Tolerability and Single Agent Anti-Neoplastic Activity of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory AML or MDS

Abstract APVO436 is a recombinant T-cell engaging humanized bispecific antibody designed to redirect host T-cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). This first in human clinical trial of APVO436 (NCT03647800) was designed as a multi-institutional, open-label, multiple-dose Phase 1B dose escalation study in patients with relapsed /refractory (R/R) AML and myelodysplastic syndrome (MDS). 58 R/R adult AML/MDS patients were screened; 12 patients were screen failures, and the remaining 46 eligible patients were enrolled in the study between 15/05/18 and 04/06/21. Thirty nine patients (84.8%) had R/R AML and 7 had R/R MDS. The median age was 68 years. Patients had failed 1-8 prior lines of therapy (Mean±SE: 3.2±0.3). A 3+3 design was used to guide the dose escalation. APVO436 was administered as weekly intravenous (IV) infusions at 10 different dose levels (Cohorts 1-10), ranging from a minimum anticipated biological effect level (MABEL) of 0.3 mcg to 60 mcg. In Cohorts 5-10, APVO436 was administered according to an intra-patient step-up strategy to reduce the risk for cytokine release syndrome (CRS). Response criteria of the International Working Group (IWG) were used for assessment of MDS patients. Standard European LeukemiaNet (ELN) 2017 criteria were used for response assessments in AML patients. The date of data cutoff was July 22, 2021. The primary endpoint of identifying a clinically active recommended phase 2 dose (RP2D) level for further clinical development of APVO436 was met. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). No hematologic DLT was observed in any of the 10 dose cohorts. Ten patients experienced 12 episodes of Grade 3 febrile neutropenia and each one of these 12 episodes was reported as not related to APVO436. APVO436-related transient neurotoxicity occurred only in 5 of 46 patients (10.9%). It was mild with Grade 1 AEs including headache, tremor, dizziness, lethargy, insomnia, memory loss, and confusion. A single case of Grade 3 confusion was encountered on the first day of treatment and resolved within a day. The single dose RP2D level has been identified as 18 mcg flat dose (Cohort 6; ~0.2 mcg/kg based on the body weights of the patients enrolled). Stable disease (SD), partial remissions (PR) and complete remissions (CR) were observed in 8 R/R AML patients as best overall responses to APVO436 at the RP2D level. Seven of 8 had failed 2-4 prior lines of anti-AML therapy and one patient had relapsed after achieving a remission on frontline venetoclax plus decitabine therapy. The onset and duration of the SD, PR or CR in these 8 patients is illustrated by the Swimmer plot depicted in Figure 1. One patient had clearance of peripheral blasts with >50% decrease in the BM blast percentage. Two primary AML patients with >25% BM blasts and unfavorable cytogenetics and/or adverse risk group genomic mutations achieved a PR at 58 days and 75 days, respectively, that deepened to a CR with full hematologic recovery at 92 and 113 days, respectively. Time-to-progression ranged from 87 to 238 days (Median: 177 days). Notably, the median overall survival OS was >300 days for the 8 R/R AML patients with a favorable response (prolonged SD and PRs/CRs). Five of the 8 patients remain alive at 110, 124, 323, 352, and 395 days, respectively. By contrast, the median OS for the remaining 31 AML patients in the intent to treat patient population (including 5 who were not evaluable for response) was 100 days (95% CI: 49.8-150.2) and 24 of 31 (77.4%) died (Log Rank c 2 = 5.298, P=0.021) (Figure 2). There were too few MDS patients to accurately analyze the clinical activity of APVO436. The time to progression in 6 evaluable patients ranged from >78 days to 321 days. Three of these 6 patients had marrow CRs. In conclusion, the safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential. Figure 1 Figure 1. Disclosures Watts: Takeda: Consultancy, Research Funding; Genentech: Consultancy; Rafael Pharma: Consultancy; Celgene/BMS: Consultancy. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Mims: BMS: Consultancy; Syndax Pharmaceuticals: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Kura Oncology: Consultancy; Leukemia and Lymphoma Society: Consultancy; Aptevo: Research Funding; Jazz Pharmaceuticals: Consultancy; Glycomemetics: Research Funding; Xencor: Research Funding; Daiichi-Saynko: Consultancy. Patel: Aptevo Therapeutics: Research Funding; BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Peerview: Honoraria. Shami: Bastion Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chimerix: Research Funding; Takeda: Consultancy; Gilead: Consultancy; BMS: Consultancy; Chimerix: Research Funding; Amgen: Research Funding; JSK Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Aptevo: Research Funding. Cull: Aptevo: Research Funding. Cogle: Celgene: Membership on an entity's Board of Directors or advisory committees; Aptevo therapeutics: Research Funding. Lee: Aptevo therapeutics: Consultancy; oncotelic therapeutics: Current equity holder in publicly-traded company. Uckun: Aptevo therapeutics: Consultancy; Reven Pharmaceuticals (Reven LLC): Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotelic therapeutics: Current equity holder in publicly-traded company.

