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1.
J Clin Pharmacol ; 58(3): 357-363, 2018 03.
Article in English | MEDLINE | ID: mdl-29106740

ABSTRACT

Nintedanib is an intracellular inhibitor of tyrosine kinases used in the treatment of non-small cell lung cancer and idiopathic pulmonary fibrosis (IPF). This phase 1 open-label study investigated the influence of mild and moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of nintedanib following oral administration of a single 100-mg dose. Subjects with hepatic impairment classified as Child-Pugh A (mild hepatic impairment) or Child-Pugh B (moderate hepatic impairment) were eligible. The control group comprised healthy matched subjects. Primary end points were Cmax and AUC0-∞ of nintedanib. Thirty-three subjects received nintedanib (8 in each of the Child-Pugh A and Child-Pugh B groups and 17 controls). The shape of the plasma concentration-time curve for nintedanib was similar between Child-Pugh A or B and healthy subjects. Nintedanib exposure was ∼2-fold higher in Child-Pugh A subjects and ∼8-fold higher in Child-Pugh B subjects than in healthy subjects. Adverse events were reported in 3 Child-Pugh B subjects (37.5%), no Child-Pugh A subjects, and 3 healthy subjects (17.6%). In conclusion, exposure to nintedanib was higher in Child-Pugh A and B subjects than in matched healthy subjects. A single dose of nintedanib 100 mg had an acceptable safety and tolerability profile in subjects with hepatic impairment. Results of this dedicated phase 1 study are in line with exploratory investigations into the PK of nintedanib in patients with advanced solid tumors or IPF and hepatic impairment.


Subject(s)
Indoles/administration & dosage , Indoles/pharmacokinetics , Liver Diseases/metabolism , Aged , Female , Humans , Indoles/blood , Liver Diseases/blood , Male , Middle Aged , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacokinetics
2.
Lung Cancer ; 108: 154-160, 2017 06.
Article in English | MEDLINE | ID: mdl-28625629

ABSTRACT

OBJECTIVES: Dysregulation of the downstream PI3K/AKT/mTOR signaling pathway is a proposed mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We investigated safety and antitumor activity of afatinib plus sirolimus as a potential combination to reverse acquired resistance to EGFR-TKIs in a phase IB trial in patients with EGFR mutation-positive non-small-cell lung cancer (EGFR mut NSCLC) and/or disease progression following prior erlotinib/gefitinib. MATERIALS AND METHODS: Patients with EGFR mut NSCLC and/or disease progression following at least prior erlotinib/gefitinib were included in the trial. The primary endpoint was incidence of dose-limiting toxicities (DLT) to determine the maximum tolerated dose (MTD). Four initial dose cohorts were proposed to evaluate DLTs. Other endpoints included tumor response, safety, progression-free survival (PFS) and pharmacokinetics. RESULTS: Thirty-nine patients received afatinib and sirolimus. Additional dose cohorts were added since the second cohort (afatinib 40mg/day and sirolimus 5mg/day) was considered to have excessive toxicity. All patients experienced adverse events (AE) [grade 3: 66.7%; serious AE: 56.4%]. The most frequent AEs were diarrhea (94.9%), mucosal inflammation (64.1%), asthenia (53.8%) and rash (53.8%). Discontinuations and dose reduction due to AEs occurred in 23.1% and 25.6% of patients. MTD was determined as afatinib 30mg and sirolimus 1mg. Responses were observed in 5 patients (12.8%) [2 (5.1%) with confirmed partial response (PR); 3 (7.7%) with unconfirmed PR], and stable disease in 18 patients (46.2%). Four of the 5 responses were at doses above MTD. PFS at 6 months was estimated in 33.3% (median PFS 3.4 months). Pharmacokinetic parameters of afatinib and sirolimus were similar after single administration or in combination. CONCLUSION: The combination of afatinib and sirolimus showed lower responses than expected. Together with increased AEs and poor tolerability, this precludes clinical use and further clinical development of this combination. No pharmacokinetic interactions were observed. CLINICALTRIALS. GOV IDENTIFIER: NCT00993499.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Afatinib , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Disease Progression , Drug Monitoring , Female , Gefitinib , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Quinazolines/administration & dosage , Quinazolines/therapeutic use , Retreatment , Sirolimus/administration & dosage , Treatment Outcome
3.
Lancet Oncol ; 13(4): 375-84, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22377126

