Academic literature on the topic 'Extensions de cycle C3→C4 et C3→C4→C5'

Abstract Background: Autologous stem-cell transplantation (ASCT) is the standard of care for younger patients with multiple myeloma (MM). The degree of tumor reduction after ASCT is the crucial factor associated with a prolonged PFS and OS, being the M-protein decrease at the time of transplant the most important predictor of residual disease after ASCT. While there is an agreement that bortezomib and dexamethasone associated to a third drug is the induction of choice, which should be the third drug (thalidomide, lenalidomide, doxorubicin or cyclophosphamide) and the optimal number of cycles remain unknown. The results of phase 3 PETHEMA study GEM05menos65 showing a CR rate of 35% increasing overtime during the 6 induction cycles of VTD (Rosiñol et al, Blood 2012) prompted us to study the kinetics of response to VTD and TD in this study and in similar historic data with the VD regimen in phase 2 PETHEMA VELCA/DEXA trial (Rosiñol et al, JCO 2007). Objective: To study the kinetics of response by cycle during the 6 cycles of induction with VTD, TD and VD using a random effects model methodology. Patients and Methods: In GEM05menos65 study patients were randomized to receive 6 induction cycles of either VTD or TD followed by ASCT. One hundred and thirteen patients were treated with TD (thalidomide 200 mg daily; dexamethasone 40 mg on days 1-4 and 9-12) and 122 with VTD (TD at identical doses plus bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11) (Rosiñol et al, Blood 2012) and had complete data set for this analysis. In VELCA/DEXA study 40 patients received 6 induction cycles of bortezomib and dexamethasone on an alternating basis (Rosiñol et al, JCO 2007). Linear random effects models were employed to analyze the tumor response kinetics using the absolute decrease value of the serum M-protein after each cycle. Because the nonlinearity in the change of the M-protein overtime, a piecewise linear model was used to estimate mean changes in M-protein in each of the 6 cycles. Results: Three different comparisons were made: 1) the decrease of the M-protein by cycle within each treatment group, 2) the total M-protein decrease at the end of induction with VTD compared to TD and VD and 3) the decrease by cycle comparing VTD vs TD and VTD vs VD. Concerning the M-protein decrease by cycle within each arm, statistically significant decreases versus the previous cycle were observed in the first 5 cycles of VTD, the first 3 of TD and the first 4 of VD. The serum M-protein reduction at the end of the 6 induction cycles was significantly higher with VTD when compared with TD (p<0.0001) and VD (p<0.0001). Finally, when comparing the serum M-protein decrease between VTD and TD by cycle, the M-protein reduction was significantly higher with VTD in the first 5 cycles and the same analysis between VTD and VD showed that the serum M-protein decrease was significantly higher with VTD in the first 3 cycles (Tables 1 and 2). Conclusions: In the cycle by cycle analysis VTD continued to improve M-protein reduction significantly in the first 5 cycles. When compared with TD and VD, the M-protein decrease at the end of induction was significantly higher with VTD. Furthermore, in the cycle by cycle comparison there was a significantly higher efficacy of VTD over TD in the first 5 cycles and over VD in the first 3 cycles. Our results suggest a synergistic rather than only an additive effect between thalidomide and bortezomib supporting the use of an IMiD as the drug of choice to be combined with bortezomib and dexamethasone. Finally, our study supports an induction period beyond 3 or 4 cycles when using a bortezomib/IMiD regimen in order to maximize the induction efficacy. Table 1. Comparison between VTD versus TD by cycles overtime. Serum M-protein (g/dl) Change (VTH-TH) Estimate SE 95% CI P-value C1 – Baseline -3.0747 0.3461 (-3.7539, -2.3954) <.0001 C2 – C1 -1.1343 0.1294 (-1.3883, -0.8802) <.0001 C3 – C2 -0.4474 0.09586 (-0.6356, -0.2593) <.0001 C4 – C3 -0.2140 0.08224 (-0.3753, -0.05257) 0.0094 C5 – C4 -0.1339 0.07550 (-0.2821, -0.01428) 0.0765 C6 – C5 0.01862 0.05395 (-0.08725, 0.1245) 0.7300 Table 2. Comparison between VTD versus VD by cycles overtime. Serum M-protein (g/dl) Change (VTH-VD) Estimate SE 95% CI P-value C1 – Baseline -3.1553 0.2243 (-3.5957, -2.7150) <.0001 C2 – C1 -1.3748 0.2279 (-1.8223, -0.9272) <.0001 C3 – C2 -0.4266 0.2354 (-0.8887, 0.03552) 0.0703 C4 – C3 -0.05473 0.2439 (-0.5337, 0.4242) 0.8225 C5 – C4 -0.02217 0.2530 (-0.5189, 0.4745) 0.9302 C6 – C5 0.06493 0.2908 (-0.5060, 0.6358) 0.8234 Disclosures Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Oriol:Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Gutierrez:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Martinez-Lopez:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Feng:Janssen: Employment. van de Velde:Janssen: Employment. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.