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Risk and Severity of Cytokine Release Syndrome in Patients with Relapsed/Refractory (R/R) AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

Blood ◽

10.1182/blood-2021-149366 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3416-3416

Author(s):

Tara L. Lin ◽

Justin M Watts ◽

Alice S. Mims ◽

Prapti Patel ◽

Paul J Shami ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Bispecific Antibody ◽

Study Drug ◽

Survival Outcome ◽

Cytokine Release ◽

Publicly Traded ◽

Advisory Committees ◽

Grade 3 ◽

Dose Levels

Abstract APVO436 is a recombinant T-cell engaging humanized bispecific antibody designed to redirect host T-cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies. We evaluated the risk, severity, and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose escalation phase of a Phase 1B study (ClinicalTrials.gov identifier: NCT03647800). A total of 46 R/R AML/MDS patients received single agent APVO436 as weekly intravenous infusions at 10 different dose levels, ranging from 0.3 mcg to 60 mcg. CRS was the 7th th most common AE after pyrexia, diarrhea, infusion related reaction, peripheral edema, fatigue, and anemia affecting 10 (21.7%) of the 46 patients. Grade 3-4 CRS was the 6 th most common Grade ≥3 AE following febrile neutropenia, anemia, hyperglycemia, decreased platelet count, and sepsis occurring in 4 of the 46 patients (8.7%) treated with APVO436 in Study 5001 regardless of any relationship with the study drug APVO436. CRS was reported as an SAE in 7 (70%) of the 10 patients who developed CRS. CRS lead to dose interruptions in 4 patients, dose reduction in 1 patient, and permanent discontinuation of the study drug in 1 patient. Only 2 of the 46 patients experienced DLT and it was related to CRS in both patients. One patient treated in Cohort 4 who developed grade 2 CRS died due to complications from acute renal failure. Notwithstanding the fact that it is a potentially life-threatening complication, CRS did not significantly affect the overall survival outcome of the safety population (Figure 1). The average survival times were 169.1±42.1 days for patients who developed CRS and 173.9±27.2 days for the remainder of patients (P=0.9) (Table 1). The median survival was 188 days for patients with CRS and 151 days for those without CRS (Log-rank C 2 = 0.042, P=0.7) (Figure 1). Premedication with steroids (Dexamethasone) did not eliminate the risk of CRS. Of 4 patients who developed Grade ≥3 CRS, 2 had received steroid prophylaxis. Notably, CRS did not show an apparent dose-relationship. The average dose levels were 0.28±0.21 (Median: 0.19) µg/kg for those patients who developed CRS and 0.28±0.27 (Median: 0.20) µg/kg for those who did not develop CRS (P=0.97). There was a borderline significant age difference between patients who did versus patients who did not develop CRS (72.9±1.6 years [Median 73.5 years] vs. 63.3±2.3 years [Median: 65.0 years] (P=0.04). Diagnosis, dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS (Table 1). There was a statistically insignificant (P=0.1) trend toward higher absolute lymphocyte count (ALC) for patients who experienced CRS. Patients with a higher leukemia burden, as determined by higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood did not have a higher incidence of CRS. Cytokine profiling in select patients who developed Grade 2-4 CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response is IL-6: Within 1-2 days following the first dose of APVO436, the mean serum IL-6 concentration was elevated 145-fold over baseline (755 vs 5.2) and at the end of one week it was still elevated 83-fold over baseline. APVO436-associated CRS was generally manageable with standard of care and in most cases it resolved rapidly with the administration of tocilizumab at standard doses combined with dexamethasone. APVO436-related CRS was not required for clinically meaningful responses in R/R AML patients, and it did not affect their survival outcome. Notably patients who developed CRS after APVO436 therapy were not more or less likely to have a favorable response. Among 8 patients with favorable responses, 4 experienced a CRS and 4 did not. APVO436-related CRS was not required for clinically meaningful responses in R/R AML patients, and it did not affect the survival outcome. Prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS as well as patients who did not experience CRS after APVO436 infusions. Figure 1 Figure 1. Disclosures Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Watts: Takeda: Consultancy, Research Funding; Genentech: Consultancy; Rafael Pharma: Consultancy; Celgene/BMS: Consultancy. Mims: Kura Oncology: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi-Saynko: Consultancy; Glycomemetics: Research Funding; Leukemia and Lymphoma Society: Consultancy; Aptevo: Research Funding; Xencor: Research Funding. Patel: Peerview: Honoraria; BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding. Shami: Chimerix: Research Funding; BMS: Consultancy; Gilead: Consultancy; Takeda: Consultancy; Chimerix: Research Funding; Bastion Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; JSK Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Aptevo: Research Funding. Cull: Aptevo: Research Funding. Cogle: Celgene: Membership on an entity's Board of Directors or advisory committees; Aptevo therapeutics: Research Funding. Lee: oncotelic therapeutics: Current equity holder in publicly-traded company; Aptevo therapeutics: Consultancy. Uckun: oncotelic therapeutics: Current equity holder in publicly-traded company; Aptevo therapeutics: Consultancy; Reven Pharmaceuticals (Reven LLC): Consultancy, Membership on an entity's Board of Directors or advisory committees.

