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Richat Abbas - One of the best experts on this subject based on the ideXlab platform.

  • Application of Physiologically Based Pharmacokinetic Modeling to the Understanding of Bosutinib Pharmacokinetics: Prediction of Drug-Drug and Drug-Disease Interactions.
    Drug metabolism and disposition: the biological fate of chemicals, 2017
    Co-Authors: Chiho Ono, Richat Abbas, Poe-hirr Hsyu, Cho-ming Loi, Shinji Yamazaki
    Abstract:

    Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Bosutinib is predominantly metabolized by CYP3A4 as the primary clearance mechanism. The main objectives of this study were to 1) develop physiologically based pharmacokinetic (PBPK) models of Bosutinib; 2) verify and refine the PBPK models based on clinical study results of Bosutinib single-dose drug-drug interaction (DDI) with ketoconazole and rifampin, as well as single-dose drug-disease interaction (DDZI) in patients with renal and hepatic impairment; 3) apply the PBPK models to predict DDI outcomes in patients with weak and moderate CYP3A inhibitors; and 4) apply the PBPK models to predict DDZI outcomes in renally and hepatically impaired patients after multiple-dose administration. Results showed that the PBPK models adequately predicted Bosutinib oral exposures in patients after single- and multiple-dose administrations. The PBPK models also reasonably predicted changes in Bosutinib exposures in the single-dose DDI and DDZI results, suggesting that the PBPK models were sufficiently developed and verified based on the currently available data. Finally, the PBPK models predicted 2- to 4-fold increases in Bosutinib exposures by moderate CYP3A inhibitors, as well as comparable increases in Bosutinib exposures in renally and hepatically impaired patients between single- and multiple-dose administrations. Given the challenges in conducting numerous DDI and DDZI studies of anticancer drugs in patients, we believe that the PBPK models verified in our study would be valuable to reasonably predict Bosutinib exposures under various scenarios that have not been tested clinically.

  • Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib.
    Clinical pharmacokinetics, 2016
    Co-Authors: Richat Abbas, Poe-hirr Hsyu
    Abstract:

    Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disorder. Bosutinib is an oral, once-daily SRC/ABL tyrosine kinase inhibitor with very potent inhibitory activity. Bosutinib is effective against all phases of intolerant or resistant Philadelphia chromosome-positive CML that do not harbor the T315I or V299LABL kinase domain mutations. Peak plasma concentrations of Bosutinib occur at 4-6 h following oral administration, and dose-proportional increases in exposure are observed at doses ranging from 200 to 800 mg. Absorption of Bosutinib increases with food. Bosutinib is distributed extensively into the tissues. It is highly plasma protein bound (94 %) and is primarily metabolized in the liver by cytochrome P450 3A4. Bosutinib is well tolerated overall and has a unique but manageable toxicity profile. This article provides a review of the available clinical pharmacokinetic, pharmacodynamic, and drug-drug interaction data on Bosutinib in healthy subjects, patients with CML, and special populations.

  • Effect of rifampin on the pharmacokinetics of Bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects.
    Drug metabolism and personalized therapy, 2015
    Co-Authors: Richat Abbas, Joseph Boni, Daryl Sonnichsen
    Abstract:

    Background Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor and a CYP3A4 enzyme substrate. This study assessed the safety, tolerability, and pharmacokinetics of Bosutinib when coadministered with the CYP3A4 inducer rifampin in 24 healthy men. Methods Subjects received single oral doses of Bosutinib 500 mg (Days 1 and 14) and once-daily oral doses of rifampin 600 mg (Days 8-17); serial blood samples were analyzed. Results Bosutinib exposures were reduced following concomitant administration of rifampin vs. Bosutinib alone, measured by peak plasma concentration (C(max); 112 vs. 16.0 ng/mL; 86% reduction), total area under the concentration-time curve (AUC; 2740 vs. 207 ng·h/mL; 92% reduction), and AUC to the last measurable concentration at time T (2440 vs. 158 ng·h/mL; 94% reduction). Median time to C(max) and mean half-life were shorter for Bosutinib plus rifampin vs. single-agent Bosutinib. Oral clearance increased approximately 13-fold; the volume of distribution increased from 9560 to 72,900 L. Treatment-emergent adverse events appeared less frequently with Bosutinib plus rifampin (59%) vs. single-agent Bosutinib (79%); diarrhea was reported in 11 (46%) vs. 4 (18%) subjects, respectively. Conclusions Concomitant use of potent or moderate CYP3A inducers with Bosutinib should be avoided because of the effects of drug-drug interaction observed between Bosutinib and rifampin.

  • A Clinical Study to Examine the Potential Effect of Lansoprazole on the Pharmacokinetics of Bosutinib when Administered Concomitantly to Healthy Subjects
    Clinical drug investigation, 2013
    Co-Authors: Richat Abbas, Cathie Leister, Daryl Sonnichsen
    Abstract:

    Background Bosutinib is an orally bioavailable, dual Src and Abl tyrosine kinase inhibitor approved in the USA for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia following development of resistance or intolerance to prior therapy. In vitro studies demonstrated that Bosutinib displays pH-dependent aqueous solubility, suggesting that concomitant administration of agents that alter gastric pH could affect Bosutinib absorption.

  • Evaluation of the pharmacokinetics and safety of Bosutinib in patients with chronic hepatic impairment and matched healthy subjects.
    Cancer chemotherapy and pharmacology, 2012
    Co-Authors: Richat Abbas, Cathie Leister, Stephan Chalon, Myriam El Gaaloul, Daryl Sonnichsen
    Abstract:

    Bosutinib, a dual Src/Abl kinase inhibitor in development for treatment of chronic myeloid leukemia, is primarily metabolized by the CYP3A4 hepatic enzyme. This study evaluated the pharmacokinetics and safety of Bosutinib in patients with chronic hepatic impairment and matched healthy subjects. Hepatically impaired patients were aged 18-65 years and of Child-Pugh classes A, B, or C; healthy subjects were matched by age, sex, body mass index, and smoking habits. A single oral dose of Bosutinib 200 mg was administered on day 1 within 5 min after completion of breakfast. Compared with healthy subjects (n = 9), maximal plasma concentration (C(max)) and area under the curve increased 2.42-fold and 2.25-fold in Child-Pugh A (n = 6), 1.99-fold and 2.0-fold in Child-Pugh B (n = 6), and 1.52-fold and 1.91-fold in Child-Pugh C patients (n = 6). Time to C(max) decreased from 4 h in healthy subjects to 2.5, 2.0, and 1.5 h in Child-Pugh A, B, and C patients, respectively; the elimination half-life increased from 55 h in healthy subjects to 86, 113, and 111 h in Child-Pugh A, B, and C patients. Bosutinib oral clearance was lower in hepatically impaired patients compared with healthy subjects. Frequently reported adverse events included prolonged QTc interval (37.0%, n = 10), nausea (11.1%, n = 3), and vomiting (7.4%, n = 2). A single oral dose of Bosutinib 200 mg showed acceptable tolerability in healthy subjects and in patients with mild, moderate, or severe chronic hepatic impairment.

