overall safety profiles of both regimens in the randomized arms receiving 2.4 mg/kg ADC were similar. The most common tx-emergent adverse events (AE) ≥25%: fatigue (55%), diarrhea (43%), nausea (37%), peripheral neuropathy (PN) (39%), neutropenia (27%), constipation (26%), sensory PN (25%), and decreased appetite (25%). Grade ≥ 3 AE >3%: neutropenia (24%), diarrhea (6%), dyspnea (5%), febrile neutropenia (4%), hyperglycemia (4%), fatigue (3%), and thrombocytopenia (3%). Serious AEs were reported in 43% and 36% of PiV and PoV treated pts, respectively. Discontinuation of study treatment for AE was reported in 49% and 41% of PiV and PoV treated pts, respectively. Thirty-five pts discontinued treatment due to PN with a median time to discontinuation of 5.6 mo. PN reversibility was observed following treatment interruptions and ADC dose modifications. Two of 9 Grade 5 AEs (sepsis, urosepsis) were attributed to CD22 ADC; no Grade 5 AEs were attributed to CD79b ADC. In Cohort C the most common tx-emergent AE ≥ 25%: fatigue (55%), nausea (45%), neutropenia (40%), sensory PN (30%), diarrhea (25%), constipation (25%) and pyrexia (25%). Grade ≥ 3 neutropenia was reported in 7 pts; no other Grade ≥ 3 AE was reported in >1 pt. Serious AE were reported in 5 pts. Two pts discontinued study treatment for AE. No Grade 5 AEs were reported. Overall response rate (ORR), complete (CR) and partial (PR) response rates, n (%) [95% CI], and median PFS in DLBCL (95% CI) are shown in the table. Median PFS in the FL cohorts are not reported due to insufficient follow-up duration. Table PoV (CD79b) + R PiV (CD22) + R PoV [1.8 mg/kg] + R (Cohort C) R/R DLBCL ORR CR PR mPFS (mo.) N=39 22 (56%) [41, 71] 6 (15%) [7, 30] 16 (41%) [26, 58] 5.4 (2.8-8.4) N=42 24 (57%) [41, 72] 10 (24%) [12, 39] 14 (33%) [20, 48] 5.2 (4.1-NR) N/A R/R FL ORR CR PR N=20 14 (70%) [47, 86] 8 (40%) [21, 64] 6 (30%) [14, 53] N=21 13 (62%) [40, 80] 2 (10%) [2, 30] 11 (52%) [30, 72] N=16 7 (44%) [20, 70] 0 7 (44%) [20, 70] Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation. Pts receiving PoV at 1.8 mg/kg had proportionately lower exposure of antibody conjugated MMAE compared to pts treated at the 2.4 mg/kg dose level. Conclusions: PoV and PiV + R were generally well-tolerated with similar toxicity profiles. Neutropenia, PN, and diarrhea were the principal toxicities. Similar efficacy was observed with both ADCs in heavily pretreated pts with DLBCL. The higher CR rate with PoV + R compared to PiV + R suggests greater clinical activity in r/r FL. Lower overall response rates were observed in r/r FL pts treated with a lower dose of PoV. Results based on longer follow-up to further assess differences in safety and tolerability between the two PoV doses in r/r FL will be presented. Additional data of pts who received crossover ADC + R treatment following documented disease progression on initial ADC + R treatment will also be presented. Combination studies of PoV + R with chemotherapy and with ADC schedules to reduce PN are ongoing or in planning. Disclosures Morschhauser: Genentech/roche: Honoraria, travel grants Other; Celgene: advisory boards, advisory boards Other, Honoraria. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Flinn:Genentech, inc.: Research Funding. Advani:Genentech, inc.: Research Funding. Diefenbach:Genentech, inc.: Research Funding. Press:Genentech, inc.: Research Funding. Chen:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Salles:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tilly:Genentech, inc.: Research Funding. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Assouline:Roche: Honoraria, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hagenbeek:millenium: Membership on an entity's Board of Directors or advisory committees. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Yalamanchili:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Sharman:Gen: Research Funding.

scholarly journals IgM-Gammopathies Transformed into Aggressive Lymphoma: Incidence, Basal Clinical Features and Outcome of a Registry Based, Spanish Retrospective Series

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4011-4011
Author(s):  
Irene Dogliotti ◽  
Cristina Jiménez ◽  
Federica Cavallo ◽  
Noemi Puig ◽  
Gian Maria Zaccaria ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Board Of Directors ◽  
B Lymphocytes ◽  
Clinical Features ◽  
Research Funding ◽  
Initial Diagnosis ◽  
Aggressive Lymphoma ◽  
Advisory Committees ◽  
Histological Transformation