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An Open-Label Phase 2 Study Of Ofatumumab In Combination With a Novel AKT Inhibitor (Afuresertib) In Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.4175.4175 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4175-4175

Author(s):

Christine I. Chen ◽

Susi Snitzler ◽

Trina Wang ◽

Harminder Paul ◽

Lisa W Le ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Treatment Phase ◽

Phase 2 ◽

Akt Inhibitor ◽

Advisory Committees ◽

Phase 2 Study ◽

Previously Treated ◽

Grade 3

Abstract Introduction Ofatumumab is a novel anti-CD20 monoclonal antibody which led to impressive single-agent responses of 47-58% in a phase 2 study of CLL patients (pts) with refractory disease (Wierda et al 2010). Unfortunately, response durations were short (median 5.6-7.1 mos). In order to improve upon these results, we combined ofatumumab with a novel pan-AKT kinase inhibitor, afuresertib (GSK2110183). The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in relapsed/refractory hematologic malignancies (Spencer et al ASH 2011). We present an interim analysis of the initial 19 of 31 planned pts in an ongoing trial of ofatumumab and afuresertib in relapsed/refractory CLL. Methods Previously treated CLL pts who have received at least one prior fludarabine-containing regimen with disease progression are eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV is administered weekly for 8 doses, then once every 4 week cycle for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allows for evaluation of pharmacodynamic (PD) changes in phosphoproteins and pharmacokinetic (PK) studies. Pts are assessed for safety and response on day 1 of each cycle. Pts achieving SD, PR or CR by the end of the Treatment Phase proceed to the Maintenance Phase with single-agent afuresertib for a maximum of 12 mos (12 cycles). Results Demographics: To date, 19 pts have been enrolled. Median age is 65 yrs (range 43-76), baseline median Hb 108g/L (range 80-145), absolute lymphocytes 29.7 x109/L (range 1.0-464.9), β2M 4.42mg/L (range 1.42-3.21), bulky nodes ≥5cm in 5 pts (32%), organomegaly in 8 pts (42%), del17p/del11q on FISH in 9 pts (47%), and ZAP70+ in 13 pts (68%). Eight pts (42%) were fludarabine-refractory; only 2 pts had received prior alemtuzumab. The median number of prior therapies was 2 (range 1-6). Toxicity: Hematologic: 4 pts (21%) developed Gr 3-4 neutropenia during at least 1 cycle; 1 pt (5%) had a febrile neutropenia event. Only 2 pts (10.5%) have developed Gr 3-4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Most common related grade 3-4 toxicities were GI: dyspepsia (53%), diarrhea (37%), nausea (21%), temporally related to oral afuresertib and easily managed symptomatically. Infusion reactions to ofatumumab were frequent (12 pts; 63%) with grade 3 reactions in 3 pts. Five pts (26%) developed non-infectious pneumonitis, with 3 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation with weekly ofatumumab infusions. Most infections were mild, with only 1 grade 3 cellulitis. Efficacy: Of the 19 response-evaluable pts receiving a median of 6 cycles (range 1-9), 8 pts (42%) have achieved a PR, 11 SD (58%), and no CR. Response onset was rapid at a median 0.9 mos (range 0.8-2.8). At a median follow-up of 6.8 mos (range 0.3-12.9 mos), 5 pts (26%) have progressed and one patient has died after cycle 1 on therapy due to progressive CLL. PD Studies: CD19+ cells are assayed for phosphorylated AKT and its downstream targets RAS40 and GSK3 in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Peripheral blood samples are collected at screening and on cycle 1 day 10, after dosing with afuresertib. Of the 7 patients evaluated thus far, 5 demonstrated constitutive AKT phosphorylation at baseline. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. Conclusion Preliminary results from this phase 2 study suggests that a combination of ofatumumab plus a novel oral AKT inhibitor, afuresertib, has activity in previously treated CLL and is generally well-tolerated with minimal myelotoxicity. Response data are encouraging but whether durable responses can be achieved requires more mature follow-up. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Off-label use of ofatumumab and afuresertib for the treatment of relapsed/refractory CLL. Smith:GSK: Employment, Equity Ownership. Johnston:Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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

Blood ◽

10.1182/blood.v126.23.1528.1528 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1528-1528 ◽

Cited By ~ 4

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.

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

Blood ◽

10.1182/blood.v128.22.233.233 ◽

2016 ◽

Vol 128 (22) ◽

pp. 233-233 ◽

Cited By ~ 53

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.

