Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial

BackgroundPatients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.MethodsThis was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.ResultsThe composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.ConclusionsThe combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need

A Study to Assess the Efficacy of Enasidenib and Risk-Adapted Addition of Azacitidine in Newly Diagnosed IDH2-Mutant AML

Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998

A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485

KMT2A partial tandem duplication occurs in approximately 5–10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of KMT2A partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter2 daily on days 1–10 and vorinostat 400 milligrams daily on days 5–10. Cytarabine was dose-escalated from 1.5 grams/meter2 every 12 hours to 3 grams/meter2 every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with KMT2A partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the KMT2A partial tandem duplication subset. (clinicaltrials.gov identifier 01130506)

Real‐world genomic testing and treatment patterns of newly diagnosed adult acute myeloid leukemia patients within a comprehensive health system

Abstract Background We evaluated the frequency of genomic testing and treatment patterns by age category in patients with newly diagnosed (ND) acute myeloid leukemia (AML) treated in both academic‐ and community‐based health systems within a single Midwestern State. Methods Retrospective analysis of data from the Indiana University Health System Enterprise Data Warehouse and two local cancer registries, of 629 patients aged ≥18 years with ND AML during 2011–2018. Primary outcome variables were, proportion of patients with genomic analysis and frequency of mutations. Chemotherapy was categorized as “standard induction” or “other chemotherapy”/targeted therapy, and hypomethylating agents. Results Overall, 13% of ND AML patients between 2011 and 2018 had evidence of a genomic sequencing report with a demonstrated increase to 37% since 2016. Genomic testing was more likely performed in patients: aged ≤60 years than >60 years (45% vs. 30%; p = 0.03), treated in academic versus community hospitals (44% vs. 26%; p = 0.01), and in chemotherapy recipients than non‐therapy recipients (46% vs. 19%; p < 0.001). Most common mutations were ASXL1, NPM1, and FLT3. Patients ≥75 years had highest proportion (46%) of multiple (≥3) mutations. Overall, 31.2% of patients with AML did not receive any therapy for their disease. This subgroup was older than chemotherapy recipients (mean age: 71.4 vs. 55.7 years, p < 0.001), and was highest (66.2%) in patients ≥75 years. Conclusions Our results highlight the unmet medical need to increase access to genomic testing to afford treatment options, particularly to older AML patients in the real‐world setting, in this new era of targeted therapies

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

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

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

A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

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). In this first-in-human (FIH) multicenter phase 1B study, we sought to determine the safety and tolerability of APVO436 in R/R AML/myelodysplastic syndrome (MDS) patients and identify a clinically active recommended phase 2 dose (RP2D) level for its further clinical development. A total of 46 R/R AML/MDS patients who had failed 1–8 prior lines of therapy received APVO436 as weekly intravenous (IV) infusions at 10 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.3 mcg to 60 mcg. 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%). The single dose RP2D level was identified as 0.2 mcg/kg. Preliminary efficacy signals were observed in both AML and MDS patients: Prolonged stable disease (SD), partial remissions (PR), and complete remissions (CR) were observed in R/R AML patients as best overall responses to APVO436 at the RP2D level. Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential

Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory 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). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an 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), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The 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

Interaction of Antifungal Drugs with CYP3A- and OATP1B-Mediated Venetoclax Elimination

Venetoclax, a BCL-2 inhibitor used to treat certain hematological cancers, exhibits low oral bioavailability and high interpatient pharmacokinetic variability. Venetoclax is commonly administered with prophylactic antifungal drugs that may result in drug interactions, of which the underlying mechanisms remain poorly understood. We hypothesized that antifungal drugs may increase venetoclax exposure through inhibition of both CYP3A-mediated metabolism and OATP1B-mediated transport. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms, or OATP1B2 that received venetoclax alone or in combination with ketoconazole or micafungin. In mice lacking all CYP3A isoforms, venetoclax AUC was increased by 1.8-fold, and pretreatment with the antifungal ketoconazole further increased venetoclax exposure by 1.6-fold, despite the absence of CYP3A. Ensuing experiments demonstrated that the deficiency of OATP1B-type transporters is also associated with increases in venetoclax exposure, and that many antifungal drugs, including micafungin, posaconazole, and isavuconazole, are inhibitors of this transport mechanism both in vitro and in vivo. These studies have identified OATP1B-mediated transport as a previously unrecognized contributor to the elimination of venetoclax that is sensitive to inhibition by various clinically-relevant antifungal drugs. Additional consideration is warranted when venetoclax is administered together with agents that inhibit both CYP3A-mediated metabolism and OATP1B-mediated transport