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This was an open-label, multicenter, phase-1 study to evaluate the drug interaction between steady-state ibrutinib and moderate (erythromycin) and strong (voriconazole) CYP3A inhibitors in patients with B-cell malignancies and to confirm dosing recommendations. During cycle 1, patients received oral ibrutinib 560 mg qd alone (Days 1-4 and 14-18), and ibrutinib 140 mg (Days 5-13; 19-27) plus erythromycin 500 mg tid (Days 5-11) and voriconazole 200 mg bid (Days 19-25). Twenty-six patients (median [range] age: 64.5 [50-88] years) were enrolled. Geometric mean ratio (90% confidence intervals) after co-administration of ibrutinib 140 mg with erythromycin and voriconazole was 74.7 (53.97-103.51) and 143.3 (107.77-190.42), respectively, versus ibrutinib 560 mg alone. The most common (≥20%) adverse events were diarrhea (27%) and neutropenia (23%). The results demonstrate that ibrutinib 140 mg with voriconazole or erythromycin provides exposure within the clinical range for patients with B-cell malignancies.

Background Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. MethodsIn this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Findings Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6•8 months (95% CI 5•0-8•5; 165 [67%] of 246 patients had an event) in the melflufen group and 4•9 months (4•2-5•7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0•79, [95% CI 0•64-0•98]; p=0•032), at a median follow-up of 15•5 months (IQR 9•4-22•8) in the melflufen group and 16•3 months (10•1-23•2) in the pomalidomide group. Median overall survival was 19•8 months (95% CI 15•1-25•6) at a median follow-up of 19•8 months (IQR 12•0-25•0) in the melflufen group and 25•0 months (95% CI 18•1-31•9) in the pomalidomide group at a median follow-up of 18•6 months (IQR 11•8-23•7; HR 1•10 [95% CI 0•85-1•44]; p=0•47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs...

BCD-020 (Acellbia, rituximab biosimilar candidate) was shown to be highly similar to innovator rituximab (MabThera®/Rituxan®) in terms of its quality characteristics, in vitro biological activity, as well as toxicology and PK/PD characteristics in non-human primates. International multicenter comparative randomized open-label clinical study was carried out in a period from 2011 to 2013 and involved over 30 centers in Russia, Ukraine and India. Its methodology and design complies with current EMA guidelines on similar biological products containing monoclonal antibodies (EMA/CHMP/BMWP/403543/2010). 92 patients with follicular non-Hodgkin’s lymphoma, stage I-IV by Ann Arbor, or marginal zone lymphoma, stage I-IV by Ann Arbor, ECOG 0-2, who had at least 1 measurable lesion were enrolled. According to study protocol patients with secondary transformed B-cell lymphomas or with highly aggressive types of tumor, bulky disease, severe concomitant somatic disorders and some other conditions were excluded. If a patient had previous story of chemotherapy or radiation he could be included after at least 3 weeks post-treatment. Participation of patients who were previously treated with any kind of monoclonal antibodies was prohibited. After signing standard informed consent form and completion of 28-days screening period eligible patients underwent stratification in accordance to their prognostic risk (FLIPI or IPI) and previous treatment (naïve or pretreated). Subsequently patients were randomized (1:1) into 2 groups: 46 patients were included in the main group where Acellbia (rituximab biosimilar) was administered at a dose of 375 mg/m2 as a slow IV infusion on day 1, 8, 15 and 22; 46 patients were included in the reference group where MabThera was used at the same regimen. Use of any other medicines for the treatment of lymphoma was strictly prohibited. Efficacy was assessed on the basis of computed tomography and bone marrow evaluation which were performed 1 month after the completion of treatment. Median age of patients in each group was 57.5 years (main group [50.0-64.0], reference group [47.0-65.0]). Manageable comorbidities were reported in 50% of patients in the main group and 34.78% of patients in the reference group, p=0.2053. Comparative analysis of the prognostic risk factors confirmed the equivalence of study groups. The number of pretreated patients in both groups was equal – 8 individuals per group. Statistical analysis didn’t find any difference in overall response rate in general population of patients (39.52% patients in the main group vs. 36.57% patients in the reference group, p=0.8250), as well as in population of pretreated patients (28.6% vs 37.5% respectively, p=1.00) and in population of naïve patients (42.8% vs 39.4% respectively, p=1.00). The lower limit of the two-tailed 95% CI for difference in proportions of ORR was equal to -0.17 and exceeded the predefined non-inferiority margin -0.2, which confirmed non-inferiority of Acellbia to MabThera in terms of efficacy. Treatment-associated AE of any grade were reported in 21.74% patients in both arms, in the absence of statistically or clinically significant difference (p = 0.8005). There were 2 cases of CTCAE 4.03 grade 3-4 AEs in each group. PK and PD parameters were shown to be equivalent in both study groups. Thus, study results suggest that Acellbia has same efficacy and safety in patients with B-cell non-Hodgkin’s lymphoma. Disclosures Chernyaeva: JCS BIOCAD: Employment. Ivanov:JCS BIOCAD: Employment. Isaev:JCS BIOCAD: Employment.