Jorge E. Cortes - One of the best experts on this subject based on the ideXlab platform.

  • Pregnancy outcomes in patients treated with Bosutinib.
    International journal of hematologic oncology, 2020
    Co-Authors: Jorge E. Cortes, Carlo Gambacorti-passerini, Michael W Deininger, Elisabetta Abruzzese, Liza Deannuntis, Tim Henrik Brummendorf
    Abstract:

    Aim Preclinical studies have shown reproductive toxicity with Bosutinib, but little is known about its effects during conception or pregnancy in humans. Methods Pregnancy cases in patients receiving Bosutinib were identified from the Pfizer safety database. Results Thirty-three pregnancy reports were identified. Sixteen cases of maternal exposure: six live births, four abortions and six with unknown outcomes. Seventeen instances of paternal exposure: nine live births, five abortions and three with unknown outcomes. Conclusion Adverse effects of Bosutinib exposure at conception or during pregnancy in humans cannot be excluded, particularly if therapy is not interrupted upon recognition of pregnancy. Contraceptive use is recommended for female patients receiving Bosutinib, and patients should be made aware of the potential risks associated with Bosutinib use during pregnancy.

  • Cross-Intolerance with Bosutinib after Prior Tyrosine Kinase Inhibitors in Patients with Chronic Phase Chronic Myeloid Leukemia: BYOND Phase 4 Study
    Blood, 2019
    Co-Authors: Bjørn Tore Gjertsen, Eric Leip, Andrea Viqueira, Jorge E. Cortes, Andreas Hochhaus, Gianantonio Rosti, Justin M. Watts, Guillermo Ortí, Philipp Le Coutre, Frank Giles
    Abstract:

    Background: Some patients receiving a tyrosine kinase inhibitor (TKI) for chronic phase (CP) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) experience drug intolerance and require switching to an alternative TKI. Bosutinib, a TKI approved for newly diagnosed CP Ph+ CML and Ph+ CML resistant/intolerant to prior therapy, has a distinct adverse event (AE) profile vs other TKIs used to treat Ph+ CML. Methods: The ongoing phase 4 BYOND study (NCT02228382) is further evaluating efficacy and safety of Bosutinib for CML resistant/intolerant to prior TKIs. Patients with Ph+ CP CML (n=156) previously treated with imatinib, dasatinib, and/or nilotinib received Bosutinib (starting dose 500 mg once daily). Cross-intolerance (AEs leading to permanent discontinuation of both prior TKI and Bosutinib), recurrent AEs (grades 1/2 or 3/4), and Bosutinib dose modifications due to recurrent AEs were assessed across AEs and AE clusters. This analysis was based on ≥1 year after the last enrolled patient (median treatment duration 23.7 months [range 0.2-42.2]). Results: Of 141, 95, and 79 patients who received prior imatinib, dasatinib, or nilotinib, respectively, 63 (45%), 70 (74%), and 60 (76%) were intolerant and discontinued treatment due to an AE as the primary reason. 1 (2%) imatinib-intolerant and 5 (7%) dasatinib-intolerant patients had cross-intolerance with Bosutinib; no cross-intolerance with Bosutinib was reported for the 60 nilotinib-intolerant patients (Table). 15 patients discontinued >1 TKI due to the same AE. Of these, only 1 with prior imatinib and dasatinib intolerance due to anemia (below), was cross-intolerant to Bosutinib. No deaths occurred due to cross-intolerance to Bosutinib. Imatinib-intolerant: The most common cause of imatinib intolerance was musculoskeletal pain in 19 patients. Of these, 9 patients experienced grade 1/2 recurrence and 1 had a grade 3/4 AE. There was no cross-intolerance with Bosutinib due to musculoskeletal pain. 6 patients were intolerant due to edema, which recurred as grade 1/2 in 3 Bosutinib-treated patients. In 2 patients with intolerance due to diarrhea, both had grade 1/2 diarrhea with Bosutinib. 2 patients were imatinib-intolerant due to neutropenia or thrombocytopenia (n=1 each) and experienced grade 3/4 recurrence with Bosutinib. 1 patient was cross-intolerant to Bosutinib due to anemia. Dasatinib-intolerant: The most common reason for prior dasatinib intolerance was pleural effusion. Of 36 patients, 10 (28%) had recurrence of grade 1/2 AE and 4 (11%) had grade 3/4 AE with Bosutinib that caused dose delay and reduction in 6 (17%) and 4 (11%) patients, respectively. 1 patient had cross-intolerance with Bosutinib due to pleural effusion. Of 8 patients dasatinib-intolerant due to dyspnea, 1 had cross-intolerance with Bosutinib (this patient also developed pleural effusion with dasatinib). Of 2 patients with dasatinib intolerance due to pulmonary hypertension, 1 had grade 1/2 and 1 had grade 3/4 recurrence with Bosutinib, leading to cross-intolerance in 1 patient. 2 other dasatinib-intolerant patients experienced cross-intolerance due to anemia and nausea (n=1 each). Grade 3/4 recurrence of thrombocytopenia was experienced in 1 of 3 patients with prior dasatinib-intolerance. 1 patient with dasatinib intolerance due to diarrhea had grade 3/4 diarrhea with Bosutinib that was managed with dose delay/reduction. Nilotinib-intolerant: 6 patients discontinued nilotinib due to peripheral ischemia, of whom 1 experienced grade 3/4 recurrence with Bosutinib. None of the 4 patients with nilotinib intolerance due to acute coronary syndrome had recurrence with Bosutinib. Of 3 patients with prior intolerance due to pancreatitis, 1 had grade 3/4 recurrence with Bosutinib. 2 patients had recurrent diarrhea with Bosutinib, both grade 1/2. There were no Bosutinib dose reductions, delays, or recurrence of AEs in patients with prior nilotinib intolerance due to rash, hematologic AEs, hepatotoxicity, or metabolic disorders. Conclusions: Incidence of cross-intolerance, dose delay, or dose reduction with Bosutinib in patients intolerant to prior TKIs was low. Despite recurrence of certain same grade 1/2 or grade 3/4 AEs that caused prior TKI intolerance, these were manageable and patients were able to remain on Bosutinib. These findings support the use of Bosutinib in patients with CP Ph+ CML intolerant to prior TKI treatment. Disclosures Gjertsen: Haukeland University Hospital / University of Bergen: Employment; ERA PerMed: Research Funding; BerGenBio: Consultancy; Astellas: Consultancy; BerGenBio AS: Membership on an entity's Board of Directors or advisory committees; KinN Therapeutics AS: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; ACTII AS: Equity Ownership; Seattle Genetics: Consultancy; Research Council of Norway: Research Funding; EU Horizon 2020: Research Funding; The Norwegian Cancer Society: Research Funding; Helse Vest Health Trust: Research Funding. Hochhaus:Pfizer: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding; Novartis: Research Funding. Rosti:BMS: Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Watts:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ortí:Bristol-Myers Squibb: Consultancy, Other: Travel Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: Travel Expenses, Speakers Bureau. le Coutre:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer Inc: Employment, Equity Ownership. Cortes:Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Giles:Novartis: Consultancy; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Actuate Therapeutics Inc: Employment. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Meyers Squibb: Consultancy.

