19 results on '"Boisserie, F."'
Search Results
2. LBA36 Final analysis of RATIONALE-301: Randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma
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Qin, S., primary, Kudo, M., additional, Meyer, T., additional, Finn, R.S., additional, Vogel, A., additional, Bai, Y., additional, Guo, Y., additional, Meng, Z., additional, Zhang, T., additional, Satoh, T., additional, Hiraoka, A., additional, Marino, D., additional, Assenat, E., additional, Wyrwicz, L., additional, Campos, M. Calvo, additional, Hsing-Tao, K., additional, Boisserie, F., additional, Li, S., additional, Chen, Y., additional, and Zhu, A.X., additional
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- 2022
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3. SO-14 Randomized, phase 3 study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma (HCC): RATIONALE-301 age ≥65 years subgroup
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Vogel, A., Kudo, M., Qin, S., Chen, Y., Li, S., Boisserie, F., Abdrashitov, R., Finn, R., Meyer, T., and Zhu, A.
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- 2023
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4. Global phase III study of tislelizumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma (HCC): A trial-in-progress
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Qin, S., primary, Finn, R.S., additional, Kudo, M., additional, Meyer, T., additional, Vogel, A., additional, Ducreux, M.P., additional, Macarulla, T.M., additional, Tomasello, G., additional, Boisserie, F., additional, Hou, J., additional, Li, C., additional, Song, J., additional, and Zhu, A.X., additional
- Published
- 2018
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5. POSSIBLE ROLE OF NPFF AN “ANTIOPIOID” PEPTIDE IN OPIATE TOLERANCE AND DEPENDENCE
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SIMONNET, G, BOISSERIE, F, LH, GOLD, ALLARD, M, and STINUS, L
- Published
- 1993
6. Efficacy and safety of tislelizumab, an anti-PD-1 antibody, versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma in a phase 3, randomized, open-label, multicenter study - Trial in progress
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Qin, S., primary, Finn, R., additional, Kudo, M., additional, Meyer, T., additional, Vogel, A., additional, Ducreux, M., additional, Macarulla, T., additional, Tomasello, G., additional, Boisserie, F., additional, Hou, J., additional, Li, C., additional, Song, J., additional, and Zhu, A., additional
- Published
- 2018
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7. A PHASE 1 STUDY OF BET INHIBITION USING RG6146 IN RELAPSED/REFRACTORY (R/R) MYC-EXPRESSING DIFFUSE LARGE B CELL LYMPHOMA (DLBCL)
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Caimi, P.F., primary, Eder, J.P., additional, Jacobsen, E.D., additional, Jacobson, C.A., additional, LaCasce, A.S., additional, Shipp, M.A., additional, Chapuy, B., additional, Labriola-Tomphins, E., additional, Boisserie, F., additional, Passe, S., additional, Chesné, E., additional, Pierceall, W., additional, Zhi, J., additional, DeMario, M., additional, Vaishampayan, U., additional, Dowlati, A., additional, Shapiro, G.I., additional, Fisher, D.C., additional, and Armand, P., additional
- Published
- 2017
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8. 776TiP - Global phase III study of tislelizumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma (HCC): A trial-in-progress
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Qin, S., Finn, R.S., Kudo, M., Meyer, T., Vogel, A., Ducreux, M.P., Macarulla, T.M., Tomasello, G., Boisserie, F., Hou, J., Li, C., Song, J., and Zhu, A.X.
- Published
- 2018
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9. P-182 - Efficacy and safety of tislelizumab, an anti-PD-1 antibody, versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma in a phase 3, randomized, open-label, multicenter study - Trial in progress
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Qin, S., Finn, R., Kudo, M., Meyer, T., Vogel, A., Ducreux, M., Macarulla, T., Tomasello, G., Boisserie, F., Hou, J., Li, C., Song, J., and Zhu, A.
