Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia.

This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10-4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.

Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase 1b study (GO28440).

Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100-400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3-4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3-4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.

Effect of bosutinib on the absorption of dabigatran etexilate mesylate, a P-glycoprotein substrate, in healthy subjects.

PURPOSE: Bosutinib, a dual Src and Abl tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, demonstrated concentration-dependent inhibitory effects on P-glycoprotein (P-gp)-mediated digoxin efflux in vitro, suggesting that bosutinib may inhibit P-gp substrates. The effect of bosutinib on dabigatran etexilate mesylate (EM) absorption, a P-gp substrate, was evaluated. METHODS: In this open-label, randomized, single-dose, one-cohort, two-sequence, two-period crossover study, healthy, fed subjects received dabigatran EM (150 mg × 1 orally) alone or 1 h after receiving bosutinib tablets (100 mg × 5 orally). RESULTS: Dabigatran EM monotherapy and concurrent administration of dabigatran EM with bosutinib resulted in similar values for concentration time curves from time zero extrapolated to infinity (AUCinf), but slightly lower maximum plasma concentration (C max) values (AUCinf, 1182 and 1186 ng·h/mL, respectively; C max, 129.8 and 114.1 ng/mL). The time to maximum concentration for dabigatran was 2.99 and 3.99 h for combination therapy. The ratio of the adjusted geometric means (test/reference) of dabigatran AUCinf and C max (90 % confidence interval) were 101.4 % (89.6-114.9 %) and 89.7 % (77.8-103.4 %), respectively, following administration of dabigatran EM with bosutinib (test) relative to dabigatran EM administered alone (reference). Six subjects receiving combination treatment reported a total of seven adverse events (AEs) versus none for subjects receiving monotherapy alone. All AEs were mild to moderate and considered treatment related. CONCLUSION: These data demonstrate that single doses of bosutinib do not affect dabigatran exposure, suggesting that bosutinib is not a clinical inhibitor of P-gp. TRIAL REGISTRATION: ClinicalTrials.gov NCT02102633. https://clinicaltrials.gov/ct2/show/NCT02102633?term=NCT02102633&rank=1.

Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects.

PURPOSE: Bosutinib is an oral, dual Src and Abl tyrosine kinase inhibitor (TKI) approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia resistant or intolerant to prior TKI therapy. Bosutinib is primarily metabolized by cytochrome P450 (CYP) 3A4, suggesting drug interaction potential with other CYP3A4 modulators. This open-label, randomized, 2-sequence, 2-period crossover study assessed the effect of single-dose aprepitant, a moderate CYP3A4 inhibitor, on the single-dose pharmacokinetic profile of oral bosutinib 500 mg. METHODS: Nineteen healthy, fed adults received bosutinib (100 mg × 5) alone or coadministered with aprepitant (125 mg × 1) in each treatment period (with a ≥14-day washout); serial blood samples were analyzed. Safety was evaluated. RESULTS: Following coadministration of aprepitant with bosutinib, the area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) and maximum plasma concentration (C max) were higher than in bosutinib alone (AUCinf, 4719 and 2268 ng•h/mL; C max, 146.0 and 94.94 ng/mL). For bosutinib with aprepitant versus bosutinib alone, mean terminal elimination half-life was similar (25.99 vs 27.79 h), time to C max was longer (6.02 vs 4.15 h), and apparent oral clearance (CL/F) was decreased (105.9 vs 220.4 L/h). The ratio of adjusted geometric means of AUCinf and C max for bosutinib with aprepitant relative to bosutinib alone were 199 % (90 % confidence interval, 167-237 %) and 153 % (127-184 %), respectively. Both treatments were well tolerated. CONCLUSION: In healthy volunteers, administering a single dose of aprepitant increased the AUC and C max following a single dose of bosutinib by 99 and 53 %, respectively. These results are consistent with a moderate CYP3A4 inhibitor effect of aprepitant on bosutinib (Trial Registration: ClinicalTrials.gov NCT02058277).

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial.

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3-5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.

Absolute Bioavailability of Bosutinib in Healthy Subjects From an Open-Label, Randomized, 2-Period Crossover Study.