  • Patient-reported outcomes in the phase 3 BFORE trial of Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia.
    Journal of cancer research and clinical oncology, 2019
    Co-Authors: Jorge E. Cortes, Carlo Gambacorti-passerini, Dong-wook Kim, Michael W Deininger, Michael J Mauro, Charles Chuah, Dragana Milojkovic, Philipp Le Coutre, Valentín García-gutiérrez, Rocco J. Crescenzo
    Abstract:

    In the phase 3 BFORE trial (NCT02130557), treatment with Bosutinib resulted in a significantly higher major molecular response rate at 12 months versus imatinib in the modified intent-to-treat (mITT) population of patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). Assessment of patient-reported outcomes (PROs) was an exploratory objective. Patients with newly diagnosed CP CML were randomized 1:1 to receive once-daily Bosutinib 400 mg or imatinib 400 mg as first-line therapy. Patients completed the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EuroQoL-5 Dimensions (EQ-5D) questionnaires at baseline, every 3 months for the first 24 months of treatment, every 6 months thereafter, and at treatment completion. We report PRO results at month 12 in the mITT population (Bosutinib: n = 246; imatinib: n = 241). Mean FACT-Leu combined and subscale scores were similar at baseline in the Bosutinib and imatinib arms; at month 12, all scores demonstrated improvement or maintenance of health-related quality of life (HRQoL) in both treatment arms. Repeated-measures mixed-effects models showed no significant difference between Bosutinib and imatinib for any FACT-Leu score. Functional health status, as measured by EQ-5D, also demonstrated improvement or maintenance with Bosutinib and imatinib at month 12. Similar improvements in PROs compared with baseline were seen after 12 months of treatment with first-line Bosutinib or imatinib in the BFORE trial. Newly diagnosed patients with CP CML receiving Bosutinib or imatinib can preserve or improve HRQoL during treatment, although clinical efficacy was superior with Bosutinib.

  • management of adverse events associated with Bosutinib treatment of chronic phase chronic myeloid leukemia expert panel review
    Journal of Hematology & Oncology, 2018
    Co-Authors: Jorge E. Cortes, Vamsi Kota, Michael W Deininger, Jane F. Apperley, Daniel J Deangelo, Philippe Rousselot, Carlo Gambacortipasserini
    Abstract:

    Bosutinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI), has been available for several years as a treatment for chronic-, accelerated-, and blast-phase chronic myeloid leukemia (CML), for patients with resistance or intolerance to prior therapy. In 2017, the BFORE trial demonstrated efficacy of Bosutinib as first-line treatment in adult patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). The most common adverse events (AEs) of any grade in Bosutinib-treated patients in BFORE were diarrhea, nausea, thrombocytopenia, increased alanine aminotransferase, and increased aspartate aminotransferase, consistent with the most commonly reported AEs in earlier studies. To balance the efficacy and tolerability of treatment to optimize patient adherence with medications, treating physicians commonly use various strategies such as initiating treatment at a lower dose, dose reduction, or dose interruption, depending on the type and severity of the AEs and the clinical setting. In light of the recent data from first-line treatment, an expert panel of hematologists reviewed management strategies for the use of Bosutinib in treatment of CP-CML and made the recommendations reported here. Although the panel focused on first-line treatment, the principles can be for the most part extended to Bosutinib use in later lines of treatment. Recommendations include advice regarding prophylaxis and management for diarrhea. The panel also considered optimum timing for referral to a specialist for specific AEs. Across the commonly occurring AEs, the panel highlighted the importance of education and communication with patients about anticipated AEs.

  • Bosutinib or Imatinib in Older Vs Younger Patients with Newly Diagnosed Chronic Myeloid Leukemia in the Phase 3 BFORE Trial
    Blood, 2018
    Co-Authors: Michael W Deininger, Eric Leip, Vamsi Kota, Carlo Gambacorti-passerini, Jeffrey H. Lipton, Dragana Milojkovic, Andreas Hochhaus, Valentín García Gutiérrez, Sonja Nick, Jorge E. Cortes
    Abstract:

    Introduction: Bosutinib is approved for newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) and CML resistant or intolerant to prior therapy. Efficacy and safety of first-line Bosutinib and imatinib were assessed in older vs younger patients in the ongoing phase 3 BFORE trial (NCT02130557). Methods: In all, 536 patients were randomized 1:1 to receive Bosutinib or imatinib (400 mg once daily). We compared outcomes in patients aged ≥65 years (older group) vs Results: In the Bosutinib arm (n=268), 53 were older and 215 were younger patients. In the imatinib arm (n=268; 3 untreated), 48 (2 untreated) were older and 220 (1 untreated) were younger patients. Sokal risk scores were balanced between treatment arms but higher in the overall older (8.9% low, 70.3% intermediate, 20.8% high) vs younger (44.1% low, 34.7% intermediate, 21.1% high) populations, reflecting that age is part of the score. Bosutinib was discontinued in 32.1% of older and 28.4% of younger patients; the most common primary reason was treatment-related adverse events (AEs; 18.9% and 15.3%, respectively). Imatinib was discontinued in 32.6% of older and 33.8% of younger patients, most frequently due to suboptimal response or treatment failure (13.0% and 13.2%, respectively). The percentage of patients who discontinued treatment due to treatment-emergent AEs (TEAEs) was similar in the older vs younger group in both arms (Bosutinib: 22.6% vs 19.1%; imatinib: 8.7% vs 12.3%). In older vs younger patients, median (range) duration of treatment was similar: 24.8 months (0.3-33.3) vs 24.9 months (0.3-33.5) for Bosutinib and 25.6 months (2.9-33.1) vs 24.5 months (0.7-33.4) for imatinib. Median relative dose intensity was slightly lower in older vs younger patients in the Bosutinib arm (92.8% vs 99.3%) but was 100% in both age groups in the imatinib arm. The difference in rates of major molecular response (MMR) at 12 months (primary endpoint) with Bosutinib vs imatinib was consistent across age groups (older: 43.4% vs 35.4%; younger: 47.4% vs 36.4%; P=0.7879 for test of interaction), as was the difference in rates of CCyR by 12 months (older: 68.8% vs 69.0%; younger: 79.3% vs 65.8%; P=0.1689). MR rates at 24 months (and MR1 at 3 months) were generally similar in older vs younger patients within each arm and higher with Bosutinib than with imatinib (Table 1). Time to achieve MMR on Bosutinib was not different in older vs younger patients (hazard ratio: 1.227; P=0.2380, after adjustment for baseline and time-dependent covariates in a multivariable proportional subdistribution hazards model). Rates of common TEAEs in each treatment arm were similar ( Conclusions: In the phase 3 BFORE trial, Bosutinib showed clinical activity in older and younger patients with newly diagnosed CP CML. Difference in rates of MMR at 12 months for Bosutinib vs imatinib was consistent in older and younger patients. MR rates at 24 months were similar in older and younger patients and higher with Bosutinib than with imatinib. Although the incidence of grade 3/4 TEAEs, serious TEAEs, and dose modifications due to TEAEs were higher in older vs younger Bosutinib-treated patients, treatment discontinuation rates were similar between age groups, suggesting that, regardless of patient age, TEAEs were manageable with Bosutinib. Disclosures Deininger:Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Blueprint: Consultancy. Kota:Pfizer: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Lipton:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Milojkovic:Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Garcia Gutierrez:Incyte: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Leip:Pfizer: Employment, Equity Ownership. Nick:Pfizer: Employment, Equity Ownership. Hochhaus:Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Cortes:Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Brummendorf:Merck: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding.

