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In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 10160-10162

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157347

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

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In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1744-1744

Abstract: Background Entospletinib (GS-9973) is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk). Syk is a mediator of B-cell receptor signaling in normal and transformed B-cells. Targeting the B-cell receptor (BCR) signaling pathway has been a successful therapeutic strategy for chronic lymphocytic leukemia (CLL), with both ibrutinib, an inhibitor of BTK (BTKi) and idelalisib, an inhibitor of PI3Kdelta (PI3Ki), approved for this indication. Entospletinib activity in CLL was recently reported, and preclinical data suggested that entospletinib may be effective even in the context of resistance to BTK therapy, including that conferred by activation of PLCγ2. (Liu, Blood -2015-02-626846) Methods GS-US-339-0102 is an ongoing phase2 trial of entospletinib in CLL and NHL (NCT01799889). The study protocol was amended to add 40 patients in each of 2 CLL cohorts who have been previously treated with BCR signaling pathway (BTK/PI3K) inhibitors. These patients were treated with entospletinib monotherapy (400mg BID) and evaluated using modified Hallek/IWG-CLL criteria every 2-3 months as previously described in Sharman, Blood 2015:125(5). Results As of July 20, 2015, 8 patients with preceding BCR pathway signaling inhibitor treatment have been enrolled, 5 with preceding BTKi therapy (4 with ibrutinib, 1 with AVL-292) and 3 with preceding PI3Ki therapy (idelalisib). The median duration of preceding BTKi treatment was 51 weeks (range 2-85 weeks) and the median duration of preceding PI3Ki treatment was 106 weeks (range 74-168 weeks). Two patients had progressed on prior BTKi and 2 were intolerant (cause missing for 1 patient), while 2 patients progressed on PI3Ki and 1 was intolerant. All 5 patients with preceding BTKi and 2 out of 3 patients with prior PI3Ki remain on entospletinib treatment. Of the 5 patients who were previously treated with BTKi, the ongoing duration of treatment with entospletinib is 8, 8, 13, 25, and 39 weeks. For the 3 patients with preceding PI3Ki, two patients have ongoing treatment of 18 and 26 weeks; one patient stopped treatment and died after 23 weeks due to a cardiac arrest that is not believed to be related to the study drug. The most common treatment-emergent AEs (N=number; any Grade/≥Gr 3, independent of causality) were decreased appetite (3/0), contusion (2/0), dyspepsia (2/0), fatigue (2/0), dehydration (1/1), cardiac arrest (1/1); common laboratory abnormalities were anemia (5/1), neutropenia (4/1), thrombocytopenia (3/2), increased lipase (1/1). Early responses were seen with entospletinib treatment (3 partial response (PR), 1 stable disease, & 3 patients were too early to evaluate) and 1 PD. PR occurred in 1 BTKi and 2 PI3Ki previously treated patients. One patient with preceding PI3Ki developed progressive disease after 8 weeks. Conclusions Early experience from this trial with ongoing enrollment demonstrates that entospletinib has clinical activity following therapy with either BTKi or PI3Ki. No additional safety signals were seen from earlier studies. Additional investigation of treatment with entospletinib following progression with B-cell receptor signaling pathway inhibitors is warranted. Disclosures Sharman: Celgene Corporation: Consultancy, Research Funding; TG Therapeutics, Inc.: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Calistoga: Honoraria; Janssen: Research Funding. Shustov:Celegene, BMS: Consultancy, Honoraria, Research Funding. Smith:celegene, spectrum, genentech: Honoraria. Boyd:US Oncology: Research Funding; Celgene: Speakers Bureau; Genentech, Inc.: Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; GSK: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding. Abella:Gilead: Employment. He:Gilead Sciences: Employment. Eng:Gilead: Employment. Hu:gilead: Employment. Reddy:gilead: Employment. Mitra:Gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1744.1744