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Long-Term Efficacy and Safety of the Oral Pyruvate Kinase Activator Mitapivat in Adults with Non-Transfusion-Dependent Alpha- or Beta-Thalassemia

Blood ◽

10.1182/blood-2021-150386 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 576-576

Author(s):

Kevin H.M. Kuo ◽

D. Mark Layton ◽

Ashutosh Lal ◽

Hanny Al-Samkari ◽

Joy Bhatia ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Publicly Traded ◽

Ineffective Erythropoiesis ◽

Advisory Committees ◽

The Core ◽

Grade 3 ◽

Hb Concentration ◽

Extension Period

Abstract Background: The thalassemias are a group of red blood cell (RBC) disorders in which ineffective erythropoiesis and hemolysis occur due to imbalanced production and precipitation of globin chains. Thalassemic RBCs have insufficient levels of ATP to meet increased energy demands associated with globin chain imbalance, protein degradation, and cellular oxidative stress responses. Mitapivat (AG-348) is a first-in-class, small-molecule, oral activator of RBC pyruvate kinase (PKR), a key enzyme regulating ATP production via glycolysis. In a phase 2, open-label trial of mitapivat in adults with α- or β-non-transfusion-dependent (NTD) thalassemia (NCT03692052), 80.0% (16/20) of patients (pts) met the primary endpoint of a hemoglobin (Hb) response (increase ≥ 1.0 g/dL from baseline at 1 or more assessments between Wks 4-12, inclusive). Improvements in markers of hemolysis and erythropoiesis were also observed in pts and mitapivat was generally well tolerated. Methods: Pts aged ≥ 18 (yrs) with a known medical history of α- or β-thalassemia, Hb concentration of ≤ 10.0 g/dL, and ≤ 5 RBC units transfused in prior 24 wks and none in 8 wks prior to study drug were eligible for the study. All pts started mitapivat at 50 mg twice daily (BID), escalating to 100 mg BID based on individual safety and Hb assessments. After completion of the 24-wk core period, pts were continued on mitapivat treatment in the extension period if they had achieved a Hb response, or a delayed Hb response (Hb increase of ≥ 1.0 g/dL at ≥ 1 assessment after Wk 12), with no ongoing grade ≥ 3 treatment-emergent adverse events (AE) related to study drug. Eligible pts continued mitapivat at the dose received at their Wk 24 visit. Study visits are conducted every 12 wks and will continue for up to 10 yrs. The extension period of the study is ongoing, here we report data up to Wk 72 visit (data cutoff March 27, 2021). Results: Of the 19 pts who completed the core period, 17 entered the extension period. During the extension period, 16 pts received 100 mg BID mitapivat and 1 received 50 mg BID. As of the cutoff date, 1 pt had discontinued (patient decision). Median (range, in wks) duration of mitapivat treatment for pts who entered the extension period was 70.9; (54.7, 105.6), with 8 of 17 pts receiving 72 wks or more of treatment as of the cutoff date for this analysis. The Median age of pts who entered the extension period was 44 yrs (range 29, 67). Mean baseline (standard deviation [SD]) Hb, total bilirubin and lactate dehydrogenase (LDH) was 8.1 (1.2) g/dL, 40.1 (26.2) μmol/L and 272.4 (121.7) U/L, respectively. Median baseline erythropoietin (EPO) was 70.5 (range 15, 11191) IU/L. Improvements in Hb concentration achieved in the core period were sustained in the extension study (n = 8 at Wk 72; Figure 1). Mean Hb (SD) increase from baseline to Wk 60 (which includes 4 pts with α- and 9 with β-thalassemia) and Wk 72 (which includes 8 pts with β-thalassemia) were 1.5 (0.4) g/dL and 1.7 (0.5) g/dL, respectively. Improvements in markers of hemolysis and ineffective erythropoiesis observed in the core period were maintained in the extension period up to Wk 72 (mean [SD] bilirubin and LDH, -15.8 [16.6] μmol/L and -63.6 [216.0] U/L, respectively; median [range] EPO, -33.0 [-72.0, -16.0] IU/L). The safety profile was consistent with that observed during the core period. AEs occurring in ≥ 15% of pts during the extension period were headache (5/17) and back pain (3/17), none of which were grade ≥ 3. No notable trends for changes in bone mineral density were observed (Figure 2). There were no treatment-related serious AEs during the extension period. Conclusions: In pts with either α- or β-thalassemia, a favorable efficacy-safety profile was observed with long-term treatment with mitapivat. Results show sustained improvements in Hb, hemolysis and ineffective erythropoiesis - despite the globin genotypic heterogeneity of the cohort - and no new safety findings. Mitapivat, through its unique mechanism of action, may represent a novel therapeutic approach for this condition. Two phase 3 trials of mitapivat in α- and β-thalassemia, one in pts who are NTD and one in pts who are transfusion-dependent, will be initiated in 2021. Figure 1 Figure 1. Disclosures Kuo: Bluebird Bio: Consultancy; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Apellis: Consultancy; Pfizer: Consultancy, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy. Layton: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cerus: Membership on an entity's Board of Directors or advisory committees. Lal: Chiesi: Consultancy; Agios Pharmaceuticals: Consultancy; bluebird bio, Inc.: Research Funding; La Jolla Pharmaceutical Company: Research Funding; Terumo Corporations: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Insight Magnetics: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Al-Samkari: Dova/Sobi: Consultancy, Research Funding; Moderna: Consultancy; Argenx: Consultancy; Rigel: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Agios: Consultancy, Research Funding. Bhatia: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Tong: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lynch: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Uhlig: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Vichinsky: Agios Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

