Radiothérapie bifractionnée continue à 80,4 Gy et chimiothérapie par CDDP-5 FU concomitante (BIRCF) dans les carcinomes épidermoïdes localement avancés non résécables de l'oropharynx et de l'hypopharynx: résultats de l'essai de phase II de la FNCLCC, et mise en place d'un essai multicentrique randomisé de phase III: BIRCF versus RT bifractionnée exclusive

Zusammenfassung. Herzinsuffizienz ist ein klinisches Syndrom mit unterschiedlichen Ätiologien und Phänotypen. Die überwachte Bewegungstherapie und individuelle körperliche Aktivität ist bei allen Formen eine Klasse-IA-Empfehlung in aktuellen Leitlinien. Eine Bewegungstherapie kann unmittelbar nach Stabilisierung einer akuten Herzinsuffizienz im Spital begonnen werden (Phase I). Sie kann nach Entlassung in einem stationären oder ambulanten Präventions- und Rehabilitationsprogramm fortgesetzt werden (Phase II). Typische Elemente sind Ausdauer-, Kraft- und Atemtraining. Die Kosten werden von der Krankenversicherung für drei bis sechs Monate übernommen. In erfahrenen Zentren können auch Patienten mit implantierten Defibrillatoren oder linksventrikulären Unterstützungssystemen trainieren. Wichtiges Ziel der Phase II ist neben muskulärer Rekonditionierung auch die Steigerung der Gesundheitskompetenz, um die Langzeit-Adhärenz bezüglich körperlicher Aktivität zu verbessern. In Phase III bieten Herzgruppen Unterstützung.

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AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1124 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1464.1-1465

Author(s):

J. Blaess ◽

J. Walther ◽

J. E. Gottenberg ◽

J. Sibilia ◽

L. Arnaud ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systematic Review ◽

B Cells ◽

Phase I ◽

Phase Ii ◽

Clinical Development ◽

Phase Iii ◽

Jak Inhibitors ◽

Exclusion Criteria ◽

Immunomodulating Drugs

Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared

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Determination of Efficacy of Single and Double 4.7 mg Deslorelin Acetate Implant on the Reproductive Activity of Female Pond Sliders (Trachemys scripta)

Animals ◽

10.3390/ani11030660 ◽

2021 ◽

Vol 11 (3) ◽

pp. 660

Author(s):

Edoardo Bardi ◽

Martina Manfredi ◽

Raffaella Capitelli ◽

Emanuele Lubian ◽

Alessandro Vetere ◽

...

Keyword(s):

Phase Ii ◽

Egg Production ◽

Reproductive Activity ◽

Trachemys Scripta ◽

Phase Iii ◽

Control Group ◽

Sexual Hormones ◽

Significant Difference ◽

Group 6 ◽

Plasmatic Concentration

The use of long-acting gonadotropin-releasing hormone (GnRH) agonists to suppress fertility has been poorly investigated in reptiles, and the few available studies show inconsistent results. The efficacy of single and double intramuscular 4.7 mg deslorelin acetate implants in captive pond sliders (Trachemys scripta) was investigated, with 20 animals divided into three groups: a single-implant group (6 animals), a double-implant group (6 animals), and a control group (no implant). During one reproductive season (March to October), plasmatic concentration of sexual hormones (estradiol, progesterone, and testosterone) and ovarian morphometric activity via computed tomography were monitored about every 30 days. A significative decrease in the number of phase II ovarian follicles was detected in the double-implant group compared with the control group, but no significant difference was noted in the number of phase III and phase IV follicles, egg production, and plasmatic concentration of sexual hormones. Results show that neither a single nor a double deslorelin acetate implant can successfully inhibit reproduction in female pond sliders during the ongoing season, but the lower number of phase II follicles in the double-implant group can possibly be associated with reduced fertility in the following seasons.

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A phase II study of high-dose cisplatin and VP-16 in neuroblastoma: a report from the Société Française d'Oncologie Pédiatrique.

Journal of Clinical Oncology ◽

10.1200/jco.1987.5.6.941 ◽

1987 ◽

Vol 5 (6) ◽

pp. 941-950 ◽

Cited By ~ 43

Author(s):

T Philip ◽

R Ghalie ◽

R Pinkerton ◽

J M Zucker ◽

J L Bernard ◽

...