ABSTRACT

BACKGROUND: Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer; however, few data exist for this regimen in inflammatory breast cancer. In our phase 2 trial, we aimed to assess efficacy and safety of neoadjuvant bevacizumab combined with trastuzumab and chemotherapy in patients with primary HER2-positive inflammatory breast cancer. METHODS: In our phase 2, multicentre, open-label, single-arm, non-comparative trial, we enrolled women (aged ≥ 18 years) with histologically confirmed HER2-positive non-metastatic inflammatory breast cancer at private or public oncology centres in France. Before surgery, patients were treated with fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1-4) and docetaxel, bevacizumab, and trastuzumab (cycles 5-8) in 3-week cycles. After surgery, patients received adjuvant radiotherapy, trastuzumab, and bevacizumab. For the primary endpoint, we assessed the proportion of patients who achieved a pathological complete response (defined by central review of surgical specimens according to Sataloff classification, counting missing data as failure) and adverse events in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00717405. FINDINGS: Between Oct 23, 2008, and Oct 28, 2009, we enrolled 52 patients at 21 centres. 42 (81%) of 52 patients received all eight cycles of neoadjuvant therapy and 49 (94%) underwent surgery. After neoadjuvant therapy, 33 of 52 patients had a pathological complete response according to central review (63·5%, 95% CI 49·4-77·5). The most common adverse events were asthenia and nausea (both occurred in 36 [69%] of 52 patients). 25 (48%) patients had grade 3-4 neutropenia, which was the most common grade 3-4 adverse event. Only one grade 3 or worse adverse event regarded as related to bevacizumab was reported (hypertension, one patient). Four patients (8%) had cardiac failure. INTERPRETATION: Neoadjuvant treatment with bevacizumab, trastuzumab, and chemotherapy was efficacious and well tolerated in patients with previously untreated primary inflammatory breast cancer. Further confirmation of use of bevacizumab in inflammatory breast cancer is needed. FUNDING: Roche (France).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Inflammatory Breast Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Asthenia/chemically induced , Bevacizumab , Combined Modality Therapy , Female , Humans , Inflammatory Breast Neoplasms/pathology , Inflammatory Breast Neoplasms/surgery , Middle Aged , Nausea/chemically induced , Neoadjuvant Therapy/methods , Neoplasm Staging , Neutropenia/chemically induced , Postoperative Care , Receptor, ErbB-2/analysis , Trastuzumab
4.
Clin Colorectal Cancer ; 11(1): 38-44, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21803002

ABSTRACT

BACKGROUND: This prospective phase II study assessed the efficacy and safety of bevacizumab plus chemotherapy regimens commonly used in the second-line treatment of metastatic colorectal cancer (mCRC). METHODS: Patients with mCRC who progressed or relapsed after first-line oxaliplatin-based or irinotecan-based treatment received bevacizumab 2.5 mg/kg/week plus chemotherapy until disease progression. The primary endpoint was disease-control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety. RESULTS: Fifty-three patients (66% men; median age, 62 years old) received second-line bevacizumab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI; 57%), folinic acid, fluorouracil, oxaliplatin (FOLFOX; 26%), irinotecan (15%), or capecitabine plus irinotecan (XELIRI; 2%). The DCR was 87% (95% CI, 77%-97%); ORR was 32% (95% CI, 19%-46%). Median PFS was 6.5 months (95% CI, 5.8-7.8 months) and median OS 19.3 months, (95% CI, 14.2-25.1 months).The most frequent grade 3/4 adverse events included neutropenia (21%), diarrhea (15%), asthenia, and vomiting (9% each). Five patients (9%) had grade 3/4 targeted toxicities: grade 3 hypertension (n = 2), grade 3 venous thromboembolism (n = 2), and grade 4 arterial thromboembolism (n = 1). None of these events led to death during the study. CONCLUSION: Bevacizumab plus standard second-line chemotherapy is highly active in patients with mCRC and has an acceptable safety profile.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Salvage Therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Bevacizumab , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Capecitabine , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Follow-Up Studies , Humans , Irinotecan , Leucovorin/administration & dosage , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Prospective Studies , Survival Rate , Treatment Outcome
5.
Nephrol Ther ; 7(3): 182-7, 2011 Jun.
Article in French | MEDLINE | ID: mdl-21227765

ABSTRACT

The observational study DiaNE provides a current state of anemia management with Epoetine bêta in hemodialysis patients regarding European recommendations over a 3-year period in France. Patients still treated with Epoetine bêta twelve months after their inclusion in DiaNE were eligible for a 24-month extension phase entitled DiaNE 2. Data regarding 439 patients followed during three years, from M0 to M36, were analyzed. Hemoglobin (Hb) level of the cohort remained over the target value of 11g/dL during the study (M0: 11.3±1.2g/dL; M36: 11.8±1.3g/dL). The anemia management had evolved with European recommendations updates and was in accordance with the last recommended target range (11-12g/dL) in a third of patients. During the follow-up, the majority of patients (97%) had at least one modification of treatment with Epoetine bêta (change in frequency of injections, adjustment of doses) mainly justified by excursion of Hb level out of the target range. However, the median dose of Epoetine bêta was relatively stable. The number of patients with iron treatment remained stable (60%). In spite of undertaken efforts, anemia management of hemodialysed patients in France still needs optimization for maintaining Hb level in the recommended target range.


Subject(s)
Anemia/drug therapy , Erythropoietin/therapeutic use , Renal Dialysis , Aged , Female , France , Humans , Male , Recombinant Proteins , Time Factors
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