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A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

Blood ◽

10.1182/blood-2021-150049 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3411-3411

Author(s):

Maro Ohanian ◽

Martha L. Arellano ◽

Moshe Y. Levy ◽

Kristen O'Dwyer ◽

Hani Babiker ◽

...

Keyword(s):

Clinical Trial ◽

High Risk ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

Grade 3 ◽

Refractory Aml

Abstract INTRODUCTION: APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN in vitro. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253) 3 complex which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863). AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity. METHODS: Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m 2 with planned escalation to 403 mg/m 2. RESULTS: As of June 7, 2021, a total of 18 patients (median age 64.0 years, 16 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 - 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66 (n=4), 100 (n=4) and 150 mg/m 2 (n=8). Most patients were RBC (87.5% of AML and 100% of MDS) and/or platelet (75% of AML and 50% MDS) transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Only 1 patient had a drug-related TEAE of grade 3 or greater (fatigue, Grade 3, probably related). Preliminary PK analysis (Figure 1) showed that serum levels of APTO-253 were dose proportional. C max and AUC 0-72h for C1D1 dosing were 0.06, 0.02, 0.36 ± 0.37, 0.44 ± 0.41 and 0.72 ± 0.70 µM and 0.11, 0.15, 3.98 ± 1.77, 4.79 ± 0.87 and 2.51 ± 1.73 µM*h for dose levels of 20, 40, 66, 100 and 150 mg/m 2, respectively. Plasma levels for Fe(253) 3 were significantly higher than those for the APTO-253 monomer. For example, C max and AUC 0-72h of Fe(253) 3 for C1D1 dosing of patients in Cohort 150 mg/m 2 were 2- and 20- fold higher than the ATPO-253 monomer at 15.09 ± 0.42 µM and 51.52 ± 28.26 µM*h, respectively. Following dosing at 150 mg/m 2, serum concentrations of Fe(253) 3 were above 0.5 µM for > 48 h, which approaches the therapeutic range based on in vitro studies. CONCLUSIONS: APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting. Figure 1 Figure 1. Disclosures Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Levy: AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties; Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Bejar: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Takeda: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Consultancy; Silence Therapeutics: Consultancy.

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Procalcitonin As a Potential Biomarker for Differentiating Bacterial Infectious Fevers from Cytokine Release Syndrome

Blood ◽

10.1182/blood-2018-99-120065 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4216-4216

Author(s):

Joseph Maakaron ◽

Sam Penza ◽

Zeinab El Boghdadly ◽

Caron A. Jacobson ◽

Bradley Hunter ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Inflammatory Markers ◽

Research Funding ◽

Bacterial Infections ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Advisory Committees ◽