Keyword(s):

Hearing Loss ◽

Phase Ii ◽

Phase Ii Study ◽

Bone Marrow Involvement ◽

Stage Iv ◽

Observation Time ◽

Phase Iii ◽

High Dose ◽

Initial Stage ◽

Duration Of Response

Forty-seven children or adolescents with initial stage IV (42 patients) or stage III (five) advanced neuroblastoma (12 were progressing after relapse and 35 had never reached complete remission [CR] after conventional therapy) were included in a phase II study of the combination of high-dose VP-16 (100 mg/m2/d X 5) and high-dose cisplatin (CDDP) (40 mg/m2/d X 5). Twenty patients had received prior CDDP therapy (total dose, 100 to 640 mg/m2; median, 320 mg/m2) and 38 of 47 had bone marrow involvement when included in the study. The overall response rate was 55%, with 22% CR. Duration of response was 5 to 18 months, with a median of 10 months. Eight patients are still disease free, with a median observation time of 13 months, but all had received additional therapy after two courses of this regimen. Gastrointestinal toxicity was frequent but tolerable. Myelosuppression was severe but of brief duration, ie, nadir of neutrophils was observed at day 15 with 95% of the patients recovering a normal count before day 28, and nadir of platelet count was at day 17 with only two severe and reversible episodes of bleeding. The overall incidence of sepsis was 8% (seven of 92 courses), with no death related to infection. No acute renal failure was observed after two courses, and only three of 47 children experienced a clear reduction of renal function. After two courses, only two children showed a hearing loss in the 1,000 to 2,000 Hz range, although hearing loss above the 2,000 Hz level was frequently encountered. It is concluded that high-dose VP-16 and CDDP is an effective regimen in advanced neuroblastoma with acceptable toxicity. Phase III studies are needed in previously untreated patients. J Clin Oncol 5:941-950.

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Trimodality bladder-sparing approach versus radical cystectomy for invasive bladder cancer

Journal of Radiotherapy in Practice ◽

10.1017/s1460396914000107 ◽

2014 ◽

Vol 13 (4) ◽

pp. 428-437 ◽

Cited By ~ 5

Author(s):

Samy M. AlGizawy ◽

Hoda H. Essa ◽

Mostafa E. Abdel-Wanis ◽

Ahmed M. Abdel Raheem

Keyword(s):

Bladder Cancer ◽

Radical Cystectomy ◽

Phase Ii ◽

Transurethral Resection ◽

Residual Disease ◽

Bladder Tumour ◽

Phase Iii ◽

Invasive Bladder Cancer ◽

Combined Modality ◽

Combined Chemoradiotherapy

AbstractPurposeTo compare the outcome among patients with invasive bladder cancer treated with cystectomy alone with outcome among those treated with combined-modality treatment in a randomised phase III trial.Patients and methodsPatients with histologically confirmed invasive non-metastatic bladder cancer T2-3, N0 and M0 were randomly assigned to two arms: Arm 1: of which all patients underwent radical cystectomy (RC) alone; and Arm 2, of which all patients were subjected to maximal transurethral resection of bladder tumour, followed 2 weeks later by combined chemoradiotherapy. The whole pelvis received 46 Gy in 23 fractions over 4·5 weeks. Chemotherapy was administered concomitantly with radiotherapy with: cisplatin 70 mg/m2 q. 3 weeks and Gemcitabine 300 mg/m2 D 1, 8 and 15 q. 3 weeks for two cycles. Patients who had complete response were shifted to phase II treatment: 20 Gy/10 fractions/2 weeks to the bladder. Patients with residual tumour underwent RC.ResultsOf the 80 patients assigned Arm 2, a visibly completed transurethral resection of the bladder tumour was possible in 48 patients (60%). Phase I of combined chemoradiotherapy (CCRT) was accomplished in 74 patients. Post-induction urologic evaluation revealed no evidence of disease in 62 patients (83·8%) and residual disease in 12 patients (16·2%). Phase II of CCRT was completed in 58 of the 62 patients. The median follow-up for all patients is 27 months (range: 4–49). The 3-year overall survival (OS) for the combined-modality group and for the surgery group were 61 and 63%, respectively (p = 0·425), whereas the disease-specific survival (DSS) for each group was 69 and 73%, respectively (p = 0·714). The 3-year OS with bladder preservation for Arm 2 patients was 50%.Multivariate analysis for the whole series showed that tumour stage and performance status (PS) were the only factors independently associated with DSS, although PS was the only factor independently associated with OS. In addition, residual disease after transurethral resection of the bladder tumour in Arm 2 patients was independently associated with both DSS and OS.Acute toxicity was moderate and most of the late toxicities were grade 2 with no grade 4 toxicity and no treatment-related deaths, none required cystectomy for bladder contraction.ConclusionThis study demonstrates that trimodality bladder-preserving approach represents a valid alternative for suitable patients. The OS and DSS rates of patients treated with trimodality bladder-preserving protocol are comparable to the results reported on patients treated with immediate radical cystectomy.