Background Transformation into aggressive lymphoma (AL) is a rare complication of indolent lymphoproliferative disorders (LPDs) and is characterized by poor outcome. Immunoglobulin M (IgM) gammopathies are a spectrum of conditions, from monoclonal gammopathy of undetermined significance (MGUS) to Asymptomatic Waldenstroem Macroglobulinemia (AWM) and Symptomatic WM (SWM) that can eventually evolve to transformed WM (tWM). Actually, tWM represents a clinical challenge, mainly because of its poor characterization. Aims This registry study aims to better characterize tWM, focusing on prognostic factors heralding transformation to AL. Methods Two registries of IgM-MGUS, AWM and SWM [Owen, Semin Oncol 2003] based in Salamanca and in the region of Castilla and Leon (Spain) were investigated to identify cases with histological transformation. IgM-secreting patients with other LPDs (e.g. chronic lymphocytic leukemia, marginal zone lymphoma, IgM-multiple myeloma) were excluded from the analysis. All patients provided written informed consent in accordance to Helsinki's declaration. Statistical analysis was carried out using R v 3.3.3. tool; survival analyses were performed with Log-Rank method, while group comparison was performed with t-student for continuous variables and Chi-square tests for categorical variables. Results Data from 903 patients with IgM-secreting disorders diagnosed between 1976 and 2019 were analyzed; 587 cases with confirmed diagnosis of IgM-MGUS, AWM or SWM were selected. Out of 587 IgM-gammopathies, 22 cases with histological transformation to AL were identified. Cumulative incidence of tWM was: 1.4% at 5, 3.4% at 10 and 5.3% at 12 years, respectively (figure 1). Clinical features at first diagnosis of patients subsequently developing tWM where then analyzed: 3/22 tWM evolved from previous IgM-MGUS, while the remaining patients originally presented with AWM (6/22) or SWM (13/22). IPSS-WM prognostic score was LR for 5, IR for 12 and HR for 3/20 patients, respectively [Morel, Blood 2009]. Glancing on distributions between groups according to the outcome, tWM differed from not transformed (NT) cases for: lower median age at diagnosis (66 vs 72 years, p=0.018), lower platelets levels (median 188 vs 235 x 10^9/mmc, p=0.017), higher LDH ratio (0.8 vs 0.67, p=0.015), higher incidence of chromosome 6q deletion by FISH (40 vs 14%, p=0.021) and higher clonal B lymphocytes infiltration on marrow aspirate by flow cytometry (15 vs 4.5%, p= 0.022). Moreover, 13/22 patients received anti-WM treatment within 3 months from initial diagnosis, mainly chlorambucil-based; 5/22 patients received rituximab in first line and 13 in second line. From the whole series, after a median follow-up of 80 months, median transformation-free survival was 61 months from initial diagnosis (range: 0-228). Among these, Only 1/22 of tWM patient is still alive; 19/21 deaths were thus related to AL/WM, with a median survival after transformation of 12 months (0-53). In the whole series (n=587), median OS from initial diagnosis of IgM gammopathy was 76 months for the tWM group (6-225), that is shorter than the NT group (128 months, p=0.012, figure 2). Focusing only on patients treated at initial diagnosis, median survival after first treatment (SAFTI) was 62 vs 90 months for tWM vs NT (p=0.011, figure 3), and median time to next treatment was 28 vs 46 months, respectively (p=0.13). Overall, 10/22 tWM patients received ≥3 treatment lines, and median number of lines prior to transformation was 2 (0-3). Finally, in the whole series IPSS-WM score at diagnosis confirmed to impact on survival (median OS=151, 119 and 56 months for LR, IR and HR groups, respectively, p <0.001). However, this was not the case for tWM cases only, where OS was no longer different between groups. Conclusions In this retrospective study, we confirmed dismal outcome for tWM patients; incidence of transformation was comparable to expectations at 5 years, but higher at subsequent follow-up. At initial diagnosis of IgM gammopathy, younger age, low platelets level, high LDH ratio, high B lymphocytes infiltration by flow cytometry and presence of 6q deletion were significantly enriched among patients subsequently developing tWM. IPSS-WM score looked less predictive among tWM patients probably given to the limited numbers of tWM series. Novel prognostic tools are eagerly awaited for tWM patients. Figure Disclosures Cavallo: Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Puig:The Binding Site: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria. Ferrero:Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document