This study evaluated the absolute bioavailability of bosutinib and assessed its safety and tolerability after single-dose oral and intravenous administration. In this phase 1 open-label, 2-sequence, 2-period crossover study, healthy, fed subjects aged 18-55 years were randomized to 1 of 2 treatment sequences (n = 7/sequence): oral bosutinib (100 mg × 5) followed by intravenous bosutinib (120 mg in approximately 240 mL over 1 hour), with a ≥14-day washout, or intravenous bosutinib and then oral bosutinib. Results of plasma pharmacokinetics analyses demonstrated that exposure to intravenous bosutinib was 3-fold higher than for oral bosutinib (16.2 and 5.5 ng·h/mL/mg, respectively), and mean terminal half-life was similar (35.5 and 31.7 hours). The ratio of adjusted geometric means (90%CI) for the dose-normalized area under the plasma concentration-time profile (AUC0-∞ /D) was 33.85% (30.65%-37.38%). Most treatment-emergent adverse events (AEs) were mild in severity. Gastrointestinal (GI) AEs occurred in 9 of 13 subjects given oral bosutinib, whereas no subjects given intravenous bosutinib experienced GI AEs, suggesting bosutinib present in the GI tract had an effect. Bosutinib exhibited an absolute bioavailability of 33.85% based on the ratio of AUC0-∞ /D. Both oral and intravenous bosutinib were safe and well tolerated in healthy, fed adult subjects.

[Ethical issues in multiple sclerosis under physicians and patients point of view]. / Questões éticas na esclerose múltipla sob o ponto de vista de médicos e pacientes.

UNLABELLED: Multiple sclerosis (MS) is a neurologic disorder that mostly affects young adults and can usually evolute to physical disability. Thus, caring patients with MS brings many ethic questions for the physician. OBJECTIVE: To identify physicians and patients' perceptions about the illness and so improve doctor-patient relationship. METHOD: It was made two different questionnaires, one for patients and another for physicians, 103 patients and 44 physicians answered them. RESULTS: 96.1% of patients knew their diagnosis, all others would like to know it. From those, 74.7% thought that that way it was disclosured was correct and 90.9% said that the doctor should tell us it. The worst symptoms described were fatigue (29.1%) and motor deficits (28.1%). By other side, 68% of patients told they suffered because of the illness. The most important reason for doctors to tell the diagnosis to the patients was to improve adherence to treatment (56.8%). A familiar present at this moment was demanded for 54.6% of doctors. When asked about orientations in a pregnancy, 50% of physicians did not answer correctly. Finally, 50% of physicians were against complementary and alternative therapies. CONCLUSION: Patients want to know their diagnosis and doctors should tell them in the most adequate moment and give more information. A debate about palliative care is also necessary.

Questões éticas na esclerose múltipla sob o ponto de vista de médicos e pacientes / Ethical issues in multiple sclerosis under physicians and patients point of view

A esclerose múltipla (EM) é afecção neurológica que acomete principalmente adultos jovens e evolui, geralmente, para graus variados de incapacidade física dos pacientes. Assim, a abordagem destes pacientes faz com que o médico depare-se com diversas questões éticas. OBJETIVO: Identificar as percepções de médicos e pacientes sobre a doença e, com isso, melhorar o relacionamento médico-paciente. MÉTODO: Foram feitos dois questionários, um respondido por 44 médicos e outro, por 103 pacientes, abordando questões sobre o diagnóstico e a conduta na EM. RESULTADOS: 96,1 por cento dos pacientes sabiam seu diagnóstico, os outros gostariam de sabê-lo. Daqueles, 74,7 por cento achavam que a forma contada foi correta e 90,9 por cento que o médico é que deve contá-lo. Os sintomas que mais os incomodam são a fadiga (29,1 por cento) e os déficits motores (28,1 por cento). Por outro lado, 68 por cento dos pacientes afirmaram sofrer com a doença. O motivo mais importante para os médicos contarem o diagnóstico foi para melhorar a adesão ao tratamento (56,8 por cento). A presença de um familiar neste momento é exigida por 54,6 por cento dos médicos. Quando perguntados sobre as orientações de uma gravidez, 50 por cento dos médicos não responderam adequadamente. Finalmente, 50 por cento dos médicos manifestaram-se de forma contrária às terapias complementares. CONCLUSÃO: Os pacientes querem saber seu diagnóstico e o médico deve contá-lo da forma mais adequada e dar mais informações. Um debate sobre cuidados paliativos também faz-se necessário.