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- 2018
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10. Pain facilitory systems activated by opiate receptor stimulation: Possible role of NPFF, an anti-opioid peptide
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Simonnet, G., primary, Devillers, J.-P., additional, and Boisserie, F., additional
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- 1994
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11. Celecoxib for the prevention of sporadic colorectal adenomas.
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Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, Tang J, Rosenstein RB, Witts J, Corle D, Hess TM, Woloj GM, Boisserie F, Anderson WF, Viner JL, Bagheri D, Burn J, Chung DC, Dewar T, and Foley TR
- Abstract
Background: Studies showing that drugs that inhibit cyclooxygenase-2 (COX-2) reduce the number of colorectal adenomas in animals and patients with familial adenomatous polyposis suggest that COX-2 inhibitors may also prevent sporadic colorectal neoplasia.Methods: We randomly assigned patients who had adenomas removed before study entry to receive placebo (679 patients) or 200 mg (685 patients) or 400 mg (671 patients) of celecoxib twice daily. Randomization was stratified for the use of low-dose aspirin. Follow-up colonoscopies were performed at one and three years after randomization. The occurrence of newly detected colorectal adenomas was compared among the groups with the life-table extension of the Mantel-Haenszel test.Results: Follow-up colonoscopies were completed at year 1 in 89.5 percent of randomized patients, and at year 3 in 75.7 percent. The estimated cumulative incidence of the detection of one or more adenomas by year 3 was 60.7 percent for patients receiving placebo, as compared with 43.2 percent for those receiving 200 mg of celecoxib twice a day (risk ratio, 0.67; 95 percent confidence interval, 0.59 to 0.77; P<0.001) and 37.5 percent for those receiving 400 mg of celecoxib twice a day (risk ratio, 0.55; 95 percent confidence interval, 0.48 to 0.64; P<0.001). Serious adverse events occurred in 18.8 percent of patients in the placebo group, as compared with 20.4 percent of those in the low-dose celecoxib group (risk ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.5) and 23.0 percent of those in the high-dose group (risk ratio, 1.2; 95 percent confidence interval, 1.0 to 1.5; P=0.06). As compared with placebo, celecoxib was associated with an increased risk of cardiovascular events (risk ratio for the low dose, 2.6; 95 percent confidence interval, 1.1 to 6.1; and risk ratio for the high dose, 3.4; 95 percent confidence interval, 1.5 to 7.9).Conclusions: These findings indicate that celecoxib is an effective agent for the prevention of colorectal adenomas but, because of potential cardiovascular events, cannot be routinely recommended for this indication. (ClinicalTrials.gov number, NCT00005094 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]- Published
- 2006
12. Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial.
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Qin S, Kudo M, Meyer T, Bai Y, Guo Y, Meng Z, Satoh T, Marino D, Assenat E, Li S, Chen Y, Boisserie F, Abdrashitov R, Finn RS, Vogel A, and Zhu AX
- Subjects
- Adult, Male, Humans, Middle Aged, Sorafenib adverse effects, Treatment Outcome, Carcinoma, Hepatocellular pathology, Liver Neoplasms pathology, Antineoplastic Agents adverse effects
- Abstract
Importance: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment., Objective: To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC., Design, Setting, and Participants: The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy-naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022., Intervention: Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily., Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety., Results: A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib., Conclusions and Relevance: In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib., Trial Registration: ClinicalTrials.gov Identifier: NCT03412773.
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- 2023
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13. A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma.
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Shapiro GI, LoRusso P, Dowlati A, T Do K, Jacobson CA, Vaishampayan U, Weise A, Caimi PF, Eder JP, French CA, Labriola-Tompkins E, Boisserie F, Pierceall WE, Zhi J, Passe S, DeMario M, Kornacker M, and Armand P
- Subjects
- Adult, Aged, Aged, 80 and over, Azepines blood, Azepines pharmacokinetics, Dose-Response Relationship, Drug, Female, Humans, Lymphoma, Large B-Cell, Diffuse blood, Male, Middle Aged, Neoplasms blood, Neoplasms metabolism, Small Molecule Libraries administration & dosage, Small Molecule Libraries adverse effects, Small Molecule Libraries pharmacokinetics, Azepines administration & dosage, Azepines adverse effects, Lymphoma, Large B-Cell, Diffuse drug therapy, Neoplasm Proteins metabolism, Neoplasms drug therapy, Nuclear Proteins metabolism, Proteins antagonists & inhibitors
- Abstract
Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor., Methods: We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation., Results: Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression., Conclusions: This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations., Clinical Trials Registration: NCT01987362.