Background:Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase, is indicated for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (including 17p deletion), and Waldenström's macroglobulinemia. Because ibrutinib is extensively cleared by cytochrome P450 (CYP) 3A4, concomitant treatment with CYP3A inhibitors has been shown to increase ibrutinib exposure in healthy adults. However, sparse PK data from uncontrolled phase 2 studies with moderate CYP3A inhibitors showed a lower magnitude of drug-drug interactions (DDI) than observed in studies with healthy subjects or in silico simulations under nonfasted conditions (data on file). This phase 1 study was conducted to evaluate potential DDIs between ibrutinib and CYP3A inhibitors in patients with B-cell malignancies and to confirm recommended dose adjustments. Methods: This was an open-label, multicenter, DDI study of ibrutinib with erythromycin (moderate CYP3A inhibitor) and voriconazole (strong CYP3A inhibitor) in patients (≥ 18 years) with relapsed/refractory B-cell malignancy. During the first treatment cycle, patients received an oral dose of 560 mg ibrutinib on days 1-4 (steady-state) and days 14-18. On days 5-13 and 19-27, the dose was reduced to 140 mg ibrutinib and combined with erythromycin (500 mg tid on days 5-11) and then with voriconazole (200 mg bid on days 19-25). On PK sampling days (days 4 [alone], 11 [with erythromycin], and 25 [with voriconazole]), ibrutinib was administered 30 min before a standard breakfast. On these PK sampling days, the morning doses of voriconazole and erythromycin were administered 1 hr prior to ibrutinib and together with ibrutinib, respectively. PK samples were taken pre- and up to 24 hr postdose; key PK parameters were summarized for ibrutinib, PCI-45227 (ibrutinib metabolite), erythromycin, and voriconazole. After completion of the DDI assessment during cycle 1, patients continued treatment with ibrutinib monotherapy at therapeutic doses. Safety was evaluated throughout the study. Results:All patients (N = 26) completed the PK assessments in cycle 1; 54% were men, and the median age was 65 years. The geometric mean ratio (GMR) for dose-normalized maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0 to 24 hr (AUC24h) for ibrutinib was 3.35 and 2.99, respectively, when given in combination with erythromycin (Table). When ibrutinib was coadministered with voriconazole, the GMR for Cmax and AUC24h was 6.71 and 5.74, respectively (Table). Four out of 26 patients showed either no interaction between ibrutinib and erythromycin or a lower ibrutinib exposure (AUC ratios 0.27-0.99). Three of these 4 patients also displayed minimal interaction with voriconazole (AUC ratios 1.08-1.96); baseline ibrutinib AUCs for the 3 patients were at the high end of the range, indicating lower CYP3A abundance and thus less impact from CYP inhibition. Physiologically-based PK modeling under fed conditions predicted a 5.5- and 7.1-fold increase in the GMR for ibrutinib Cmax and AUC, respectively, when dosed with erythromycin and an increase of 6.3- and 7.6-fold, respectively, when dosed with voriconazole. The simulated interaction factor for voriconazole is contained in the 90% CI of the observed GMRs (borderline for AUC), whereas the model over-predicted Cmax and AUC by ~50% and ~130%, respectively. Treatment-emergent adverse events (TEAEs) were reported in 22/26 patients (85%); The most common TEAEs (all causality, ≥ 10% of patients) were diarrhea (27%); neutropenia (23%); abdominal pain, fatigue, pyrexia, and thrombocytopenia (15% each); anemia, dry mouth, cough, dyspnea, and hypertension (12% each). Drug-related TEAEs ≥ grade 3 were neutropenia (15.4%); hypertension (7.7%); and diarrhea, thrombocytopenia, herpes zoster, cough, dyspnea, atrial fibrillation, and cardiac failure (3.8% each). Conclusions:PK data indicate that 140 mg ibrutinib, when combined with a moderate or strong CYP3A inhibitor, achieved exposures generally consistent with those after a 560 mg dose given alone. Coadministration of 140 mg ibrutinib with erythromycin or voriconazole demonstrated an acceptable safety profile, and the adverse event profile was consistent with the ibrutinib safety profile at therapeutic doses. These findings support the 140 mg/day ibrutinib dose when given in combination with erythromycin or voriconazole. Disclosures de Jong: Janssen: Employment. Hellemans:Janssen: Employment, Equity Ownership. De Wilde:Janssen: Employment. Patricia:Janssen: Employment. Masterson:Janssen: Employment. Osmanov:Seattle Genetics: Research Funding. Cordoba:Janssen: Research Funding, Speakers Bureau. Panizo:Roche Pharmaceuticals: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. de Zwart:Janssen: Employment. Snoeys:Janssen: Employment, Equity Ownership. Chauhan:Janssen: Consultancy. Jiao:Janssen: Employment. Sukbuntherng:Pharmacyclics, LLC: Employment, Equity Ownership; Global Blood Therapeutics: Equity Ownership. Ouellet:Janssen: Employment.