Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma.

BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

Upadacitinib plus topical corticosteroids in atopic dermatitis: Week 52 AD Up study results.

BACKGROUND: Primary (week 16) results from the ongoing phase 3, double-blind AD Up study (NCT03568318) demonstrate a positive benefit-risk profile for upadacitinib + topical corticosteroid (TCS) in patients with moderate-to-severe atopic dermatitis. OBJECTIVE: We evaluated the efficacy and safety of upadacitinib + TCS through 52 weeks. METHODS: Patients aged 12 to 75 years with chronic moderate-to-severe atopic dermatitis (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] ≥16, Validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] ≥3, and Worst Pruritus Numerical Rating Scale [WP-NRS] score ≥4) were randomized 1:1:1 to once-daily upadacitinib 15 mg + TCS, upadacitinib 30 mg + TCS, or placebo (PBO) + TCS (rerandomized at week 16 to upadacitinib + TCS). Safety and efficacy, including proportion of patients experiencing ≥75% improvement in EASI (EASI-75), vIGA-AD of clear/almost clear with improvement ≥2 grades (vIGA-AD 0/1), and WP-NRS improvement ≥4, were assessed through week 52. Missing data were primarily handled by nonresponse imputation incorporating multiple imputation for missing values due to coronavirus disease 2019 (COVID-19). RESULTS: Of 901 patients, 300 were randomized to upadacitinib 15 mg + TCS, 297 to upadacitinib 30 mg + TCS, and 304 to PBO + TCS. For all end points, efficacy for upadacitinib 15 mg + TCS and upadacitinib 30 mg + TCS at week 16 was maintained through week 52. At week 52, the proportions of patients treated with upadacitinib 15 mg + TCS and upadacitinib 30 mg + TCS who experienced EASI-75 were 50.8% and 69.0%, respectively; 33.5% and 45.2%, respectively, experienced vIGA-AD 0/1; and 45.3% and 57.5%, respectively, experienced WP-NRS improvement ≥4. Upadacitinib + TCS was well tolerated through 52 weeks; no new important safety risks beyond the current label were observed. No deaths were reported; major adverse cardiovascular events and venous thromboembolic events were infrequent (≤0.2/100 patient-years). CONCLUSIONS: Results through 52 weeks demonstrate long-term maintenance of efficacy and a favorable safety profile of upadacitinib + TCS in patients with moderate-to-severe AD.

Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting. FINDINGS: Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group. INTERPRETATION: Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis. FUNDING: AbbVie.

Efficacy and safety results of depatuxizumab mafodotin (ABT-414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor.

BACKGROUND: Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific. METHODS: This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD. RESULTS: Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional. CONCLUSIONS: Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174-83. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumours.

BACKGROUND: Veliparib is a potent poly(ADP-ribose) polymerase inhibitor. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib combined with various FOLFIRI regimens in patients with solid tumours. METHODS: Patients received veliparib (10-270 mg BID, days 1-5, 15-19) and FOLFIRI (days 1-3, 15-17) in three regimens containing 5-fluorouracil 2,400 mg/m2: irinotecan 150 mg/m2 and folinic acid 400 mg/m2 (part 1); irinotecan 180 mg/m2, folinic acid 400 mg/m2, and 5-fluorouracil 400 mg/m2 bolus (part 2), or irinotecan 180 mg/m2 (part 3). The RP2D was further evaluated in safety expansion cohorts. Preliminary antitumour activity was also assessed. RESULTS: Ninety-two patients received ≥1 veliparib dose. MTD was not reached; RP2D was set at 200 mg BID veliparib plus FOLFIRI (without 5-fluorouracil bolus). Most common treatment-emergent adverse events were neutropenia (66.3%), diarrhoea, and nausea (60.9% each). Dose-limiting toxicities (n = 4) were grade 3 gastritis and grade 4 neutropenia and febrile neutropenia. Veliparib exposure was dose-proportional, with no effects on the pharmacokinetics of FOLFIRI components. Fifteen patients had a partial response (objective response rate, 17.6%). CONCLUSIONS: The acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination.