Daryl Sonnichsen - One of the best experts on this subject based on the ideXlab platform.

  • Effect of rifampin on the pharmacokinetics of Bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects.
    Drug metabolism and personalized therapy, 2015
    Co-Authors: Richat Abbas, Joseph Boni, Daryl Sonnichsen
    Abstract:

    Background Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor and a CYP3A4 enzyme substrate. This study assessed the safety, tolerability, and pharmacokinetics of Bosutinib when coadministered with the CYP3A4 inducer rifampin in 24 healthy men. Methods Subjects received single oral doses of Bosutinib 500 mg (Days 1 and 14) and once-daily oral doses of rifampin 600 mg (Days 8-17); serial blood samples were analyzed. Results Bosutinib exposures were reduced following concomitant administration of rifampin vs. Bosutinib alone, measured by peak plasma concentration (C(max); 112 vs. 16.0 ng/mL; 86% reduction), total area under the concentration-time curve (AUC; 2740 vs. 207 ng·h/mL; 92% reduction), and AUC to the last measurable concentration at time T (2440 vs. 158 ng·h/mL; 94% reduction). Median time to C(max) and mean half-life were shorter for Bosutinib plus rifampin vs. single-agent Bosutinib. Oral clearance increased approximately 13-fold; the volume of distribution increased from 9560 to 72,900 L. Treatment-emergent adverse events appeared less frequently with Bosutinib plus rifampin (59%) vs. single-agent Bosutinib (79%); diarrhea was reported in 11 (46%) vs. 4 (18%) subjects, respectively. Conclusions Concomitant use of potent or moderate CYP3A inducers with Bosutinib should be avoided because of the effects of drug-drug interaction observed between Bosutinib and rifampin.

  • A Clinical Study to Examine the Potential Effect of Lansoprazole on the Pharmacokinetics of Bosutinib when Administered Concomitantly to Healthy Subjects
    Clinical drug investigation, 2013
    Co-Authors: Richat Abbas, Cathie Leister, Daryl Sonnichsen
    Abstract:

    Background Bosutinib is an orally bioavailable, dual Src and Abl tyrosine kinase inhibitor approved in the USA for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia following development of resistance or intolerance to prior therapy. In vitro studies demonstrated that Bosutinib displays pH-dependent aqueous solubility, suggesting that concomitant administration of agents that alter gastric pH could affect Bosutinib absorption.

  • Evaluation of the pharmacokinetics and safety of Bosutinib in patients with chronic hepatic impairment and matched healthy subjects.
    Cancer chemotherapy and pharmacology, 2012
    Co-Authors: Richat Abbas, Cathie Leister, Stephan Chalon, Myriam El Gaaloul, Daryl Sonnichsen
    Abstract:

    Bosutinib, a dual Src/Abl kinase inhibitor in development for treatment of chronic myeloid leukemia, is primarily metabolized by the CYP3A4 hepatic enzyme. This study evaluated the pharmacokinetics and safety of Bosutinib in patients with chronic hepatic impairment and matched healthy subjects. Hepatically impaired patients were aged 18-65 years and of Child-Pugh classes A, B, or C; healthy subjects were matched by age, sex, body mass index, and smoking habits. A single oral dose of Bosutinib 200 mg was administered on day 1 within 5 min after completion of breakfast. Compared with healthy subjects (n = 9), maximal plasma concentration (C(max)) and area under the curve increased 2.42-fold and 2.25-fold in Child-Pugh A (n = 6), 1.99-fold and 2.0-fold in Child-Pugh B (n = 6), and 1.52-fold and 1.91-fold in Child-Pugh C patients (n = 6). Time to C(max) decreased from 4 h in healthy subjects to 2.5, 2.0, and 1.5 h in Child-Pugh A, B, and C patients, respectively; the elimination half-life increased from 55 h in healthy subjects to 86, 113, and 111 h in Child-Pugh A, B, and C patients. Bosutinib oral clearance was lower in hepatically impaired patients compared with healthy subjects. Frequently reported adverse events included prolonged QTc interval (37.0%, n = 10), nausea (11.1%, n = 3), and vomiting (7.4%, n = 2). A single oral dose of Bosutinib 200 mg showed acceptable tolerability in healthy subjects and in patients with mild, moderate, or severe chronic hepatic impairment.

  • Ascending single-dose study of the safety profile, tolerability, and pharmacokinetics of Bosutinib coadministered with ketoconazole to healthy adult subjects.
    Clinical therapeutics, 2012
    Co-Authors: Richat Abbas, Cathie Leister, Myriam El Gaaloul, Stephan Chalon, Daryl Sonnichsen
    Abstract:

    Abstract Background Bosutinib (SKI-606) is an orally bioavailable, competitive tyrosine kinase inhibitor that selectively targets both Src and Abl tyrosine kinases. Bosutinib is metabolized primarily through the cytochrome P450 3A4 pathway. Inhibition of Bosutinib metabolism by coadministration with the potent cytochrome P450 3A4 inhibitor ketoconazole could potentially increase plasma concentrations of Bosutinib, allowing for the study of Bosutinib tolerability at supratherapeutic concentrations in a healthy subject population. Objective This study assessed the safety profile, tolerability, and pharmacokinetics of different dose combinations of Bosutinib coadministered with ketoconazole in healthy adults, and determined whether supratherapeutic concentrations of Bosutinib can be achieved with ketoconazole. Methods This was a randomized, Phase I, double-blind, placebo-controlled, sequential-group study conducted in healthy adults. Single oral doses of Bosutinib 100, 200, 300, 400, 500, and 600 mg or placebo were administered with ketoconazole and food on day 1; daily single oral doses of ketoconazole 400 mg were administered on days –1 and 1 through 4. Results Forty-eight subjects were enrolled. Their mean (SD) age was 32.0 (10.7) years (range, 18–50 years). The majority of the subjects (n = 44 [92%]) were white, 2 (4%) were black or African American, and 2 (4%) were of other races. Bosutinib was associated with acceptable tolerability at doses from 100 to 600 mg, with adverse events either mild (n = 30 [63%]) or moderate (n = 12 [25%]) in severity; no subject discontinued treatment due to adverse events, and no serious events were reported. Mean (SD) values for Bosutinib 100 to 600 mg ranged from 58.4 (13.3) to 426 (100) ng/mL for C max and 2980 (802) to 23,000 (4020) ng·h/mL for AUC 0–∞ ; mean AUC 0–24 and AUC 0–last ranged from 876 (234) to 7080 (1640) ng· h/mL and from 2740 (854) to 22,200 (3630) ng · h/mL, respectively. C max and AUC were linear and dose proportional. Mean C max at 600 mg was 2.1-fold higher than the steady-state C max previously observed for patients with chronic myelogenous leukemia who received Bosutinib 500 mg once daily with food. Conclusions Single doses of Bosutinib up to 600 mg coadministered with multiple doses of ketoconazole were acceptably well tolerated in this small, selected group of healthy male volunteers. In addition, supratherapeutic exposure was achieved within this range for Bosutinib when coadministered with ketoconazole. ClinicalTrials.gov identifier: NCT00777530.

  • A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of Bosutinib (SKI-606) in healthy adult subjects.
    Cancer chemotherapy and pharmacology, 2011
    Co-Authors: Richat Abbas, Bruce Hug, Cathie Leister, Myriam El Gaaloul, Stephan Chalon, Daryl Sonnichsen
    Abstract:

    Purpose Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, is in clinical development for the treatment of patients with chronic myelogenous leukemia (CML). To support clinical development, we conducted a dose-escalation and food-effect evaluation of safety, tolerability, and pharmacokinetics (PK) of Bosutinib in healthy adults.

Tim H. Brümmendorf - One of the best experts on this subject based on the ideXlab platform.

  • impact of diarrhea on health related quality of life analysis of the phase 3 bfore trial of Bosutinib vs imatinib for newly diagnosed chronic phase chronic myeloid leukemia
    Blood, 2018
    Co-Authors: Tim H. Brümmendorf, Carla Mamolo, Joseph C Cappelleri, Rocco J. Crescenzo, Liza Deannuntis, Arlene Reisman, Andrew G Bushmakin, Andrea Viquiera, Jorge E. Cortes
    Abstract:

    Introduction: In the ongoing phase 3 BFORE trial (NCT02130557), a significantly higher major molecular response rate at Month 12 was seen with Bosutinib vs imatinib in patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML), and Bosutinib treatment was accompanied by improvement or maintenance of health-related quality of life (HRQoL), as assessed by the patient-reported Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) instrument. Diarrhea is a common side effect of Bosutinib and occurred more frequently in Bosutinib- vs imatinib-treated patients in the primary analysis of the BFORE trial (all grades: 70.1% vs 33.6%). Here, the impact of diarrhea, specifically on HRQoL, was assessed in patients receiving Bosutinib or imatinib in the BFORE trial. Methods: Patients with CP CML were randomized 1:1 to receive first-line Bosutinib or imatinib. HRQoL was analyzed in the modified intent-to-treat (mITT) population, comprised of Philadelphia chromosome-positive patients with typical BCR-ABL transcripts. The FACT-Leu consists of the 27-item FACT-General (FACT-G) scale with 4 domains (physical, social, emotional, and functional well-being) and the 17-item leukemia-specific subscale; higher scores and changes in scores indicate better HRQoL. Patients completed questionnaires at baseline, every 3 months for the first 2 years and every 6 months thereafter while on treatment, and at treatment completion. In this post hoc analysis, FACT-Leu scores from the first 12 months of treatment were analyzed in patients with diarrhea (any event during treatment) or chronic diarrhea (event lasting ≥28 days). Longitudinal analyses were conducted and standardized effect sizes were calculated to characterize the strength of effect on the FACT-Leu scores for the diarrhea and chronic diarrhea subgroups. Standardized effect sizes of approximately 0.1, 0.2, 0.5, and 0.8 (in absolute values) were considered trivial, small, medium, and large, respectively. Results: In the mITT population (Bosutinib: n=246; imatinib: n=241), 163 (66.3%) patients in the Bosutinib arm and 74 (30.7%) in the imatinib arm had diarrhea and were evaluable for HRQoL; 34 (13.8%) and 20 (8.3%), respectively, had chronic diarrhea (≥28 days). Among patients who developed diarrhea, the FACT-Leu total score and most subscale scores improved from baseline to Month 12 in both treatment arms, although changes were generally not significant (P>0.05) and could be interpreted as small or trivial, based on effect size (Table). For patients with diarrhea in the Bosutinib arm, changes from baseline in the leukemia-specific subscale could be characterized as small improvements starting at Month 6 of treatment; in the imatinib arm, an improvement was not seen until Month 12, and all changes could only be characterized as trivial (Figure). Among patients with chronic diarrhea, the changes from baseline at Month 12 were not significant for all FACT-Leu total or subscale scores in the Bosutinib arm and could be interpreted as small or trivial; in the imatinib arm, changes from baseline in all FACT-Leu scores were numerically negative and nonsignificant with the exception of the physical well-being domain (P Conclusions: In this post hoc analysis of the BFORE trial, HRQoL was not negatively affected by diarrhea or chronic diarrhea in the Bosutinib arm. Although the analysis is limited by the small number of patients, chronic diarrhea during treatment with imatinib appeared to have a greater impact on HRQoL than chronic diarrhea during treatment with Bosutinib, based on the magnitude of the effect sizes and direction of changes, particularly for physical well-being. These data suggest that patients with CP CML treated with Bosutinib can preserve or slightly improve HRQoL during therapy, regardless of the presence of diarrhea or chronic diarrhea. Disclosures Brummendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. Mamolo:Pfizer: Employment, Equity Ownership. Reisman:Pfizer: Employment, Equity Ownership. Bushmakin:Pfizer: Employment, Equity Ownership. Cappelleri:Pfizer: Employment, Equity Ownership. Crescenzo:Pfizer: Employment. DeAnnuntis:Pfizer Inc: Employment, Equity Ownership. Viquiera:Pfizer: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding.