Intravenous Antibiotics ◽

New Onset

Abstract Introduction Axicabtagene citoleucel (axi-cel) is a recently approved, highly effective treatment for relapsed and refractory aggressive B cell lymphomas. It is complicated by the occurrence of cytokine release syndrome (CRS) in > 90% of patients (Neelapu, Locke et al. 2017). CRS is characterized by high fevers and elevation in inflammatory markers such as C-reactive protein (CRP) and ferritin. It can progress to hypotension and end-organ damage. The clinical distinction between CRS and bacterial infections is virtually impossible. Procalcitonin (PCT) is FDA approved to aid in antibiotic management and stopping antibiotics in sepsis. It has been shown in several studies and meta-analyses to reduce antibiotic exposure without affecting mortality, including patients with cancer (Bouadma, Luyt et al. 2010, Schuetz, Chiappa et al. 2011, Sedef, Kose et al. 2015). Methods We sought to evaluate the utility of PCT as an infectious biomarker in patients undergoing commercial treatment with axi-cel. Patient data was collected retrospectively from two institutions and analyzed for clinical and laboratory characteristics, presence of documented infections, and presence and severity of cytokine release syndrome. PCT levels were drawn per the treating team's discretion based on clinical changes (new onset fever, new onset hypotension, requirement of vasopressors, change in level of care). Results A total of 30 patients received axi-cel for relapsed and refractory aggressive B-cell lymphoma and had PCT levels checked during their admission (Table 1). Median age was 61.5 years. Median baseline CRP and ferritin on day of infusion were 22.9 mg/L and 654 ng/mL, respectively. All patients had febrile episodes and evidence of at least grade I CRS by Lee criteria. Median duration of CRS was 6 days. Twenty-two patients (73.3%) had grade 2 or higher CRS. Median maximal temperature was 39.5 0C with a median duration of 5 days. Median number of days till first fever was 1 and median neutrophil count on day of first fever (> 38 0C) was 1475/mm3. Twenty-seven (90%) of the patients were on levofloxacin prophylaxis. Eight patients (26.7%) had an absolute neutrophil count (ANC) of less than 500/mm3 on the day of first fever. All but one patient (97%) were started on intravenous antibiotics during their admission. None of the patients had positive blood cultures. One patient had C. difficile infection and one patient had invasive sinusitis with mucormycosis. The timing of these infections did not correspond to the diagnosis of these infections. Median PCT was 0.86 ng/mL. Twelve patients (40%) had values below the cut-off for bacterial infections. Two of these patients required vasopressors. Three patients expired (10%). Two had progressive disease and one had an invasive fungal infection. Figure 1 shows one patient (panel A) who had normal PCT during their CRS episode and another who had abnormal ones. Discussion Axi-cel is a novel and promising therapy for treatment of relapsed and refractory aggressive B-cell lymphomas. Therapy is complicated by occurrence of CRS in 94% of patients, which can be fatal if not properly identified and managed. CRS can mimic sepsis and patients are frequently placed on broad-spectrum intravenous antibiotics, inducing risk for multi-drug resistant organisms and C. difficile infections. Unlike ferritin and CRP, PCT is typically only elevated in settings of bacterial infections, trauma and surgery and is FDA approved to be utilized in a treatment algorithm for earlier discontinuation of antibiotics in septic patients. It has not been studied in CRS. PCT was checked per the treating team's discretion and the trend was not followed for most of these patients. We herein hypothesize that PCT does not follow the same kinetics of other inflammatory markers frequently interrogated and may serve as a way to distinguish infection from CRS in this population, where 100% of patients experienced CRS and fevers, but 40% had normal PCT levels. The utility of PCT in antibiotic stewardship and the cut-off of 0.5 ng/mL should be further explored to guide antibiotic use in this population. Disclosures Jacobson: Pfizer: Consultancy; Kite: Consultancy; Humanigen: Consultancy; Novartis: Consultancy; Precision Bioscience: Consultancy; Bayer: Consultancy. Abramson:Merck: Consultancy; Juno Therapeutics: Consultancy; Celgene: Consultancy; Humanigen: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Karyopharm: Consultancy; Verastem: Consultancy. Kline:Merck: Honoraria, Research Funding; iTeos: Research Funding. Cohen:BioInvent: Consultancy; Janssen: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Gopal:Teva: Research Funding; Asana: Consultancy; Brim: Consultancy; Aptevo: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Incyte: Consultancy. Acharya:Teva: Honoraria; Juno Therapeutics: Research Funding. Jaglowski:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Juno: Consultancy; Kite Pharma: Consultancy, Research Funding.

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Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: Initial Results of a Phase II Study

Blood ◽

10.1182/blood-2018-99-114125 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 354-354 ◽

Cited By ~ 7

Author(s):

Raajit K. Rampal ◽

Srdan Verstovsek ◽

Sean M Devlin ◽

Eytan M. Stein ◽

Tapan M. Kadia ◽

...

Keyword(s):

Platelet Count ◽

Combination Therapy ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Single Agent ◽

