Bioequivalence and Relative Bioavailability Studies to Assess a New Acalabrutinib Formulation That Enables Coadministration With Proton-Pump Inhibitors.

Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved to treat adults with chronic lymphocytic leukemia, small lymphocytic lymphoma, or previously treated mantle cell lymphoma. As the bioavailability of the acalabrutinib capsule (AC) depends on gastric pH for solubility and is impaired by acid-suppressing therapies, coadministration with proton-pump inhibitors (PPIs) is not recommended. Three studies in healthy subjects (N = 30, N = 66, N = 20) evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability of acalabrutinib maleate tablet (AT) formulated with pH-independent release. Subjects were administered AT or AC (orally, fasted state), AT in a fed state, or AT in the presence of a PPI, and AT or AC via nasogastric (NG) route. Acalabrutinib exposures (geometric mean [% coefficient of variation, CV]) were comparable for AT versus AC (AUCinf 567.8 ng h/mL [36.9] vs 572.2 ng h/mL [38.2], Cmax 537.2 ng/mL [42.6] vs 535.7 ng/mL [58.4], respectively); similar results were observed for acalabrutinib's active metabolite (ACP-5862) and for AT-NG versus AC-NG. The geometric mean Cmax for acalabrutinib was lower when AT was administered in the fed versus the fasted state (Cmax 255.6 ng/mL [%CV, 46.5] vs 504.9 ng/mL [49.9]); AUCs were similar. For AT + PPI, geometric mean Cmax was lower (371.9 ng/mL [%CV, 81.4] vs 504.9 ng/mL [49.9]) and AUCinf was higher (AUCinf 694.1 ng h/mL [39.7] vs 559.5 ng h/mL [34.6]) than AT alone. AT and AC were similar in BTK occupancy. Most adverse events were mild with no new safety concerns. Acalabrutinib formulations were comparable and AT could be coadministered with PPIs, food, or via NG tube without affecting the PKs or PDs.

Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients.

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: NCT02029443, NCT02475681, NCT02970318 and NCT02337829). Acalabrutinib was given orally at total daily doses of 100-400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32-89]; median follow-up: 25.9 months [range, 0-58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with highrisk CLL (clinicaltrials gov. Identifier: NCT02477696) prospectively assess differences in CV toxicity between the two agents.

Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial.

BACKGROUND: Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL). METHODS: Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days. RESULTS: Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26-48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3-4 events; these events were generally reversible. No treatment-related deaths were reported. CONCLUSIONS: Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://clinicaltrials.gov/ct2/show/NCT01829711.

XPD DNA nucleotide excision repair gene polymorphisms associated with DNA repair deficiency predict better treatment outcomes in secondary acute myeloid leukemia.

Pharmacogenetic studies in DNA repair pathway have consistently demonstrated correlations between the XRCC1 Arg399Gln, XPD Lys751Gln and XPD Asp312Gln genotypes, previously associated with suboptimal DNA repair, and differential cancer treatment outcomes. We evaluated these polymorphisms and XPD haplotypes in adult de novo (n=214) and secondary (n=79) acute myeloid leukemia (AML) patients treated with cytarabine and anthracycline chemotherapy. Genotyping was performed by MALDI-TOF mass spectrometry. Logistic and proportional hazards regression models were used to evaluate relationships. Differential responses were observed in secondary, but not de novo, AML. Among secondary AML patients, the odds of achieving complete remission (CR) were higher for the XPD 312Asn/Asn (OR= 11.23; 95% CI, 2.23-56.63) and XPD 751Gln/Gln (OR= 7.07; 95% CI, 1.42-35.18) genotypes. The XPD diplotypes were coded as the combination of two of the following haplotypes: haplotype A=(Lys)751A/(Asp) 312G; B=(Gln)751C/(Asn)312A; C=(Lys)751A/(Asn)312A; and D=(Gln)751C/(Asp)312G. The BB diplotype was associated with CR attainment [OR=18.31; 95% CI: 2.08-283.57] and longer survival [HR=0.31; 95% CI: 0.14-0.73] compared to the referent AA diplotype. The XPD 751 CC, 312GA, 312AA genotypes and the XPD DC diplotype were also associated with longer overall survival (OS).Thus, XPD codon 312 and 751 variant genotypes and haplotypes containing at least one variant allele may predict better treatment responses. If validated, these findings could support stratification of chemotherapy in secondary AML.