  • efficacy and safety following dose reduction of Bosutinib or imatinib in patients with newly diagnosed chronic myeloid leukemia analysis of the phase 3 bfore trial
    Blood, 2018
    Co-Authors: Tim H. Brümmendorf, Eric Leip, Vamsi Kota, Andrea Viqueira, Jeffrey H. Lipton, Carlo Gambacortipasserini, Michael W Deininger, Andreas Hochhaus, Roxanne Ferdinand, Jorge E. Cortes
    Abstract:

    Introduction: Bosutinib, an oral dual Src/Abl tyrosine kinase inhibitor (TKI) is approved for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), at a starting dose of 400 once daily (QD) in newly diagnosed patients in chronic phase (CP). Approval of first-line Bosutinib was based on results from the phase 3 BFORE trial, which showed improved efficacy outcomes with Bosutinib vs imatinib in this patient population. This analysis evaluated efficacy and safety of Bosutinib and imatinib following dose reductions in adult patients with newly diagnosed CP CML. Methods: This retrospective analysis included data (≥24-month follow-up) from the ongoing, open-label, phase 3 BFORE trial (NCT02130557). In all, 536 patients were randomized 1:1 to Bosutinib or imatinib at a starting dose of 400 mg QD. Doses could be reduced in 100 mg decrements for toxicity; dose reductions to Results: Of the 268 patients in the Bosutinib arm, 80 dose-reduced to 300 mg only and 23 dose-reduced to 200 mg. The median (range) overall duration of Bosutinib treatment for patients dose reduced to 300 mg was 24.3 months (1.4-33.5) and to 200 mg was 8.3 months (1.0-32.9) vs. 25.1 months (range: 0.26-33.2) for patients who remained on the 400 mg starting dose. Median (range) time to Bosutinib dose reduction to 300 mg was 83 days (18-793) and to 200 mg was 121 days (29-882); respective median (range) duration on reduced dose was 138.5 days (1-957) and 28 days (3-463). Of the 268 (3 untreated) patients in the imatinib arm, 44 dose-reduced to 300 mg. The median duration of imatinib treatment for patients dose reduced to 300 mg was 22.4 months (range: 1.2-33.0) vs. 24.8 months (range: 0.7-33.4) for patients who remained on 400 mg. Median time to imatinib dose reduction to 300 mg was 85.0 days (range: 15-687); median duration on reduced dose was 99.0 days (range: 2-787). TEAEs leading to dose reduction in ≥10 patients were alanine aminotransferase increased and/or aspartate aminotransferase increased (n=21), thrombocytopenia (n=19), lipase increased (n=15) and diarrhea (n=11) with Bosutinib, and neutropenia (n=11) with imatinib. The most common reason for treatment discontinuation in patients who dose-reduced was a TEAE related to Bosutinib (300 mg: 22.5%; 200 mg: 52.2%) or imatinib (300 mg: 27.3%). Among patients who dose-reduced to 300 mg, 16 (20%) had a major molecular response (MMR) with Bosutinib before and after reduction; an additional 36 (45%) achieved MMR for the first time after dose reduction. In the imatinib arm, 7 (15.9%) had an MMR before and after reduction; an additional 22 (50%) achieved MMR for the first time after dose reduction (Table 1). 1 (1.3%) patient lost a previously attained MMR following Bosutinib dose reduction to 300 mg. Among patients who dose-reduced to 200 mg Bosutinib, 4 (17.4%) had an MMR before and after reduction, and an additional 4 (17.4%) achieved MMR for the first time after dose reduction. Similar trends were seen for complete cytogenetic response (CCyR) before and after dose reduction (Table 1). Among patients who remained on 400 mg, 123/165 (74.5%) had a MMR with Bosutinib; 131/152 (86.2%) achieved CCyR. In the imatinib arm, 130/219 (59.4%) had a MMR and 159/198 (80.3%) achieved CCyR. The majority of TEAEs decreased in incidence with dose reduction (Table 2). Following Bosutinib dose reduction to 300 mg or to 200 mg decreases >10% were seen in the incidence of diarrhea and nausea; with a decrease for rash following dose reduction to Bosutinib 200 mg. Decreases (>10%) were noted for nausea following dose reduction to 300 mg imatinib. Conclusions: Management of TEAEs through Bosutinib dose reduction to 300 mg or 200 mg improved tolerability in patients with newly diagnosed CP CML. These reductions in TEAEs enabled patients to continue Bosutinib treatment, with a substantial number of patients achieving MMR and CCyR for the first time after dose reduction. Findings were similar for patients who dose-reduced to 300 mg imatinib. Disclosures Brummendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Incyte: Research Funding. Lipton:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Kota:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Xcenda: Honoraria; Novartis: Honoraria. Deininger:Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Blueprint: Consultancy. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer: Employment, Equity Ownership. Ferdinand:Pfizer: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

  • Bosutinib: A Novel Second-Generation Tyrosine Kinase Inhibitor
    Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer, 2018
    Co-Authors: Susanne Isfort, Philippe Schafhausen, Gunhild Keller-v. Amsberg, Steffen Koschmieder, Tim H. Brümmendorf
    Abstract:

    Bosutinib (SKI-606) is a 4-anilino-3-quinoline carbonitrile, which acts as a dual inhibitor of Src and ABL kinases. In addition, the BCR-ABL fusion gene product, a constitutively activated tyrosine kinase which is crucial for the development of chronic myeloid leukemia (CML), is highly sensitive to Bosutinib. Interestingly, distinctly lower concentrations of Bosutinib are required to ablate BCR-ABL phosphorylation when compared to the first-generation tyrosine kinase inhibitor imatinib (IM). Bosutinib is a potent inhibitor of CML cell proliferation in vitro and has demonstrated promising activity in CML patients resistant or intolerant to IM as well as in newly diagnosed patients with chronic phase CML (CML-CP). Remarkably, Bosutinib has been found to be capable of overcoming the majority of IM-resistant BCR-ABL mutations. Bosutinib has the potency to induce deep and fast responses in second- and third-/fourth-line treatment, and as a consequence, the drug has recently been licensed for patients previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Due to its potency and differing toxicity profile, it promises to be a good therapeutic option for a defined cohort of patients. The most common side effects are gastrointestinal with most of the patients suffering from nausea, vomiting, or diarrhea. For the most part, these gastrointestinal symptoms occur early after treatment initiation, are manageable, and often self-limiting. Continuous monitoring of liver enzymes upon treatment initiation is necessary during Bosutinib treatment. In addition to CML treatment, Bosutinib has shown some efficacy in selected patients suffering from advanced-stage solid tumors. In conclusion, Bosutinib is a promising novel small molecule inhibitor approved now for targeted therapy of CML and in clinical development for other malignancies.