Response Assessment ◽

Platelet Response ◽

Advisory Committees ◽

Grade 3

Abstract Background: Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thrombocytopenia in particular often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could result in improvement in both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report initial analysis of this study (NCT03069326). Methods: We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had less than PR per IWG-MRT/ELN 2013 criteria, or be refractory, to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and must have been on a stable dose of RUX for a minimum of 4 weeks immediately prior to enrollment. Treatment-naïve patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria in patients with baseline thrombocytopenia (less than lower limit of normal) included: Major response (≥75% increase in platelet count), Intermediate Response (≥50% increase) and Minor Response (≥25% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: A total of 25 patients are planned to be accrued. At the time of this writing, a total of 18 patients have been accrued. The median age was 70.5 years (47-85). 8 patients had received prior therapies other than RUX, including imetelstat, momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 7 patients enrolled to the run-in phase. 14 patients received red blood cell transfusions prior to study enrollment. Evaluation of platelet count in patients with baseline thrombocytopenia demonstrated a significant increase in platelet count at cycle 3 of therapy compared to baseline (Figure 1A and B; P<0.05). An increase in Hgb was observed over successive cycles of combination therapy (Figure 1C and D). 5 of 18 accrued patients completed ≥6 cycles of combined therapy at the time of abstract submission and were thus evaluable for response assessment. The overall response rate in these patients was 80% (4/5 patients). Clinical Improvement (Anemia response and Symptom response) occurred in 3 patients (both responses observed in all 3 patients). Major platelet response was observed in 4 of 5 patients with baseline thrombocytopenia. 1 patient met criteria for spleen response (Table 1). Grade 3/4 non-hematologic adverse events regardless of attribution included; limb edema, diverticulitis, hypertension, syncope. 1 patient experienced a thromboembolic event. 1 patient experienced a grade 3 hematologic AE (neutropenia). Conclusions: The combination of THAL and RUX has demonstrated a promising efficacy signal in this initial analysis of an ongoing phase II study, and appears to be well tolerated. Platelet count increases were observed in all patients who entered study with baseline thrombocytopenia, a response which appears to be maintained in the majority of patients observed 6 months after starting combination therapy. As well, anemia responses were observed in 3 of 5 evaluable patients. Collectively, these data indicate a potential role for this regimen in patients with anemia and/or thrombocytopenia, who otherwise have limited treatment options. Updated data on duration of response and overall response of all accrued patients will be presented. Disclosures Rampal: Constellation: Research Funding; Celgene: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stein:Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding.

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Universal: An Allogeneic First-in-Human Study of the Anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-140641 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25 ◽

Cited By ~ 1

Author(s):

Sham Mailankody ◽

Jeffrey V. Matous ◽

Michaela Liedtke ◽

Surbhi Sidana ◽

Shahbaz Malik ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Assessment ◽

Publicly Traded ◽

Advisory Committees ◽

Oncology Research ◽

Car T ◽

Grade 3 ◽

Dose Levels

Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T cell therapy addresses the logistical challenges, availability and variable product quality of autologous CAR T therapy. ALLO-715 is a genetically modified anti-BCMA AlloCAR Ttm cell product in which the TCR alpha constant gene is disrupted to reduce the risk of graft-versus-host disease (GvHD) and the CD52 gene is disrupted with Talen® technology to permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion (LD). Methods This is an open-label, Phase 1 trial (NCT04093596) in adults with R/R multiple myeloma who have received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulator, and anti-CD38 mAb. Patients (pts) must be refractory to their last treatment line. Patients receive LD followed by ALLO-715 at 1 of 4 dose levels (DL) in a 3+3 dose escalation design: 40, 160, 320, and 480 x 106 CAR+ T cells. Several LD regimens are being evaluated. These include: FCA (fludarabine (F) 90 mg/m2, cyclophosphamide (C) 900 mg/m2, and ALLO-647 (A) 39 mg divided over 3 days), FCA+ (same F and C but ALLO-647 (A+) dose of 90 mg divided over 3 days); as well as CA (same C and A divided over 3 days, but no F given). Results As of 08 July 2020, 19 pts had enrolled and 15 had received ALLO-715 at 3 DLs: 3 pts at DL1 (3 FCA and 0 CA); 7 pts at DL2 (4 FCA and 3 CA); 5 pts at DL3 (3 FCA and 2 CA). As of the data cutoff, no pts had received FCA+ or ALLO-715 DL4. Patients were heavily pre-treated and in advanced stage of disease with a median of 5 (range 3-11) prior lines of therapy and 31.6% ISS Stage III at screening. All but 1 had a prior autologous stem cell transplant. 52.6% (10/19) of patients had high risk cytogenetics, and 26.3% (5/19) had extramedullary disease. The most common Grade ≥3 adverse events were anemia (41.2%), neutropenia (41.2%), lymphopenia (29.4%), and thrombocytopenia (29.4%). Four episodes of Grade ≥3 infections occurred in 4 pts. Three of these were Grade 3 and included parvovirus B19, staphylococcal bacteremia, and pneumonia, which resolved with treatment. The fourth was a Grade 5 episode that occurred on day 8 post-ALLO-715 infusion in a rapidly progressing, refractory myeloma pt who, on day 1, developed a non-neutropenic fever and multifocal pneumonia with negative blood and sputum cultures. The patient progressed to respiratory failure and only comfort care was pursued. This death was considered related to conditioning (CA). No DLTs to ALLO-715 had been reported as of the data cutoff. In addition, no neurotoxicity (ICANS) or GvHD had been reported as of the data cutoff. Cytokine release syndrome was reported in 4 pts (24%). Three episodes were Grade 1 and 1 was Grade 2 (Lee Grading); all resolved without tocilizumab or corticosteroids. Fifteen pts were efficacy evaluable (defined as receiving ALLO-715, and undergoing at least one response assessment or discontinuing prior to the first response assessment), with a median follow-up of 2 months (range 0, 10 months). A higher dose of ALLO-715 (DL3) was associated with greater anti-cancer activity with 3/5 pts responding per IMWG (60%, 95% CI 14.7, 94.7). In pts who received DL3 FCA, 2/3 responded (1 sCR and 1 VGPR, Table 1). All DL3 pts who responded experienced at least a VGPR and achieved MRD negative status by local MRD testing. All responses were initially observed at day 14. Four (80%) out of the 5 responders were still in response at the time of the data cutoff. ALLO-715 cell expansion by qPCR was observed at all dose levels. Conclusions These early data suggest that ALLO-715 and ALLO-647 have a manageable safety profile. ALLO-715 shows evidence of clinical activity in the allogeneic setting in pts with R/R multiple myeloma and suggests that higher cell doses are associated with greater anti-cancer activity. Enrollment is ongoing in cohorts with higher ALLO-715 (480M CAR+ T-cells) and ALLO-647 (90mg). Updated safety, efficacy, PK/PD data will be presented. Clinical trial information: NCT04093596. Disclosures Mailankody: Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Matous:Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Sidana:Janssen: Consultancy. Nath:Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Oluwole:Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy. Karski:Crisper Therapeutics: Current equity holder in publicly-traded company; Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Lovelace:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhou:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Nandakumar:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Balakumaran:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Merck: Ended employment in the past 24 months. Hari:BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; GSK: Consultancy; Incyte Corporation: Consultancy.