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- 2021
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14. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma.
- Author
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Qin S, Finn RS, Kudo M, Meyer T, Vogel A, Ducreux M, Macarulla TM, Tomasello G, Boisserie F, Hou J, Li X, Song J, and Zhu AX
- Subjects
- Adult, Aged, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological adverse effects, B7-H1 Antigen antagonists & inhibitors, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular mortality, Carcinoma, Hepatocellular pathology, Female, Humans, Induction Chemotherapy, Liver Neoplasms metabolism, Liver Neoplasms mortality, Liver Neoplasms pathology, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Sorafenib administration & dosage, Sorafenib adverse effects, Treatment Outcome, Antineoplastic Agents, Immunological therapeutic use, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Sorafenib therapeutic use
- Abstract
Advanced, unresectable hepatocellular carcinoma (HCC) has a poor prognosis with median life expectancy of approximately 1 year. Overexpression of PD-L1 in tumor cells and PD-1 on tumor-infiltrating T cells has been associated with poorer prognosis, more advanced disease and higher recurrence rates in HCC. Monoclonal antibodies against PD-1 have demonstrated antitumor activity in patients with solid tumors, including HCC. Tislelizumab, an investigational, humanized IgG4 monoclonal antibody with high affinity and binding specificity for PD-1, has demonstrated preliminary antitumor activity in HCC. Here we describe a head-to-head Phase III study comparing the efficacy, safety and tolerability of tislelizumab with sorafenib as first-line treatment in unresectable HCC.
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- 2019
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15. Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC).
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Abou-Alfa GK, Yen CJ, Hsu CH, O'Donoghue J, Beylergil V, Ruan S, Pandit-Taskar N, Gansukh B, Lyashchenko SK, Ma J, Wan P, Shao YY, Lin ZZ, Frenette C, O'Neil B, Schwartz L, Smith-Jones PM, Ohtomo T, Tanaka T, Morikawa H, Maki Y, Ohishi N, Chen YC, Agajanov T, Boisserie F, Di Laurenzio L, Lee R, Larson SM, Cheng AL, and Carrasquilo JA
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- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized pharmacokinetics, Female, Humans, Iodine Radioisotopes, Male, Middle Aged, Niacinamide administration & dosage, Niacinamide adverse effects, Niacinamide analogs & derivatives, Niacinamide pharmacokinetics, Phenylurea Compounds administration & dosage, Phenylurea Compounds adverse effects, Phenylurea Compounds pharmacokinetics, Positron-Emission Tomography, Sorafenib, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Hepatocellular drug therapy, Glypicans antagonists & inhibitors, Liver Neoplasms drug therapy
- Abstract
Purpose: Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC., Patients and Methods: In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0-1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.0 and safety by CTCAE 3.0. PK and pre, during, and post-therapy
124 I radiolabeled codrituzumab PET scan imaging were performed., Results: 41 patients were enrolled: 2.5 mg/kg weekly (qw) (12), 5 mg/kg qw (12), 10 mg/kg qw (3), 1600 mg every 2 weeks (q2w) (6), and 1600 mg qw (7). Two drug limiting toxicities occurred: grade 3 hyponatremia at 5 mg/kg and grade 3 hyponatremia and hyperglycemia at 1600 mg q2w. Adverse events occurred in 80% of patients, including at least one ≥grade 3: ten (25%) increased AST, three (7.5%) increased ALT, and ten (25%) increased lipase. There were no responses and nine (25.7%) had stable disease. PK Cmax and AUCt of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed124 I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed., Conclusion: Codrituzumab plus sorafenib were tolerated at 1600 mg q2w and 400 mg bid, respectively, with no responses. Codrituzumab exerts selective distribution to HCC cells, and GPC3 does not show any down-regulation post-progression (NCT00976170).- Published
- 2017
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16. Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma.