Network evolution and risk assessment of the global phosphorus trade.

Phosphorus is an essential element for food production, but the distribution of its global reserve is highly uneven. With the increasing demand for products from all sectors of the phosphorus supply chain, the international phosphorus material trade is becoming increasingly intensive. However, the evolution of the global phosphorus trade network and potential supply risks caused by the trade structure and trade stability are rarely evaluated. By employing the complex network theory, a phosphorus material trade network and a quantitative evaluation index of the trade risk using the external supply risks are proposed to evaluate the supply risk in different countries from 2000 to 2020. According to the network analysis of global phosphorus trades for phosphate rock, phosphorus fertilizer and phosphoric acid, the number of trading countries and trading links has generally increased during the last twenty years. However, the trade structure was found to be significantly altered due to the stresses on the phosphorus reserve scarcity and trade restrictions from countries such as the United States and China. Correspondingly, Morocco has become the largest phosphorus-exporting country since 2016, while India was the world's largest phosphorus-importing country between 2008 and 2015. The topological network characteristics indicate that the phosphorus trade is well connected and more stable over time, but high supply risks were also identified, especially in developing countries in Africa within their phosphate rock and phosphorus fertilizer trade, which might threaten their food security. The obtained findings would be helpful for phosphorus trading countries to manage their trade risks in a timely manner.

Long-Term Safety and Efficacy of Risankizumab in Patients with Moderate-to-Severe Chronic Plaque Psoriasis: Results from a Phase 2 Open-Label Extension Trial.

INTRODUCTION: Although many biologic therapies are effective for clearing skin of patients with psoriasis, some lose effectiveness over time. This phase 2 open-label extension (OLE) trial was designed to investigate the long-term safety and efficacy of risankizumab. METHODS: In the phase 2, double-blind, active comparator, predecessor trial (NCT02054481), patients with moderate-to-severe chronic plaque psoriasis were treated for 24 weeks with subcutaneous (SC) risankizumab or ustekinumab, followed by a 24-week follow-up without treatment administration. Patients could enroll in the OLE (NCT02203851) when they experienced loss of treatment response (< 50% improvement in the Psoriasis Area Severity Index [PASI 50]) during follow-up) or at the end of follow-up if treatment response was ongoing. In the OLE, patients were treated every 12 weeks for at least 48 weeks with SC risankizumab 90 or 180 mg, beginning at week 12 (OLE visit 2), if the patient had not achieved PASI 90. Efficacy endpoints included the proportions of patients who achieved PASI 50/75/90/100 and static Physician's Global Assessment (sPGA) of clear or almost clear skin at week 48 (sPGA 0/1; OLE visit 5). RESULTS: Of the 110 enrolled patients, 99 (90.0%) completed the OLE. No patients discontinued the study because of adverse events. At week 48, 74.1% of patients achieved PASI 90, whereas 98.1, 91.7, 53.7, and 67.6% achieved PASI 50/75/100 and sPGA 0/1, respectively. All efficacy results were consistent or slightly increased at OLE week 48 compared with week 12. No new safety findings were observed. CONCLUSION: Risankizumab treatment was well tolerated with sustained clinical efficacy for at least 48 weeks. TRIAL REGISTRATION: ClinicalTrials.gov identifier; NCT02203851.

Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended-Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials.