  • Practical management of toxicities associated with Bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2018
    Co-Authors: Hanna Jean Khoury, Carlo Gambacorti-passerini, Tim H. Brümmendorf
    Abstract:

    Abstract Bosutinib (SKI-606) is an oral, dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) that is resistant or intolerant to prior TKI therapy or for whom other TKIs are not appropriate choices. The objective of this review is to provide a longitudinal summary of toxicities that may arise during treatment with second-line or later Bosutinib in patients with Ph+ chronic phase CML and to provide strategies for managing these toxicities. As Bosutinib is not currently indicated for newly diagnosed CML, toxicities associated with first-line treatment are not reviewed. Recognition and optimal management of these toxicities can facilitate patient compliance and affect treatment outcomes.

  • Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with Bosutinib
    American journal of hematology, 2016
    Co-Authors: Jorge E. Cortes, Hagop M. Kantarjian, Ewa Matczak, Dmitri Pavlov, Michael J Mauro, Tim H. Brümmendorf, H. Jean Khoury, Jean M. Aguiar, Kolette D. Fly, Svetoslav Dimitrov
    Abstract:

    Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term Bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line Bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line Bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in Bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line Bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of Bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later Bosutinib (0.037/0.050) and not significantly different between first-line Bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), Bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with Bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. © 2016 Wiley Periodicals, Inc.

Carlo Gambacortipasserini - One of the best experts on this subject based on the ideXlab platform.

  • management of adverse events associated with Bosutinib treatment of chronic phase chronic myeloid leukemia expert panel review
    Journal of Hematology & Oncology, 2018
    Co-Authors: Jorge E. Cortes, Vamsi Kota, Michael W Deininger, Jane F. Apperley, Daniel J Deangelo, Philippe Rousselot, Carlo Gambacortipasserini
    Abstract:

    Bosutinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI), has been available for several years as a treatment for chronic-, accelerated-, and blast-phase chronic myeloid leukemia (CML), for patients with resistance or intolerance to prior therapy. In 2017, the BFORE trial demonstrated efficacy of Bosutinib as first-line treatment in adult patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). The most common adverse events (AEs) of any grade in Bosutinib-treated patients in BFORE were diarrhea, nausea, thrombocytopenia, increased alanine aminotransferase, and increased aspartate aminotransferase, consistent with the most commonly reported AEs in earlier studies. To balance the efficacy and tolerability of treatment to optimize patient adherence with medications, treating physicians commonly use various strategies such as initiating treatment at a lower dose, dose reduction, or dose interruption, depending on the type and severity of the AEs and the clinical setting. In light of the recent data from first-line treatment, an expert panel of hematologists reviewed management strategies for the use of Bosutinib in treatment of CP-CML and made the recommendations reported here. Although the panel focused on first-line treatment, the principles can be for the most part extended to Bosutinib use in later lines of treatment. Recommendations include advice regarding prophylaxis and management for diarrhea. The panel also considered optimum timing for referral to a specialist for specific AEs. Across the commonly occurring AEs, the panel highlighted the importance of education and communication with patients about anticipated AEs.

  • efficacy and safety following dose reduction of Bosutinib or imatinib in patients with newly diagnosed chronic myeloid leukemia analysis of the phase 3 bfore trial
    Blood, 2018
    Co-Authors: Tim H. Brümmendorf, Eric Leip, Vamsi Kota, Andrea Viqueira, Jeffrey H. Lipton, Carlo Gambacortipasserini, Michael W Deininger, Andreas Hochhaus, Roxanne Ferdinand, Jorge E. Cortes
    Abstract:

    Introduction: Bosutinib, an oral dual Src/Abl tyrosine kinase inhibitor (TKI) is approved for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), at a starting dose of 400 once daily (QD) in newly diagnosed patients in chronic phase (CP). Approval of first-line Bosutinib was based on results from the phase 3 BFORE trial, which showed improved efficacy outcomes with Bosutinib vs imatinib in this patient population. This analysis evaluated efficacy and safety of Bosutinib and imatinib following dose reductions in adult patients with newly diagnosed CP CML. Methods: This retrospective analysis included data (≥24-month follow-up) from the ongoing, open-label, phase 3 BFORE trial (NCT02130557). In all, 536 patients were randomized 1:1 to Bosutinib or imatinib at a starting dose of 400 mg QD. Doses could be reduced in 100 mg decrements for toxicity; dose reductions to Results: Of the 268 patients in the Bosutinib arm, 80 dose-reduced to 300 mg only and 23 dose-reduced to 200 mg. The median (range) overall duration of Bosutinib treatment for patients dose reduced to 300 mg was 24.3 months (1.4-33.5) and to 200 mg was 8.3 months (1.0-32.9) vs. 25.1 months (range: 0.26-33.2) for patients who remained on the 400 mg starting dose. Median (range) time to Bosutinib dose reduction to 300 mg was 83 days (18-793) and to 200 mg was 121 days (29-882); respective median (range) duration on reduced dose was 138.5 days (1-957) and 28 days (3-463). Of the 268 (3 untreated) patients in the imatinib arm, 44 dose-reduced to 300 mg. The median duration of imatinib treatment for patients dose reduced to 300 mg was 22.4 months (range: 1.2-33.0) vs. 24.8 months (range: 0.7-33.4) for patients who remained on 400 mg. Median time to imatinib dose reduction to 300 mg was 85.0 days (range: 15-687); median duration on reduced dose was 99.0 days (range: 2-787). TEAEs leading to dose reduction in ≥10 patients were alanine aminotransferase increased and/or aspartate aminotransferase increased (n=21), thrombocytopenia (n=19), lipase increased (n=15) and diarrhea (n=11) with Bosutinib, and neutropenia (n=11) with imatinib. The most common reason for treatment discontinuation in patients who dose-reduced was a TEAE related to Bosutinib (300 mg: 22.5%; 200 mg: 52.2%) or imatinib (300 mg: 27.3%). Among patients who dose-reduced to 300 mg, 16 (20%) had a major molecular response (MMR) with Bosutinib before and after reduction; an additional 36 (45%) achieved MMR for the first time after dose reduction. In the imatinib arm, 7 (15.9%) had an MMR before and after reduction; an additional 22 (50%) achieved MMR for the first time after dose reduction (Table 1). 1 (1.3%) patient lost a previously attained MMR following Bosutinib dose reduction to 300 mg. Among patients who dose-reduced to 200 mg Bosutinib, 4 (17.4%) had an MMR before and after reduction, and an additional 4 (17.4%) achieved MMR for the first time after dose reduction. Similar trends were seen for complete cytogenetic response (CCyR) before and after dose reduction (Table 1). Among patients who remained on 400 mg, 123/165 (74.5%) had a MMR with Bosutinib; 131/152 (86.2%) achieved CCyR. In the imatinib arm, 130/219 (59.4%) had a MMR and 159/198 (80.3%) achieved CCyR. The majority of TEAEs decreased in incidence with dose reduction (Table 2). Following Bosutinib dose reduction to 300 mg or to 200 mg decreases >10% were seen in the incidence of diarrhea and nausea; with a decrease for rash following dose reduction to Bosutinib 200 mg. Decreases (>10%) were noted for nausea following dose reduction to 300 mg imatinib. Conclusions: Management of TEAEs through Bosutinib dose reduction to 300 mg or 200 mg improved tolerability in patients with newly diagnosed CP CML. These reductions in TEAEs enabled patients to continue Bosutinib treatment, with a substantial number of patients achieving MMR and CCyR for the first time after dose reduction. Findings were similar for patients who dose-reduced to 300 mg imatinib. Disclosures Brummendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Incyte: Research Funding. Lipton:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Kota:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Xcenda: Honoraria; Novartis: Honoraria. Deininger:Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Blueprint: Consultancy. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer: Employment, Equity Ownership. Ferdinand:Pfizer: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

  • safety and efficacy of second line Bosutinib for chronic phase chronic myeloid leukemia over a five year period final results of a phase i ii study
    Haematologica, 2018
    Co-Authors: Carlo Gambacortipasserini, Nathalie Bardybouxin, Jorge E. Cortes, Dong-wook Kim, Hagop M. Kantarjian, Jeffrey H. Lipton, Rocco J. Crescenzo, Philippe Schafhausen, Mark Shapiro, Kay Noonan
    Abstract:

    Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Philadelphia positive chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase I/II study of second-line Bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow up and treatment durations were 54.8 (range 0.6-96.3) and 25.6 (0.2-96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on Bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5. Kaplan-Meier probability of maintaining major and complete cytogenetic response was 76% and 78%, respectively, at year 2 and 71% and 69% at year 5. Cumulative incidence of on-treatment disease progression/death was similar at years 5 (19%) and 2 (15%); Kaplan-Meier overall survival was 91% at year 2 and 84% at year 5. Of 169 patients who had discontinued Bosutinib by year 5, 38 did so after year 2, most commonly for disease progression (n=11). Most adverse events initially occurred within two years. Overall, gastrointestinal events were the most common (diarrhea 86%, nausea 46%, vomiting 37%); the most common grade 3/4 toxicity was thrombocytopenia (25%). None of the 4 on-treatment deaths in years 3-5 were related to Bosutinib. Bosutinib demonstrated durable efficacy and manageable toxicity through year 5 confirming its importance in the treatment of chronic phase chronic myeloid leukemia patients resistant/intolerant to prior imatinib. This trial was registered at clinicaltrials.gov identifier: 00261846.

  • Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia results from the randomized bfore trial
    Journal of Clinical Oncology, 2017
    Co-Authors: Jorge E. Cortes, Dong-wook Kim, Irina Dyagil, Carlo Gambacortipasserini, Michael W Deininger, Michael J Mauro, Charles Chuah, Nataliia Glushko, Dragana Milojkovic, Philipp Le Coutre
    Abstract:

    Purpose Bosutinib is a potent dual SRC/ABL kinase inhibitor approved for adults with Philadelphia chromosome-positive chronic myeloid leukemia (CML) resistant and /or intolerant to prior therapy. We assessed the efficacy and safety of Bosutinib versus imatinib for first-line treatment of chronic-phase CML. Methods In this ongoing, multinational, phase III study, 536 patients with newly diagnosed chronic-phase CML were randomly assigned 1:1 to receive 400 mg of Bosutinib once daily (n = 268) or imatinib (n = 268). Per protocol, efficacy was assessed in patients who were Philadelphia chromosome-positive with typical (e13a2/e14a2) transcripts (Bosutinib, n = 246; imatinib, n = 241). Patients with Philadelphia chromosome-negative-/ BCR-ABL1-positive status and those with unknown Philadelphia chromosome status and/or atypical BCR-ABL1 transcript type were excluded from this population. Results The major molecular response (MMR) rate at 12 months (primary end point) was significantly higher with Bosutinib versus imatinib (47.2% v 36.9%, respectively; P = .02), as was complete cytogenetic response (CCyR) rate by 12 months (77.2% v 66.4%, respectively; P = .0075). Cumulative incidence was favorable with Bosutinib (MMR: hazard ratio, 1.34; P = .0173; CCyR: hazard ratio, 1.38; P < .001), with earlier response times. Four patients (1.6%) receiving Bosutinib and six patients (2.5%) receiving imatinib experienced disease progression to accelerated/blast phase. Among treated patients, 22.0% of patients receiving Bosutinib and 26.8% of patients receiving imatinib discontinued treatment, most commonly for drug-related toxicity (12.7% and 8.7%, respectively). Grade ≥ 3 diarrhea (7.8% v 0.8%) and increased ALT (19.0% v 1.5%) and AST (9.7% v 1.9%) levels were more common with Bosutinib. Cardiac and vascular toxicities were uncommon. Conclusion Patients who received Bosutinib had significantly higher rates of MMR and CCyR and achieved responses faster than those who received imatinib. Consistent with the known safety profile, GI events and transaminase elevations were more common with Bosutinib. Results indicate Bosutinib may be an effective first-line treatment for chronic-phase CML.

  • Bosutinib versus imatinib in newly diagnosed chronic phase chronic myeloid leukaemia results from the 24 month follow up of the bela trial
    British Journal of Haematology, 2015
    Co-Authors: Tim Henrik Brummendorf, Jorge E. Cortes, Karin Gogat, Carmino Antonio De Souza, Francois Guilhot, Ladan Duvillie, Dmitri Pavlov, Athena Countouriotis, Carlo Gambacortipasserini
    Abstract:

    Bosutinib is an oral, dual SRC/ABL1 tyrosine kinase inhibitor for resistant/intolerant chronic myeloid leukaemia (CML). We assessed the efficacy and safety of Bosutinib 500 mg/d (n = 250) versus imatinib 400 mg/d (n = 252) after >24 months from accrual completion in newly diagnosed chronic phase (CP)-CML (Bosutinib Efficacy and Safety in Newly Diagnosed CML trial [BELA]). Cumulative complete cytogenetic response (CCyR) rates by 24 months were similar (Bosutinib, 79%; imatinib, 80%); cumulative major molecular response (MMR) rates were 59% for Bosutinib and 49% for imatinib. Responses were durable; 151/197 vs. 172/204 and 125/153 vs. 117/131 responders remained on treatment and maintained CCyR and MMR, respectively. Since the 12-month primary analysis, no new accelerated-/blast-phase transformations occurred with Bosutinib; four occurred with imatinib. Early response (BCR-ABL1/ABL1 ≤ 10%, 3 months) was associated with better CCyR and MMR rates by 12 and 24 months (both arms). Gastrointestinal events and liver function test elevations were more common, and neutropenia, musculoskeletal events and oedema were less common with Bosutinib. Discontinuations due to adverse events were more common with Bosutinib versus imatinib (most commonly alanine aminotransferase elevation: 4% vs. <1%); most occurred within the first 12 months. Cardiovascular adverse events were similar in both arms. Bosutinib continues to demonstrate good efficacy and manageable tolerability in newly diagnosed CP-CML patients.