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Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.8406 ◽

2006 ◽

Vol 24 (1) ◽

pp. 136-140 ◽

Cited By ~ 20

Author(s):

Andrew J. Vickers ◽

Joyce Kuo ◽

Barrie R. Cassileth

Keyword(s):

Clinical Trials ◽

Phase I ◽

Cancer Patients ◽

Phase Ii ◽

Dose Finding ◽

Phase Iii ◽

High Dose ◽

Free Text ◽

Phase Ii Trials ◽

Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

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Protein misfolding, amyotrophic lateral sclerosis and guanabenz: protocol for a phase II RCT with futility design (ProMISe trial)

BMJ Open ◽

10.1136/bmjopen-2016-015434 ◽

2017 ◽

Vol 7 (8) ◽

pp. e015434 ◽

Cited By ~ 5

Author(s):

Eleonora Dalla Bella ◽

Irene Tramacere ◽

Giovanni Antonini ◽

Giuseppe Borghero ◽

Margherita Capasso ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Amyotrophic Lateral Sclerosis ◽

Placebo Group ◽

Phase Ii ◽

Critical Role ◽

Protein Translation ◽

Phase Iii ◽

Protein Accumulation ◽

Neuroprotective Effects ◽

Lateral Sclerosis

IntroductionRecent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS.Methods and analysesProtocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial.Ethics and disseminationThe study protocol was approved by the Ethics Committee of IRCCS ‘Carlo Besta Foundation’ of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration.

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Design Issues of Randomized Phase II Trials and a Proposal for Phase II Screening Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.01.149 ◽

2005 ◽

Vol 23 (28) ◽

pp. 7199-7206 ◽

Cited By ~ 246

Author(s):

Lawrence V. Rubinstein ◽

Edward L. Korn ◽

Boris Freidlin ◽

Sally Hunsberger ◽

S. Percy Ivy ◽

...

Keyword(s):

Phase Ii ◽

False Positive ◽

Standard Treatment ◽

False Negative ◽

Error Rates ◽

Targeted Treatment ◽

Phase Iii ◽

Phase Ii Trials ◽

Treatment Control ◽

Randomized Phase Ii

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing “phase II screening trials,” in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (α or type I error) and false-negative error rates (β or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.

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The decapentaplegic core promoter region plays an integral role in the spatial control of transcription.

Molecular and Cellular Biology ◽

10.1128/mcb.15.7.3960 ◽

1995 ◽

Vol 15 (7) ◽

pp. 3960-3968 ◽

Cited By ~ 21

Author(s):

D H Schwyter ◽

J D Huang ◽

T Dubnicoff ◽

A J Courey

Keyword(s):

Expression Pattern ◽

Phase Ii ◽

Promoter Region ◽

Core Promoter ◽

Critical Role ◽

Regulatory Elements ◽

Drosophila Embryo ◽

Phase Iii ◽

Core Promoter Region ◽

Flanking Region

The Drosophila melanogaster decapentaplegic (dpp) gene encodes a transforming growth factor beta-related cell signaling molecule that plays a critical role in dorsal/ventral pattern formation. The dpp expression pattern in the Drosophila embryo is dynamic, consisting of three phases. Phase I, in which dpp is expressed in a broad dorsal domain, depends on elements in the dpp second intron that interact with the Dorsal transcription factor to repress transcription ventrally. In contrast, phases II and III, in which dpp is expressed first in broad longitudinal stripes (phase II) and subsequently in narrow longitudinal stripes (phase III), depend on multiple independent elements in the dpp 5'-flanking region. Several aspects of the normal dpp expression pattern appear to depend on the unique properties of the dpp core promoter. For example, this core promoter (extending from -22 to +6) is able to direct a phase II expression pattern in the absence of additional upstream or downstream regulatory elements. In addition, a ventral-specific enhancer in the dpp 5'-flanking region that binds the Dorsal factor activates the heterologous hsp70 core promoter but not the dpp core promoter. Thus, the dpp core promoter region may contribute to spatially regulated transcription both by interacting directly with spatially restricted activators and by modifying the activity of proteins bound to enhancer elements.

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