An Open-Label, Phase 1b Study of Acalabrutinib With and Without Dexamethasone in Subjects With Multiple Myeloma

AEs and SAEs were coded by system organ class (SOC) and preferred term (PT) based on the Medical Dictionary for Regulatory Activities (MedDRA) reporting system. All AEs summarized were treatment-emergent. Summaries were also presented by the severity of the AE (per Common Toxicity Criteria for Adverse Events \[CTCAE\]) and by relationship to study drug as assessed by the investigator. Events of clinical interest (ECIs) selected for dedicated analysis were evaluated using Standardized MedDRA Queries, where available, by SOC, or by Sponsor-defined baskets of MedDRA Adverse Event Grouped Terms (AEGTs). The following ECIs were summarized: Cardiac events (including a subset of atrial fibrillation), cytopenias (anemia, leukopenia, neutropenia, and thrombocytopenia), hemorrhage (including a subset of major hemorrhage), hepatic events, hypertension, infection, interstitial lung disease/pneumonitis, second primary malignancies (second primary malignancies excluding skin), tumor lysis syndrome.

Time frame: From first dose of study drug up to Cycle 12 (48 weeks). Subjects who showed benefit from study drugs were allowed to continue until disease progression.

The percent occupied BTK was calculated in each subject's peripheral blood mononuclear cells (PBMC) sample for each assessment timepoint using an ELISA-based method. Samples from 17 subjects met the criteria for data inclusion, having a dynamic range (signal to noise) of ≥5 for the Day 1 pre-dose timepoint. Acalabrutinib administered at 100 mg bid resulted in a median steady-state (Day 8) BTK target occupancy level of 95% and 98% for Cohort 1 and Cohort 2, respectively. The Days 28 and 56 assessments, both taken at pre-dose, were \>97% occupancy for each cohort. Intersubject variability was low, with 6 of 7 (86%) subjects in Cohort 1 and 4 of 5 (80%) subjects in Cohort 2 having \>90% BTK occupancy at steady-state trough (12h post-dose). The single subject in Cohort 2 with \<90% occupancy at Day 8 pre-dose did not take their Day 7 doses.

Time frame: On Days 1 and 8: pre-dose and at 4 hours after the morning dose. On Days 28 and 56: morning pre-dose only.

Population: 17 (of 27) subjects with evaluable data. For 10 subjects the data was excluded due to: no Day 1 sample received, low cells events or parent populations, or other deviation.~Day 1 post and additional time points, further decrease of evaluable data due to: subject discontinuation, low cells events or parent populations, or other deviation.

The plasma PK of study drug was characterized using noncompartmental analysis. PK parameters were calculated whenever possible, from plasma concentrations of acalabrutinib. Missing dates or times could have been imputed for PK and pharmacodynamic (PD) samples if the missing values could be established with an acceptable level of accuracy based on other information obtained during the visit in question. If PK and PD sampling for a 33 Final Clinical Study Report Drug Substance Acalabrutinib Study Code ACE-MY-001 Edition Number 2 Date 31 October 2018 given subject was not performed according to protocol, the subject could have been excluded from the PK and PD analyses. The PK parameters were tabulated and summarized using descriptive statistics. For each PD variable, the concentration at each assessment was described. The change from baseline to each assessment was summarized. As appropriate the on treatment values were compared with the pretreatment baseline values using paired t-tests.

Time frame: On Days 1 and 22: pre-dose, and at 0.5, 0.75, 1, 2, 4, and 6 hours after the morning dose. On Days 8, 15, and 28: pre-dose and 1 hour after the morning dose.

Population: Day 1: 24 (of 27 subjects enrolled) were equally randomized (1:1 ratio) into two cohorts to receive Acalabrutinib (12 in Cohort 1), or with dexamethasone (12 in Cohort 2).~Day 22: 17 (of 24) subjects with PK data were remaining: 9 in Cohort 1 and 8 in Cohort 2. Seven subjects discontinued the study prior to Day 22.

Per EBMT: CR, negative immunofixation of serum and urine, disappearance of plasmacytomas and \< 5% plasma cells; Stringent complete response (SCR), CR + normal flow cytometry and absence of clonal plasma cells; Very good partial response (VGPR), Serum and urine M-protein detectable on immunofixation but not on electrophoresis or \> 90% reduction is serum and urine M protein; Partial response (PR), \> 50% reduction in serum M-protein and \> 90% reduction in 24 hour urine M-protein, \> 50% reduction in baseline soft tissue plasmacytoma; Minimal response (MR), 25-49% reduction of serum M-protein and 50-59% reduction in 24 hour urine M-protein, 25-49% reduction in plasmacytomas and no increase in lytic bone lesions; Stable disease (SD), not meeting criteria for CR, VGPR, MR, PR or progressive disease (PD); PD, increase of 25% or more from nadir in serum M-protein, urine M-protein, new or increased bone lesions or plasmacytomas, or hypercalcemia solely attributed to multiple myeloma.

Time frame: From first dose of study drug up to Cycle 12 (48 weeks). Subjects who showed benefit from study drugs were allowed to continue until disease progression