Upadacitinib is a Janus kinase 1 inhibitor under development for the treatment of several inflammatory disorders including rheumatoid arthritis (RA). Upadacitinib was administered in the phase 2 RA trials primarily as twice-daily regimens of an immediate-release (IR) formulation. The upadacitinib extended-release (ER) formulation was developed to enable once-daily dosing. In the present study, upadacitinib pharmacokinetics were characterized after the administration of single and multiple once-daily doses of the ER formulation in healthy subjects relative to single and multiple twice-daily doses of the IR formulation. Increase in upadacitinib exposure was dose-proportional over the evaluated 15- to 30-mg ER dose range. Single 15- and 30-mg ER doses provided equivalent AUC0-inf compared with single 12- and 24-mg IR doses, respectively. A high-fat breakfast increased upadacitinib ER Cmax and AUC0-inf by only 20% and 17%, respectively, relative to fasting conditions. The median time to peak plasma concentrations was 2 to 4 hours for the ER formulation, and steady state was achieved by day 4 of once-daily dosing. Doses of 15 and 30 mg once daily using the ER formulation provided equivalent AUC0-24 , comparable Cmax and Cmin , and a fluctuation index over a 24-hour period at steady state similar to 6 and 12 mg twice daily, respectively, using the IR formulation. These results supported the use of upadacitinib 15- and 30-mg doses of the ER formulation in the phase 3 trials in RA.

Use of Early Clinical Trial Data to Support Thorough QT Study Waiver for Upadacitinib and Utility of Food Effect to Demonstrate ECG Assay Sensitivity.

Exposure-response analyses of QT data from early-stage clinical studies represent a valuable tool to assess the QT prolongation potential for drugs in development in lieu of standalone thorough QT (TQT) studies. However, demonstrating adequate electrocardiogram assay sensitivity can be challenging in the absence of a positive pharmacological control. Upadacitinib is a Janus kinase 1 inhibitor currently being evaluated in phase III rheumatoid arthritis trials. Exposure-response analyses to evaluate the QT prolongation potential for upadacitinib from phase I trials and the utility of the effect of food on QTcF to demonstrate ECG assay sensitivity are presented. The analyses demonstrated no effect of upadacitinib on QT interval and confirmed the sensitivity of the ECG assay to detect the small QT shortening effect caused by food. Lack of bias from manual ECG adjudication was also demonstrated. These analyses supported requesting a waiver for the regulatory requirement for a dedicated thorough QT study for upadacitinib.

Pharmacokinetics of the B-Cell Lymphoma 2 (Bcl-2) Inhibitor Venetoclax in Female Subjects with Systemic Lupus Erythematosus.

BACKGROUND AND OBJECTIVE: Venetoclax is an oral selective Bcl-2 inhibitor approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion. Mechanistic and preclinical evidence warranted evaluation of venetoclax for the treatment of systemic lupus erythematosus (SLE). This work characterized the pharmacokinetics of venetoclax in female subjects with SLE. METHODS: Single (10-500 mg) and multiple (30-600 mg) escalating doses of venetoclax or matching placebo were evaluated using randomized, double-blind, placebo-controlled designs (6 active and 2 placebo per dose with 73 unique SLE patients enrolled, 25 of whom enrolled twice). The multiple-dose evaluation consisted of two cycles, each with once-daily dosing for 7 days followed by a 21-day washout. Non-compartmental and population pharmacokinetic analyses of venetoclax serial plasma concentrations were conducted. RESULTS: Venetoclax exhibited approximately dose-proportional exposures, with peak concentrations observed 4-8 h post-dose. Venetoclax steady-state exposures were achieved by day 4 of dosing, and the median area under the plasma concentration-time curve (AUC) accumulation ratio ranged from 1.1 to 1.5. A two-compartment model with first-order absorption and elimination described venetoclax pharmacokinetics. The estimates (95% bootstrap confidence interval) for venetoclax apparent clearance, central and peripheral volumes of distribution, intercompartmental clearance, absorption rate constant, and lag time were 16.3 L/h (14.6-17.9), 37 L (26-57), 122 L (98-183), 3.7 L/h (2.6-5.0), 0.13 h-1 (0.11-0.17), and 1.6 h (1.6-1.7), respectively. The population estimate for venetoclax terminal-phase elimination half-life was approximately 28 h. CONCLUSIONS: In female subjects with SLE, venetoclax displayed pharmacokinetic characteristics consistent with previous observations in subjects with hematologic malignancies. CLINICALTRIALS. GOV IDENTIFIER: NCT01686555.