8511 Background: The PACIFIC study showed that consolidative Programmed Death Ligand 1 inhibition (PD-L1i) after chemoradiation therapy (CRT) improves PFS and OS in patients with Stage IIII NSCLC (Antonia et al. NEJM 2017, 2018). Limited data, however, exist regarding the incorporation of PD-L1i concurrently during CRT. We sought to assess the safety and toxicity of PD-1i using pembrolizumab (pembro) during definitive CRT for Stage III NSCLC. Methods: In this multi-center prospective Phase I clinical trial using a 3+3 design, we evaluated the timing and dosing of pembro combined with chemotherapy (carboplatin + paclitaxel weekly) and definitive RT (60 Gy in 2 Gy/day x 30 fractions) for unresectable, locally advanced Stage III NSCLC (AJCC 7thEd). Dose Cohorts (C) evaluated were--C1: full dose (FD) pembro (200 mg IV Q3 weeks) 2-6 weeks after CRT; C2: reduced dose (RD) pembro (100 mg IV Q3 weeks) starting Day 29 of CRT; C3: FD pembro starting Day 29 of CRT; C4: RD pembro starting on Day 1 of CRT; C5: FD pembro starting on Day 1 of CRT. For each cohort, pembro was continued Q3 weeks for up to 18 cycles (as monotherapy after CRT in either RD or FD based on initial dose assignment). Dose Limiting Toxicity (DLT) was defined as Grade ≥4 pneumonitis within 21 days of cycle 1 of pembro. Results: We enrolled 23 subjects from 8/2016-11/2018; median follow up (f/u) was 11.4 mo (range, 3.1 mo- 25.2 mo). Median age was 69 yrs (range 53-85); 52% were women. No DLTs were observed in any of the cohorts (C1 to C5). Grade ≥3 immune-related adverse events (irAE) occurred in 4 patients (18%). irAE’s included: Grade 5 (bilateral), 3, 2 pneumonitis (n=1, 1, 4, respectively (6 total)); Grade 3 hyperglycemia (n=1); Grade 3 interstitial nephritis (n=1); Grade 2 thyroiditis (n=4); Grade 2 myositis (n=1); Grade 1-2 transaminitis (n=3). Median PFS for patients who received ≥2 doses (n=18) of pembro was 20.3 mo. Conclusions: Combined treatment with PD-Li and CRT for stage III NSCLC was well tolerated with promising PFS to date but showed an increased risk for irAEs, particularly pneumonitis. Based on these encouraging results, further prospective study of PD-1i and CRT for Stage III NSCLC is warranted. Clinical trial information: NCT02621398.