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3225-3225

Abstract: Introduction: Entospletinib is an orally bioavailable, selective inhibitor of spleen tyrosine kinase. Targeting the B-cell receptor (BCR) signaling pathway with Bruton's tyrosine kinase (BTK) and PI3Kd inhibitors (BTKi and PI3Kdi), approved for treatment of chronic lymphocytic leukemia (CLL), has been a successful therapeutic strategy. Entospletinib is active in CLL and preclinical data suggest that entospletinib may be effective even in the context of resistance to BTKi, including that conferred by activation of PLCγ2 (Liu et. al. Blood 2015). Methods: This is an ongoing phase 2 trial (NCT01799889) of entospletinib in CLL and non-Hodgkin lymphoma. The study protocol includes 2 CLL cohorts for patients who have been previously treated with BTKi or PI3Kdi and 2 additional cohorts for patients with Richter's transformation who have had analogous prior treatment. Patients were treated with entospletinib monotherapy (400 mg BID) and evaluated using modified Hallek/IWG-CLL criteria every 2 to 3 months as previously described (Sharman et. al. Blood 2014). Results: As of June 28, 2016, 34 patients have been enrolled, and 33 have been treated. Of the 28 patients without Richter's transformation, 23 were previously treated with a BTKi (22 ibrutinib, 1 CC-292) and 5 with a PI3Kdi (idelalisib). Median number of prior treatments was 3 (1-7) for patients with prior BTKi and 5 (3-8) for prior PI3Kdi treatment. In total, 35% of the BTKi patients and 60% of the PI3Kdi patients had either a TP53 mutation or del17p; 75% did not have IgHV hypermutation. A median of 2 months (0-14) had elapsed since the prior treatment; 17 patients had progressive disease on prior therapy, while 11 discontinued prior therapy due to intolerance. Thirteen of the 28 patients enrolled without Richter's transformation remain on study with a median PFS of 5.6 months for the prior BTKi cohort and a median PFS of 6.9 months for the prior PI3Kdi cohort. Of the 15 patients who have stopped therapy, 9 discontinued due to disease progression, 5 discontinued due to an AE, and 1 withdrew consent. Overall, 19 patients were evaluable for response (15 BTKi/4 PI3Kdi; Table 1). Of the 6 patients who achieved a PR, all lacked IgHV hypermutation and 3 had either a TP53 mutation or del17p, and 3 had progressed on prior therapy. Following Richter's transformation, 5 patients have been treated with entospletinib (3 with prior BTKi therapy and 2 with prior PI3Ki). The interval since prior treatment was short ( 〈 1 month in 4/5 with 1 missing) with 3 to 6 prior lines of treatment. One patient with prior BTKi therapy and Richter's transformation remains on study with 118 days on treatment; 4 patients discontinued treatment due to progressive disease (at 40 and 67 days following prior BTKi and 8 and 28 days following prior PI3Kdi). All patients on study experienced a treatment-emergent AE (TEAE) and 49% experienced a serious AE (SAE; Table 2). Only 1 SAE, pancreatitis, was attributed to entospletinib. The most common TEAEs and laboratory abnormalities are listed in Table 2. Additional Grade ≥3 TEAEs reported in more than 1 patient included sepsis (3), atrial fibrillation (2), dehydration (2), neutropenia (2), pneumonia (2), respiratory failure (2), and urinary tract infection (2). The only TEAE attributable to entospletinib that led to discontinuation of treatment was fatigue. Five patients died on study; 2 from progressive disease and 1 each from heart failure, Guillain-Barre syndrome, and cardiac arrest; 3 of these 5 patients died within 30 days of the last dose of study drug [disease progression (2), cardiac arrest (1)]. Conclusion: Early experience from this trial with ongoing enrollment demonstrates that entospletinib has clinical activity following therapy with either BTKi or PI3Kdi. Continued investigation of treatment with entospletinib following progression after therapy with BCR signaling pathway inhibitors is warranted. Disclosures Sharman: Gilead Sciences, Inc.: Honoraria, Research Funding. Shustov:Celgene: Consultancy, Honoraria; SPECTRUM: Consultancy, Research Funding; Seattle Genetics: Research Funding; Novartis: Research Funding; BMS: Consultancy, Honoraria. Smith:Celgene: Honoraria; Spectrum: Honoraria; Abbvie: Research Funding; Genentech: Honoraria. Kolibaba:Cell Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Research Funding; GSK: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Pharmcyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding. Abella-Dominicis:Gilead Sciences: Employment, Equity Ownership. Zhang:Gilead Sciences: Employment, Equity Ownership. Mitra:Gilead Sciences: Employment, Equity Ownership. Yasenchak:Seattle Genetics: Research Funding. Awan:Pharmacyclics: Consultancy; Innate Pharma: Research Funding; Novartis Oncology: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3225.3225

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2454-2454

Abstract: Introduction Brentuximab vedotin (BV) and nivolumab are both active and well tolerated in patients (pts) with classical Hodgkin lymphoma (cHL) and were previously studied in first salvage (overall response rate [ORR] 85%; complete response [CR] 67%) (Advani 2021) and as firstline therapy in older adults (ORR 95%; CR 79%) (Yasenchak 2019). BV is approved for the treatment of adults with treatment-naïve Stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine (AVD) (Connors 2017) and targets CD30, a receptor expressed on the Reed-Sternberg cells. Nivolumab is approved for treatment of adults with relapsed/refractory cHL and restores antitumor immunity by blocking the PD-1 receptor on activated T-cells. The combination of BV plus nivolumab demonstrated promising activity that supports this combination when evaluated as a frontline treatment option for pts over 60 years of age with cHL (Friedberg 2018). Additionally, in pts with non-bulky Stage I or II cHL, treatment with BV plus doxorubicin and dacarbazine (AD) resulted in a CR rate of 97% at end of treatment (EOT), as well as a promising 4-year progression-free survival (PFS) estimate of 91%. Importantly, there were no cases of ≥Grade 3 peripheral neuropathy and only 9% were Grade 2 (Abramson 2021). Herein, we present preliminary safety results from Part B of this phase 2 study, where combination treatment with AN+AD (BV, nivolumab, doxorubicin, and dacarbazine) was well tolerated without excessive dose modifications or discontinuations and is consistent with the known safety profiles of the individual components of this treatment regimen. Methods SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial. Part B of this study enrolled pts with Ann Arbor Stage I or II cHL with bulky mediastinal disease (defined as ≥ 10 cm) or Stage III or IV cHL. Pts received up to 6 cycles of AN+AD (consisting of BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m 2, and dacarbazine 375 mg/m 2). All study drugs were administered by IV infusion on Days 1 and 15 of each 28-day cycle. The primary endpoint was CR rate at EOT. Secondary endpoints included safety, tolerability, overall response rate, and PFS. Disease response and progression was assessed by investigators using the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2014) and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson 2016) at Cycle 2 and EOT. Results In Part B, the majority of the 58 pts enrolled were white (86%), not of Hispanic or Latino/a or Spanish origins (79%), and less than 65 years old (95%). Median age was 35 years (range: 19-78 years). Twenty-nine percent of pts had Stage II cHL with bulky mediastinal disease, while the remainder had Stage III (17%) or Stage IV (50%) cHL. Of the 58 pts enrolled, 57 received at least one dose of study treatment. Of the 57 pts who received at least one dose of study treatment, 1 pt discontinued treatment (all study drugs) by the end of Cycle 2 due to treatment-emergent adverse events (TEAEs). By end of Cycle 2, the majority of TEAEs were Grades 1 and 2; 16% of pts experienced ≥Grade 3 TEAEs. Nausea, fatigue, and alopecia were the most frequently reported treatment-related TEAEs (51%, 33%, and 26% of pts, respectively). No febrile neutropenia was observed, and there were no Grade 5 adverse events. Two pts (4%) experienced treatment-related treatment-emergent serious adverse events; 1 pt (2%) experienced hypophysitis and aseptic meningitis, and discontinued treatment, and 1 pt (2%) experienced pneumonitis. Preliminary efficacy results are anticipated for presentation. Conclusions Preliminary results demonstrate that AN+AD is well-tolerated, and no new safety signals were observed. The omission of bleomycin and vinblastine may have contributed to the absence of certain AEs, such as febrile neutropenia. This study of AN+AD is ongoing, and updated safety and efficacy results will be presented at the meeting. Disclosures Lee: BMS: Honoraria, Research Funding; Aptitude Health: Honoraria; Century Therapeutics: Consultancy; Pharmacyclics: Research Funding; Guidepoint: Honoraria; Oncternal: Research Funding; Seagen: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Honoraria. Flinn: Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Ramchandren: curis: Research Funding; MERCK: Consultancy, Research Funding; pharmacyclics: Consultancy, Research Funding; seattle genetics: Consultancy, Research Funding; BMS: Consultancy; Trillium: Research Funding. Friedman: Seagen Inc.: Research Funding. Burke: MorphoSys: Consultancy; Beigene: Consultancy, Speakers Bureau; AbbVie: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy; Bristol Myers Squibb: Consultancy; Kymera: Consultancy; AstraZeneca: Consultancy; Verastem: Consultancy; Kura: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy. Linhares: Seagen Inc.: Research Funding. Peterson: Seagen Inc.: Research Funding. Raval: Abbvie Pharmaceuticals: Speakers Bureau; Adaptive Biotechnologies: Consultancy; ADCT Therapeutics: Consultancy, Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau; Amgen Biotechnology Company: Research Funding; Astellas Pharmaceuticals: Speakers Bureau; Astrazeneca Pharmaceuticals: Consultancy, Speakers Bureau; Beigene Pharmaceuticals: Speakers Bureau; Bristol Meyers Squibb Pharmaceuticals: Consultancy; Epizyme Pharmaceuticals: Consultancy, Speakers Bureau; Genetech Biotechnology Company: Research Funding; GlaxoSmithKline Pharmaceuticals: Consultancy; Incyte Pharmaceuticals Corporation: Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Morphosys Biotech Company: Speakers Bureau; Sanofi Genzyme: Consultancy; Seagen Biotechnology Company: Research Funding; Takeda Pharmaceuticals: Consultancy, Speakers Bureau. Chintapatla: Seagen Inc.: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Yimer: Janssen: Speakers Bureau; Beigene: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Islas-Ohlmayer: Seagen Inc.: Research Funding. Dean: Seagen Inc.: Research Funding. Rana: Seagen Inc.: Research Funding. Gandhi: GlaxoSmithKline: Honoraria; Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria. Renshaw: Amgen: Speakers Bureau; SeaGen: Consultancy; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Texas Oncology: Current Employment. Gillespie-Twardy: Seagen Inc.: Research Funding. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Guo: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Yasenchak: Seagen Inc.: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-147891

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

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detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. 11109-11109

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2014.32.15_suppl.11109

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2014

detail.hit.zdb_id: 2005181-5

In: Clinical Lung Cancer, Elsevier BV, Vol. 20, No. 2 ( 2019-03), p. 74-81.e1

Type of Medium: Online Resource

ISSN: 1525-7304

URL: Article

DOI: 10.1016/j.cllc.2018.10.006

Language: English

Publisher: Elsevier BV

Publication Date: 2019

detail.hit.zdb_id: 2193644-4

In: Clinical Lymphoma and Myeloma, Elsevier BV, Vol. 7, No. 2 ( 2006-9), p. 140-144

Type of Medium: Online Resource

ISSN: 1557-9190

URL: Article

DOI: 10.3816/CLM.2006.n.052

Language: English

Publisher: Elsevier BV

Publication Date: 2006

detail.hit.zdb_id: 2193618-3

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 814-814

Abstract: Introduction RCHOP is the standard frontline treatment for patients with DLBCL. However, for patients with high-intermediate or high-risk disease (IPI 3-5), outcomes are suboptimal, with an estimated 3-year PFS of about 55%. In addition to IPI, an additional factor associated with an increased risk include non-GCB cell of origin. Brentuximab vedotin, an ADC targeting CD30, has demonstrated single-agent activity in relapsed/refractory DLBCL patients. Of note, higher ORR and CR, as well as longer duration of PFS, were observed in those patients with CD30 detected on tumor cells by routine IHC. Methods This phase 2 study was designed to evaluate combination therapy using brentuximab vedotin (BV) and standard RCHOP chemotherapy as frontline treatment in patients with high-intermediate/high risk (standard IPI score 3-5 or age-adjusted IPI [aaIPI] score 2-3) DLBCL, regardless of CD30 expression (ClinicalTrials.gov NCT01925612). Patients were randomized to receive either 1.2 mg/kg BV+RCHOP or 1.8 mg/kg BV+RCHOP for up to 6 cycles of treatment. BV was given on Day 1 of every 21-day cycle. Response was assessed per investigator using Cheson 2007. AEs, physical examination findings, and laboratory testing were utilized to characterize safety. Tumor cell CD30 expression was measured by IHC and gene expression analysis; soluble CD30 was measured in plasma. Tumor microenvironment was also evaluated for frequency of immune-infiltrating cells. The primary endpoints for this study were the tolerability of each regimen and the CR rate at the end of treatment (EOT). Key secondary endpoints included progression-free survival (PFS). Additional exploratory endpoints included CD30 expression on tumor specimens (CD30- defined as 〈 1% per IHC) and correlation of CD30 expression and response. Results Twenty-nine patients were treated with 1.2 mg/kg BV+RCHOP and 22 patients were treated with 1.8 mg/kg BV+RCHOP. Over half (63%) were high-intermediate risk (IPI 3, aaIPI 2) and 37% were high risk (IPI 4-5, aaIPI 3). Most had Stage IV disease (71%) and 27% had an ECOG score of 2. AEs in ≥50% of patients included peripheral sensory neuropathy (63%), fatigue (61%), nausea (55%), and diarrhea (53%). Grade 3 or higher events occurred in 76% of patients; the most frequent were neutropenia (33%) and febrile neutropenia (31%). The PET-negative CR rate was 69% overall; CD30+ patients had a CR rate of 76% (19/25) compared with 63% (12/19) in CD30- patients by IHC. Although PFS data are still immature (median follow up of 8 months), the estimated PFS rate at 12 months was 82% (95% CI: 58, 93) in CD30+ patients and 56% (95% CI: 32, 75) in CD30- patients. 60% (3/5) of patients with CD30- ABC-DLBCL progressed versus 27% (3/11) of CD30+ ABC-DLBCL patients. Four patients with EBV+ DLBCL were treated and all achieved CR; 3 EBV+ patients remain in remission after a median follow-up of 12 months. Within the microenvironment, a higher percentage of CD3+ T-cells was observed in patients with CR (23%; range, 4-80%) than in those with PR (14%; range, 10-15%) or PD (11%; range, 5-15%). Of the 32 patients who have not yet progressed, 50% had ≥20% CD3+ cells compared to 18% of patients with PD (2/11). Other factors, including soluble CD30 levels and infiltrating CD68+ cells, were not associated with clinical outcomes. Conclusions Interim results demonstrate that adding BV to RCHOP results in a high rate of CR in this population of IPI 3-5 DLBCL. Patients with CD30-expression in the tumor appear to have a higher CR rate and fewer early progression events than patients with CD30- DLBCL. Furthermore, subsets of patients who have a particularly poor prognosis (CD30+ ABC subtype and EBV+ DLBCL) appeared to have a favorable outcome with BV+RCHOP. Evaluation of the tumor microenvironment showed that higher frequencies of infiltrating CD3+ cells were observed in the CR group, suggesting possible immunologic correlates of response. However, CD30 expression appears to have greater prognostic significance in this study despite the relatively small sample size. These results are intriguing and merit further testing in a randomized trial. Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US 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. The drug is being evaluated in this study for use as frontline treatment in patients with high-intermediate/high risk DLBCL in combination with multiagent chemotherapy. . Halwani:Abbvie: Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Takeda/Millenium: Research Funding; BMS: Research Funding; Seattle Genetics, Inc.: Other: Travel expenses, Research Funding; Roche/Genentech: Research Funding; Kyowa Hakko Kirin: Research Funding; Amgen: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding; Genetech: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Budde:Merck: Research Funding; Ikara Inc: Patents & Royalties; Atara Biotherapeutics: Consultancy; Seattle Genetics, Inc.: Research Funding. Burke:Millenium/Takeda: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel expenses; Gilead: Consultancy; Janssen: Consultancy; Seattle Genetics, Inc.: Research Funding. Farber:Seattle Genetics, Inc.: Research Funding. Holkova:Seattle Genetics, Inc.: Research Funding. Kolibaba:GSK: Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Knapp:Celgene: Research Funding; Heron Pharmaceuticals: Other: Travel expenses, Research Funding; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Brystol-Myers Squibb: Research Funding; Genentech: Honoraria, Other: Travel expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; EMD Serono: Research Funding. Li:Seattle Genetics, Inc.: Employment, Equity Ownership. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Seetharam:Seattle Genetics, Inc.: Research Funding. Yimer:Seattle Genetics, Inc.: Research Funding. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.814.814

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 32-33

Abstract: Introduction: Current National Comprehensive Cancer Network (NCCN) guidelines recommend one of three frontline (1L) regimens to treat stage III or IV classical Hodgkin Lymphoma (cHL): doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD), or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated (e) dose-BEACOPP). PET/CT imaging is important at initial staging and in follow up including after two cycles (interim PET2) to assess and adapt treatment based on response for patients who newly start treatment with ABVD (Johnson et al., 2016). Despite NCCN guidelines, physicians in community oncology practices may face challenges optimizing outcomes for ABVD patients utilizing the interim PET2 adaptive approach. This study evaluated interim PET2 utilization and reported Deauville scores (DS) in patients with stage III or IV cHL treated in the 1L setting. Methods: This retrospective observational study included adult patients diagnosed with stage III or IV cHL and treated with 1L ABVD, A+AVD, or eBEACOPP within the US Oncology Network (USON) between 01 January 2017 and 31 January 2020. Patients enrolled in therapeutic clinical trials or received treatment for another primary cancer diagnosis were excluded. Patient data were sourced from the USON's electronic health records database, iKM™. Demographic, clinical, and treatment characteristics were sourced from structured iKM elements. Interim PET2 details, including Deauville scores, were obtained from manual chart review. Descriptive statistics were generated for all patient characteristics. Results: 262 patients with cHL were eligible. The majority of the patients were & lt;39 years (48.9%), male (56.9%), Caucasian (58.8%), stage IV cHL (50.8%), had a low ( & lt;4) International Prognostic Score (76.0%), completed most treatment cycles (median = 6 [IQR 2,4]) and were treated with 1L ABVD (74.0%). Almost all patients (98.5%) had at least one documented PET-CT of which 87.6% had one at baseline (≤90 days prior to treatment initiation) and 79% had an interim PET-CT (Figure). For patients treated with 1L ABVD with an interim PET-CT, 65% did not report a Deauville score vs. 35% with a documented Deauville score (of which, 29% with score of 1-3 and 5.0% with score of 4-5). 54% of patients treated with 1L A+AVD did not report a Deauville score compared to 42% with scores of 1-3 and 4% with scores of 4-5. The majority of patients (93%) treated with 1L ABVD with or without a reported Deauville score de-escalated to AVD. Results were consistent in the sensitivity analysis of patients with both baseline PET-CT and interim PET-CT. Conclusions: Findings from this retrospective, observational, community oncology study found that Deauville scores were reported for only 1/3 of interim PET-CT in patients treated with 1L ABVD patients with stage III or IV cHL. Despite this, initial treatment modification of de-escalation from ABVD to AVD was common and escalation to BEACOPP was rarely observed. These results suggest that albeit interim PET-CT is utilized, the Deauville scores to inform escalation or de-escalation of treatment decisions in stage III or IV cHL patients is missing and not universally reported in the community oncology setting. Our findings support a potential opportunity to educate oncologists and radiologists on the importance of consistently reporting PET-CT Deauville scores given the fact that providers may lack the complete information to ensure treatment modifications are optimized for patient outcomes. Additionally, compared with ABVD, A+AVD that does not require treatment adaptation by interim PET/CT Deauville score may be a therapy option. Figure 1 Disclosures Yasenchak: BeiGene: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria. Clark:McKesson Life Sciences: Current Employment, Current equity holder in publicly-traded company. Liu:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Beeks:F. Hoffmann-La Roche Ltd: Consultancy; McKesson: Current Employment. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Robert:McKesson: Current Employment. Yu-Isenberg:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-140698

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2740-2740

Abstract: Background Patients (pts) with relapsed/triple-class refractory (R/R; refractory to a proteasome inhibitor, immunomodulatory drug or anti-CD38 antibody) multiple myeloma (MM) have limited treatment options. A need remains for novel combination therapies with manageable toxicity and non-cross-resistant mechanisms of action. B-cell maturation antigen (BCMA) is expressed in most MM pt tumors. SEA-BCMA is an investigational, humanized, nonfucosylated IgG1 monoclonal anti-BCMA antibody. Proposed mechanisms of action of SEA-BCMA include blocking of BCMA-mediated pro-survival and proliferative signaling, mediating antibody-dependent cellular phagocytosis, and displaying enhanced antibody-dependent cellular cytotoxicity. Preclinical data demonstrate promising antitumor activity and versatile combinability. Here, we present preliminary data from the first-in-human Phase 1 clinical trial. Methods SGNBCMA-001 (NCT03582033) is an ongoing phase 1, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability and antitumor activity of SEA-BCMA in adults with R/R MM not previously exposed to any other BCMA-directed therapy. Part A tested monotherapy safety and tolerability with dose escalation (100-1600 mg flat dosing once every 2 weeks [Q2W] by intravenous infusion), and dose expansion at the highest tolerated dose. Parts B and C aim to optimize efficacy by testing intensified dosing (Part B; weekly [Q1W] induction dosing of SEA BCMA for 8 weeks is followed by Q2W maintenance dosing) and dexamethasone (DEX) combination therapy (Part C) in pts who have received ≥3 prior lines of therapy for MM and are triple-class refractory. Responses are assessed per the 2016 International Myeloma Working Group criteria. Results As of June 15, 2021, Part A completed enrollment. A total of 55 pts received SEA-BCMA (see Table 1 for pt characteristics). SEA-BCMA was generally well tolerated, and the maximum tolerated dose was not reached in the 5 dose levels tested in Part A (100, 200, 400, 800, or 1600 mg Q2W; n=2, 2, 2, 7, and 7, respectively). At 800 mg, 1 of 7 pts reported a Grade 3 infusion-related reaction (IRR), which met dose-limiting toxicity (DLT) criteria by lasting & gt;24 hours despite supportive care. This constituted the single DLT observed during dose escalation. Subsequently, dose expansion (n=15) proceeded at 1600 mg Q2W. The most common treatment-emergent adverse events (TEAEs) observed with 1600 mg Q2W (n=22) were fatigue (32%), pyrexia (23%), IRR (23%), and hypertension (23%) for non-hematological events, and anemia (14%) for hematologic events. The most common ≥Grade 3 TEAEs with 1600 mg Q2W were anemia and syncope (9% each). Following a safety monitoring review, premedication with acetaminophen + antihistamine was introduced to mitigate IRRs in expansion cohorts. Parts B and C completed parallel safety run-ins (n=6 each) at the 1600 mg dose with no DLTs observed and with similar tolerability. Pharmacokinetic (PK) analyses indicate serum SEA-BCMA exposures increased proportionally with increasing dose with a half-life of approximately 10 days. Preliminary analyses suggest the PK profile of SEA-BCMA in combination therapy with DEX (n=5) is comparable to monotherapy and is unaltered with a change in schedule from Q2W to Q1W. Three of 22 pts who received 1600 mg SEA-BCMA Q2W monotherapy (Part A) achieved a confirmed objective response (OR; OR rate: 14% [95% confidence interval: 2.91, 34.91]; 2 partial responses [PR] , 1 very good PR [VGPR]). To date, 3 pts remain on treatment (2 PRs and 1 stable disease). The median duration of treatment was 12 weeks (Figure 1; range 4-88). In Parts B and C, 2 of 8 (2 PR) and 2 of 12 (1 VGPR, 1 PR) pts reported a confirmed OR; 3 of the 4 responding pts remain on treatment in cycle 7, 8, and 9, respectively. Conclusions Preliminary results for SGNBCMA-001 suggest a favorable safety profile and combination potential. SEA-BCMA also showed encouraging duration on treatment and initial antitumor activity in a heavily pre-treated late-line R/R MM pt population. Expansion cohorts testing intensified SEA-BCMA dosing and the addition of DEX are underway to further assess the safety, tolerability, and estimate of SEA-BCMA activity in the context of these treatment approaches. An additional expansion cohort (Part D), testing the combination of SEA-BCMA with pomalidomide and DEX in pts who have received ≥2 prior lines of therapy, is now enrolling. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Liedtke: Pfizer: Honoraria; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Niesvizky: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; GSK: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding. Tomasson: Pfizer, Inc.: Research Funding; Rafael Pharmaceuticals: Research Funding; syros Pharmaceuticals: Research Funding; Janssen R & D: Research Funding; Seagen, Inc.: Research Funding. Yasenchak: Seagen Inc.: Research Funding. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Li: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Wang: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146047

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7