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Abou-Alfa GK, Puig O, Daniele B, Kudo M, Merle P, Park JW, Ross P, Peron JM, Ebert O, Chan S, Poon TP, Colombo M, Okusaka T, Ryoo BY, Minguez B, Tanaka T, Ohtomo T, Ukrainskyj S, Boisserie F, Rutman O, Chen YC, Xu C, Shochat E, Jukofsky L, Reis B, Chen G, Di Laurenzio L, Lee R, and Yen CJ
- Subjects
- Antibodies, Monoclonal, Humanized, Disease-Free Survival, Double-Blind Method, Female, Glypicans, Humans, Male, Middle Aged, Treatment Outcome, Carcinoma, Hepatocellular, Liver Neoplasms
- Abstract
Background & Aims: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy., Methods: Patients with advanced HCC who had failed prior systemic therapy, ⩾18years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis., Results: 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p=0.87), and 8.7 vs. 10 (hazard ratios 0.96, p=0.82). Projected Ctrough at cycle 3day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival., Conclusions: Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions., Lay Summary: Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome., Clinical Trial Registration: This trial is registered at Clinicaltrials.gov (NCT01507168)., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
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17. First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors.
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Dienstmann R, Lassen U, Cebon J, Desai J, Brown MP, Evers S, Su F, Zhang W, Boisserie F, Lestini B, Schostack K, Meresse V, and Tabernero J
- Subjects
- Adult, Aged, Dose-Response Relationship, Drug, Female, Fluorodeoxyglucose F18 pharmacokinetics, Humans, Male, Melanoma drug therapy, Melanoma genetics, Melanoma metabolism, Middle Aged, Mutation, Neoplasms genetics, Neoplasms metabolism, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacokinetics, Proto-Oncogene Proteins B-raf genetics, Radiopharmaceuticals pharmacokinetics, Treatment Outcome, Young Adult, Neoplasms drug therapy, Protein Kinase Inhibitors administration & dosage, Proto-Oncogene Proteins B-raf antagonists & inhibitors
- Abstract
Background: BRAF mutations are a validated target for cancer therapy. A second-generation BRAF inhibitor with an improved preclinical safety profile (RG7256) was evaluated in a first-in-man study in order to determine the safety, efficacy, pharmacokinetics and pharmacodynamics in patients with BRAF V600-mutated advanced solid tumors., Patients and Methods: Patients received RG7256 orally over 8 dose levels from 200 mg once a day (QD) to 2400 mg twice a day (BID) (50-, 100- and 150-mg tablets) using a classic 3 + 3 dose escalation design., Results: In total, 45 patients were enrolled; most (87 %) had advanced melanoma (94 % BRAF V600E). RG7256 was rapidly absorbed, with limited accumulation and dose-proportional increase in exposure up to 1950 mg BID. The maximal tolerated dose (MTD) was not reached. The most common drug-related adverse events (AEs) were dyspepsia (20 %), dry skin (18 %), rash (18 %), fatigue (16 %) and nausea (13 %), mainly grade 1. Three patients (7 %) developed cutaneous squamous cell carcinoma. Photosensitivity, arthralgia and increased liver enzyme levels were each observed in only one patient each. Of 44 evaluable patients, 14 (32 %) had a partial response (melanoma and thyroid cancer). At high dose levels (>1200 mg BID), 10 of 16 (63 %) patients had a partial response. A decrease in maximum standardized uptake value (SUVmax) on FDG-PET of ≥25 % was observed in 19 of 37 patients. On-treatment reductions in pERK were documented in eight of ten paired tumor samples., Conclusions: RG7256 has a favorable safety profile compared to other BRAF inhibitors while maintaining clinical activity, and MTD was not reached. The excessive pill burden needed to provide the desired exposure, and thus concerns about patient compliance, limited further development of this agent. Study Identifier: ClinicalTrials.gov (NCT01143753).