Abstract Background: We recently clarified the use of consolidative autologous stem cell transplantation (ASCT) as first remission consolidation therapy for high grade diffuse aggressive T and B non-Hodgkin's lymphoma (NHL)in patients with high-intermediate (HI) or High (H) age adjusted IPI disease (Stiff et al, NEJM 369:1681). After receiving CHOP or R-CHOP for 5 cycles responding patients were randomized to either 3 more induction cycles or 1 cycle followed by an ASCT using either a BCNU or TBI based preparative regimen. We found a PFS but not OS advantage for those randomized to transplant and no differential treatment effect for those with T-NHL patients as compared to B-NHL in the initial analysis of this study. In light of Phase II data suggesting a value of early ASCT for T-NHL, a lack of randomized ASCT trials for T-NHL and the inferior prognosis for T-NHL as compared to B cell disease, we further evaluated this sub group, since a post hoc analysis of the entire trial did find a survival advantage for those with H IPI disease. This then provided a unique opportunity to evaluate the role of ASCT consolidation for T-cell NHL in the setting of a prospective randomized trial. Method: Among the 370 eligible B-NHL and T-NHL patients with HI/H IPI disease treated on this trial, 40 had a T-NHL phenotype and were the subject of this analysis. Individual patient files were re-reviewed and those randomized after the first 5 cycles of CHOP were further analyzed for stage, IPI group, histology (centrally reviewed), and response to induction and consolidation and updated survival outcome. Results: Of the 40 T-NHL patients enrolled on study, 28 (70%) were randomized after induction therapy, a similar ratio to the entire trial (68%). Twelve were not randomized; 1 was ineligible for study, and of the eligible 11, 9 were HI IPI and 8 had peripheral T cell (PTCL-NOS). These 11 were not randomized due to patient choice in 2, and all of the remaining 9 pts progressed early: 2 after C1; 3 after C3, 1 after C4, and 3 after C5. For the 28 randomized, their median age was 50 and 19 were males. Of the group, 21/28 had B symptoms at diagnosis, 14 had stage IV disease, and 18 and 10 were in the HI and H IPI groups respectively. Histologies included 11 with PTCL-NOS, 7 angioimmunoblastic and 10 anaplastic large cell NHL. At randomization 13 were to continue CHOP and 15, ASCT. Of the 15 assigned to ASCT, 3 did not undergo transplant (2-refusals, 1- unable to mobilize); 7 received the BCNU-etoposide-cyclophosphamide and 5 the TBI-etoposide-cyclophosphamide preparative regimen. The 5 year estimates of PFS and OS for the randomized ASCT vs CHOP only groups (intent to treat) were 40% vs 38% (p=0.56) and 40% vs 45% (p=0.98) respectively. We found no difference in outcome based on IPI group, histology or stage of disease. Interestingly, only 1/7 patients who received BCV as the ASCT preparative regimen are long term survivors vs 4/5 receiving the TBI-based regimen. Conclusions: We did not observe a PFS/OS advantage for those with high-risk T-NHL in first remission randomized to ASCT following CHOP induction vs CHOP alone in this retrospective analysis. In addition, the 30% early drop out rate before randomization due primarily to early progression strongly suggests that more optimal induction regimens need to be developed for this disease. While the numbers are small the finding that TBI based preparative regimens might be associated with a higher PFS is of interest and deserves further study. Support: NIH/NCI grants CA180888 and CA180819; Bristol-Myers Squibb. Contributions of Dr. Raymond R Tubbs, deceased, are gratefully acknowledged. Figure 1 Figure 1. Disclosures Porcu: miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial. Winter:Pharmacyclics: Research Funding; Medivation: Other: Provision of investigational agent for clinical trial; Seattle Genetics: Research Funding; GSK: Research Funding. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Smith:Juno: Consultancy; TGTX: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Gilead: Consultancy; Portola: Consultancy; Amgen: Other: Educational lecture to sales force; Pharmacyclics: Consultancy. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board.

Cette thèse décrit une voie d'accès aux cyclopropanols chiraux et en étudie les potentialités synthétiques. Préparé à partir du méthyl-2 succinate de n-butyle, l'hydroxy-1 méthyl-2 cyclopropanecarboxaldéhyde est un précurseur de (vinylcarbinol)-1 cyclopropanols lesquels, subissent en milieu acide soit une extension de cycle C3→C4 régiospécifique en vinyl-2 cyclobutanones (BF3-Et20), soit une extension de cycle C3→C4→C5 en cyclopentène-2 ones (CH3S03H-P205). La réaction thermique des méthyl-2 vinylcyclopropanes donne par ène-réaction des produits d'ouverture de cycle limitant l'intérêt du réarrangement vinylcyclopropane-cyclopentène ; ce problème est contourné par cette nouvelle approche. