ALBERT

Description: Moxetumomab pasudotox-tdfk is a first-in-class recombinant CD22-directed cytotoxin approved in the US for the treatment of adult patients with relapsed/refractory hairy cell leukemia (HCL). The pivotal, multicenter, open-label, single-arm trial (Study 1053; NCT01829711) evaluated the efficacy, safety, immunogenicity, and pharmacokinetics of moxetumomab pasudotox-tdfk monotherapy in patients with relapsed/refractory HCL. Here we present the final analysis, describing the long-term follow-up of patients in Study 1053, with a median follow-up of 24.6 months (range 1.2-71.7). Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 courses of a purine nucleoside analog (PNA) or 1 course of a PNA followed by ≥ 1 course of rituximab or a BRAF inhibitor. Patients received moxetumomab pasudotox-tdfk 40 µg/kg intravenously on days 1, 3, and 5 of each 28-day cycle for 6 cycles, or until minimal residual disease (MRD)-negative complete response (CR), disease progression, initiation of alternate therapy, or unacceptable toxicity. Disease response and immunohistochemistry MRD status were determined by blinded independent central review. The primary endpoint was durable CR (achieving CR and maintaining hematologic remission [HR] for 〉 180 days). Durable CR with HR ≥ 360 days was measured in this final analysis. HR was defined as hemoglobin ≥ 11.0 g/dL, absolute neutrophil count ≥ 1.5 × 103/µL, and platelet count ≥ 100 × 103/µL without receiving transfusions or growth factors within the 4 preceding weeks of assessment. Eighty patients (63 males; median age 60 years [range 34-84]) were enrolled and treated with moxetumomab pasudotox-tdfk. The median number of prior systemic therapies was 3 (range 2-11); 48.8% of patients were PNA-refractory and 37.5% were unfit for PNA retreatment. The median number of treatment cycles administered was 6 (range 1-7). The durable CR rate was 36.3% (29/80 patients; 95% confidence interval [CI]: 25.8-47.8%), durable CR rate with HR ≥ 360 days was 32.5% (26/80 patients; 95% CI: 22.4-43.9%), and the overall CR rate was 41.3% (33/80 patients; 95% CI: 30.4-52.8%) (Table). Overall, 27/33 (81.6%) patients who achieved a CR also achieved MRD-negative status (33.8% of all patients). HR was achieved by 64/80 patients (80.0%). The median duration of HR from CR was 62.8 months (Figure) and median progression-free survival was 41.5 months (range 0.0+ to 71.7). Per the primary analysis, the most frequent treatment-related adverse events (AEs) were nausea (28%), peripheral edema (26%), headache (21%), and pyrexia (20%). Treatment-related Grade 3/4 AEs were reported in 24 patients (30.0%) and serious AEs in 28 (35.0%). Treatment-related AEs led to study drug discontinuation in 8 patients (10.0%): hemolytic uremic syndrome (HUS), n = 4 (5.0%); capillary leak syndrome (CLS), n = 2 (2.5%); and increased blood creatinine, n = 2 (2.5%). Grade ≥ 3 CLS events occurred in 2 patients (2.5%) and Grade ≥ 3 HUS occurred in 5 patients (6.3%). In general, CLS and HUS events were manageable and reversible with appropriate supportive care and monitoring. Based on primary and follow-up analyses of serum creatinine, there was no decline in renal function over time; 12 months post-treatment all mean (SD) serum creatinine laboratory values stayed within normal limits, which suggests current management strategies for HUS (oral hydration, i.v. fluid supplementation on the day of infusion, and the use of dexamethasone) are adequate. With 24.6 months of follow-up, 4 deaths were reported: 2 due to study disease progression and 2 due to an AE (1 each of pneumonia and septic shock). Moxetumomab pasudotox-tdfk treatment was associated with a manageable safety profile. Moxetumomab pasudotox-tdfk achieved a high rate of durable responses, demonstrating the ability to achieve MRD negativity in heavily pretreated patients with HCL. Disclosures Kreitman: Genentech: Research Funding. Dearden:Abbvie: Honoraria; Genentech: Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Zinzani:MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Robak:Amgen: Consultancy, Other: Travel grant; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding; Takeda: Consultancy, Research Funding. le Coutre:Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Gjertsen:Research Council of Norway: Research Funding; Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio: Consultancy; KinN Therapeutics AS: Equity Ownership; Seattle Genetics: Consultancy; ERA PerMed: Research Funding; Haukeland University Hospital / University of Bergen: Employment; ACTII AS: Equity Ownership; Astellas: Consultancy; BerGenBio AS: Membership on an entity's Board of Directors or advisory committees; The Norwegian Cancer Society: Research Funding; Helse Vest Health Trust: Research Funding; EU Horizon 2020: Research Funding. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support. Roboz:Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Karlin:Takeda: 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, Other: Travel Support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Kuptsova-Clarkson:AstraZeneca: Employment, Equity Ownership. Liu:Acerta Pharma: Employment. Patel:Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership.

Description: Abstract 168 The X-ray cross-complementing group 1 (XRCC1) protein plays an important role in excision and ligation of oxidized DNA bases and strand breaks, in cooperation with other enzymes in the base excision repair (BER) pathway, while XPD helicases unwind DNA prior to repair. Polymorphisms of these DNA repair genes are associated with decreased DNA repair rates and increased genotoxic damage, measured by single-strand breaks and chromosomal aberrations. Compromised repair activity may lead to accumulation of DNA damage and predispose to secondary cancers and increased treatment-related toxicity to normal tissues. It may, however, also result in decreased repair of DNA damage in malignant cells exposed to chemotherapy, facilitating their apoptosis, and therefore decreasing resistance to chemotherapy and improving treatment outcome. Functional DNA repair capacity has been found to be significantly deficient in XRCC1 399Gln and XPD 312Asn, 751Gln variant allele carriers, and NER polymorphisms, particularly ERCC2 (XPD) Lys751Gln SNP, appeared as strong determinants of in vitro toxicity to most anti-cancer agents in the NCI-60 panel of tumor cell lines. Pharmacogenetic studies of DNA repair pathways have consistently demonstrated associations between the XRCC1 Arg399Gln, XPD Lys751Gln and XPD Asp312Gln genotypes and cancer treatment outcomes, including treatment-related toxicities. Notably, the XRCC1 399Gln homozygous variant genotype has been found to decrease risk of developing both de novo and therapy-related AML, and has been associated with worse survival outcomes for other cancers. The variant glutamine allele of XPD Lys751Gln SNP has been associated with shorter disease-free survival (DFS) and overall survival (OS) for AML patients, as well as increased risk of therapy-related AML (t-AML). In this study we evaluated the role of these polymorphisms, as well as XPD haplotypes, in response to chemotherapy, OS, and toxicities in adult de novo (n=214) and secondary (n=79, including 47 with antecedent hematologic disorders and 32 with t-AML) AML patients treated with cytarabine and anthracycline-based chemotherapy regimens at Roswell Park Cancer Institute. Genotyping was performed by MALDI-TOF mass spectrometry, and logistic and proportional hazards regression models were used to evaluate relationships. Significant differential chemotherapy responses were observed in secondary, but not de novo, AML patients with variant XPD 312, XPD 751 and XPD haplotypes. In particular, among secondary AML patients, the XPD 312Asn/Asn XPD 751Gln/Gln variant was associated with eleven-fold higher odds of achieving complete remission (CR) (OR= 11.23; 95% CI, 2.23-56.63), and the odds were also increased among patients with XPD 751Gln/Gln genotypes (OR= 7.07; 95% CI, 1.42–35.18). Patients with the ‘BB/DA' (751Gln/312Asn-751Gln/312Asn/751Gln/Asp312-Lys751-Asp312) diplotype were more likely to achieve CR [OR=31.10; 95% CI: 3.98–242.88] compared to those with the AA/AC/DB diplotype in the secondary AML onset category. Additionally, in this subgroup, the XPD 751 CC, 312GA, 312AA variant genotypes and the XPD ‘BB/DA' haplotype group, which are likely to confer decreased repair function, were significantly associated with longer OS. In the whole patient population there was an association between XPD genotypes/haplotypes and chemotherapy-related toxicities, including a significantly reduced risk of nausea/vomiting (OR= 0.35, 95% CI, 0.13–0.90 for ‘BB/DA' diplotype group) and an increased incidence of infectious complications after induction chemotherapy. Overall, these findings suggest that XPD codon 312 and codon 751 variant genotypes and haplotypes containing at least one variant allele are associated with suboptimal DNA repair and may serve as predictors of more favorable AML treatment responses and diffential toxicities. With validation of results in larger samples, these findings could lead to optimizing chemotherapy AML options by treatment stratification, especially in patients with secondary AML. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Bruton tyrosine kinase (BTK) inhibitors are effective treatments for B-cell malignancies, but an increased incidence of cardiovascular (CV) toxicities has been observed with ibrutinib. Acalabrutinib (acala) is a next-generation, potent, highly selective, covalent BTK inhibitor approved for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma and mantle cell lymphoma. The objective of this analysis was to characterize CV adverse events (AEs) in patients (pts) with CLL who received acala monotherapy. Methods: Data from pts with CLL in 4 studies (ACE-CL-001 [NCT02029443]; ACE-CL-007 [ELEVATE-TN, NCT02475681]; ACE-CL-309 [ASCEND, NCT02970318]; 15-H-0016 [NCT02337829]) were pooled. Cutoff dates ranged from December 2018 to February 2019. Pts who received ≥1 dose of acala monotherapy were included. For pts who crossed over from control arms to acala, only AEs recorded after crossover were included. Acala was given orally at total daily doses of 100 mg to 400 mg, later switched to 100 mg twice daily, and continued until disease progression (PD) or toxicity. Cardiac AEs and hypertension (htn) were examined. Results: 762 pts were included (treatment-naïve: n=352 [46%]; relapsed/refractory: n=410 [54%]; median age: 67 years [range: 32-89]; Eastern Cooperative Oncology Group performance status ≤1: 93%; median acala exposure: 24.9 mo [range: 0-58.5]; median follow-up: 25.9 mo [range: 0-58.5]). A total of 199 cardiac AEs of any grade (irrespective of treatment relationship) were reported in 129 pts (17%). Cardiac AEs led to treatment discontinuation in 7 pts (0.9%). The most frequent cardiac AEs reported in ≥2% of pts were atrial fibrillation (afib: n=34; 4%; afib/flutter: n=38; 5%), palpitations (n=23; 3%), and tachycardia (n=17; 2%). The median time to afib/flutter onset was 521 days (range: 8-1280). Overall, 91% (117/129) of pts with vs 79% (503/633) without cardiac AEs had ≥1 CV risk factor before acala initiation. The most prevalent CV risk factors (≥20%) among the 129 pts with cardiac AEs were htn (n=86; 67%), hyperlipidemia (n=38; 29%), and arrhythmias (n=29; 22% [afib: n=16; 12%]). Htn AEs were reported in 9% (67/762) of pts, among whom 46 (69%) had pre-existing htn and 18 (27%) had htn risk factors. The median time to htn onset was 197 days (range: 2-1345). Thirty-seven pts (4%) had 51 grade ≥3 cardiac AEs (grade 3: n=37; grade 4: n=12; grade 5: n=2). Grade ≥3 cardiac AEs of interest included afib (n=10; 1.3%), complete atrioventricular (AV) block (n=2; 0.3%), acute coronary syndrome (n=1; 0.1%), atrial flutter (n=1; 0.1%), second degree AV block (n=1; 0.1%), and ventricular fibrillation (n=1; 0.1%). Two patients experienced grade 5 AEs (cardiac failure congestive [n=1], acute myocardial infarction [n=1]). Among the 37 pts with grade ≥3 AEs, 18 (49%) were continuing acala at data cutoff; 6 (16%) had discontinued due to the grade ≥3 cardiac AEs, 4 (11%) to other AEs, 5 (14%) to PD, 3 (8%) to death, and 1 (3%) to other reasons. Among the 51 grade ≥3 cardiac AEs, 16 (31%) led to dose delay and 36 (71%) were managed with concomitant medications. Most events (43/51 [84%]) resolved (dose delay: n=15; drug withdrawal: n=4; no dose change: n=24). Cardiac AEs occurring in the first 6 mo on acala were assessed based on a predominance of AEs (afib) during this time period with ibrutinib (Brown JR, et al, Haematologica. 2017;102:1796). Overall, 48% of pts with any-grade cardiac AEs experienced them in the first 6 mo on acala. Thirteen grade ≥3 cardiac AEs (25% of total) were observed in 9 pts in the first 6 mo (Table); all but 1 AE (grade 4 cardiac tamponade resulting in hospitalization) were managed with concomitant medications. Two of the 13 AEs resulted in treatment discontinuation (Table). Conclusions: At a median exposure of 24.9 mo, cardiac AEs occurred infrequently in pts with CLL treated with acala monotherapy; only 0.9% discontinued treatment due to cardiac AEs. Among grade ≥3 cardiac AEs, 25% were reported during the first 6 mo on treatment. Most pts with cardiac AEs had pre-existing risk factors that may have contributed to their development. The incidence of afib with acala (4%) was comparable to that of the general CLL population (6.1%; Shanafelt TD, et al. Leuk Lymphoma. 2017;58:1630). These data suggest a low risk of cardiac AEs with acala treatment in pts with CLL. The safety of acala vs ibrutinib in pts with high-risk CLL will be investigated in the phase 3, randomized ACE-CL-006 trial (NCT02477696). Disclosures Brown: Janssen, Teva: Speakers Bureau; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy; Gilead, Loxo, Sun, Verastem: Research Funding. Byrd:Acerta Pharma: Research Funding; Syndax: Research Funding; Leukemia and Lymphoma Society: Other; Trillium: Research Funding; Kartos Therapeutics: Research Funding; Vincera: Research Funding; Novartis: Research Funding; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other. Ghia:Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Sharman:TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding. Hillmen:F. Hoffmann-La Roche: Honoraria, Research Funding; Astra Zeneca: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Gilead: Research Funding. Stephens:MingSight: Research Funding; Acerta: Research Funding; Karyopharm: Consultancy, Research Funding; Gilead: Research Funding; Arqule: Research Funding; Pharmacyclics: Consultancy; Verastem: Research Funding; Beigene: Consultancy; Juno: Research Funding; Innate: Consultancy; Janssen: Consultancy. Sun:VERASTEM, GENMAB: Research Funding. Jurczak:Janssen, MeiPharma, Merck, Pharmacyclics, Roche, Tekeda, TG Therapeutics: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology: Consultancy, Current Employment; Jagiellonian University: Ended employment in the past 24 months, Research Funding. Patel:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Baek:Acerta Pharma: Current Employment. Lezhava:Astra Zeneca: Current Employment; Melinta Therapeutics Inc: Ended employment in the past 24 months. Kuptsova-Clarkson:AstraZeneca: Current Employment. Moslehi:AstraZeneca, Janssen, BMS, Boston Biomedical, Immunocure, Myovant, Boston Biomedical, Deciphera: Consultancy. Furman:Acerta: Consultancy; Abbvie: Consultancy; Verastem: Consultancy; Sunesis: Consultancy; Pharmacyclics: Consultancy; Oncotarget: Consultancy; Loxo Oncology: Consultancy; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Genentech: Consultancy.