- Published
- 2016
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18. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
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Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, Morcos PN, Lee RM, Garcia L, Yu L, Boisserie F, Di Laurenzio L, Golding S, Sato J, Yokoyama S, Tanaka T, and Ou SH
- Subjects
- Adult, Aged, Aged, 80 and over, Anaplastic Lymphoma Kinase, Brain Neoplasms mortality, Carbazoles adverse effects, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung secondary, Crizotinib, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Follow-Up Studies, Gene Rearrangement, Humans, Lung Neoplasms genetics, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Maximum Tolerated Dose, Middle Aged, Patient Selection, Piperidines adverse effects, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyridines therapeutic use, Receptor Protein-Tyrosine Kinases genetics, Risk Assessment, Survival Analysis, Treatment Outcome, Brain Neoplasms drug therapy, Brain Neoplasms secondary, Carbazoles therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Drug Resistance, Neoplasm, Lung Neoplasms drug therapy, Piperidines therapeutic use
- Abstract
Background: Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib., Methods: We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300-900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiological review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, number NCT01588028., Findings: 47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral oedema (seven [15%] grade 1-2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of γ-glutamyl transpeptidase (two [4%]), a reduction in the number of neutrophils (two [4%]), and hypophosphataemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84-217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC0-10) after multiple doses of alectinib (300-600 mg twice a day) was dose-dependent., Interpretation: Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2., Funding: Chugai Pharmaceuticals, F Hoffmann La-Roche., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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19. Simultaneous activation of spinal antiopioid system (neuropeptide FF) and pain facilitatory circuitry by stimulation of opioid receptors in rats.
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Devillers JP, Boisserie F, Laulin JP, Larcher A, and Simonnet G
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- Animals, Heroin pharmacology, In Vitro Techniques, Male, Morphine antagonists & inhibitors, Naloxone pharmacology, Narcotic Antagonists pharmacology, Rats, Rats, Sprague-Dawley, Reaction Time, Spinal Cord metabolism, Tetrodotoxin pharmacology, Morphine pharmacology, Neuropeptides metabolism, Oligopeptides metabolism, Pain physiopathology, Receptors, Opioid drug effects, Spinal Cord drug effects
- Abstract
Neuropeptide FF (NPFF) is a mammalian FMRFamide-like octapeptide with antiopioid properties that inhibits morphine-induced analgesia but also produces hyperalgesia. In the present study, a series of three experiments was carried out to investigate the interactions between opioid receptor stimulation and antiopioid systems. First, by using in vitro superfusion system with rat spinal cord slices, we showed that morphine stimulated NPFF release in a dose-dependent manner. The stimulating effect which was observed with morphine concentrations as low as 100 fM reached a maximum at 0.1 nM, then decreased and was ineffective at 10 microM. The morphine-induced release of NPFF was abolished by naloxone (1 microM) but unaltered by tetrodotoxin. Second, by an in vivo approach, we showed that a single heroin administration (2.5 mg/kg, s.c.) elicited in 30 min a drastic drop (38%) in spinal NPFF content. In a third experiment, we evaluated the capacity of naloxone in revealing an antiopioid component associated with opioid receptor stimulation. The administration of naloxone (1 mg/kg, s.c..) 25 min following that of heroin (2.5 mg/kg, s.c.) not only abolished the heroin-induced increase of tail-flick latency, but also lowered it under the basal value by 30%. These results indicate that opioid receptor stimulation activates both pain inhibitory and pain facilitatory systems in which NPFF may play a significant role and that opiate-induced analgesia is always partly masked.
- Published
- 1995
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