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Safety and Antitumor Activity Study Evaluating Loncastuximab Tesirine and Rituximab Versus Immunochemotherapy in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2020-136614 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Yuliya Linhares ◽

Mitul D Gandhi ◽

Michael Chung ◽

Jennifer Adeleye ◽

David Ungar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Advisory Board ◽

Publicly Traded ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Large B Cell

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) who fail immunochemotherapy (IC) and are unsuitable for autologous stem cell transplantation (ASCT) and those who relapse shortly after ASCT have extremely poor prognosis and need additional treatment options. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 2 study (NCT03589469), Lonca demonstrated single-agent antitumor activity with manageable toxicity in patients with relapsed/refractory (R/R) DLBCL. Rituximab is a CD20-targeting monoclonal antibody used in front-line IC for DLBCL and in salvage regimens, such as rituximab/gemcitabine/oxaliplatin (R-GemOx). The addition of rituximab to a CD19-targeting pyrrolobenzodiazepine ADC appears to prolong tumor control in preclinical studies, providing the rationale for evaluating Lonca combined with rituximab (Lonca-R) as a treatment for R/R DLBCL. Study Design and Methods: This is a Phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R versus standard IC in patients with R/R DLBCL (NCT04384484). Part 1 is a nonrandomized safety run-in with Lonca-R. The toxicity of Lonca-R will be compared with previous single-agent Lonca safety data after 20 patients have completed Cycle 1 in Part 1. Provided no significant increase in toxicity is observed, Part 2 will be initiated. Part 2 is a randomized study of Lonca-R versus R-GemOx (Figure 1). Key inclusion and exclusion criteria are reported in Table 1. The primary objective of Part 2 is to evaluate the efficacy of Lonca-R versus R-GemOx, using progression-free survival (PFS) as the primary endpoint. PFS will be defined as the time between randomization and first documentation of recurrence, disease progression or death (central review) and the primary analysis will compare PFS between treatment arms using stratified log-rank testing. Secondary objectives include evaluation of safety, pharmacokinetics, and immunogenicity of the combination, in addition to the impact of treatment on symptoms, patient-reported outcomes and patients' overall health. In Part 1 and in the Lonca-R arm of Part 2, patients will receive intravenous (iv) Lonca at 150 µg/kg on day 1 of each 21-day cycle for 2 cycles, then at 75 µg/kg on day 1 for up to 6 additional cycles. Rituximab 375 mg/m2 iv will be administered subsequent to Lonca infusion on day 1 of each cycle. Patients treated with Lonca-R will also be given dexamethasone 4 mg (oral, twice a day), where not contraindicated, on the day before, the day of, and the day after Lonca-R infusion. In the R-GemOx arm, patients will receive rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 iv on day 1 of each 14-day cycle up to a total of 8 cycles. Patients will receive premedication and supportive care according to the respective prescribing information for rituximab, gemcitabine, and oxaliplatin. The trial is planned to open in Q3/Q4 2020, and target enrollment is 350 patients. Funding: This study is sponsored by ADC Therapeutics SA; https://clinicaltrials.gov/ct2/show/NCT04384484. Disclosures Linhares: Jazz Pharmaceuticals: Consultancy; ADC Therapeutics, Verastem Oncology, Bristol Myers-Squibb (Juno), AstraZeneca: Research Funding; Miami Cancer Institute, Baptist Health South Florida: Current Employment. Gandhi:TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Adeleye:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hamadani:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. OffLabel Disclosure: Rituximab is licensed for treatment of NHL but is being used in combination with an unlicensed drug (loncastuximab tesirine) in this study

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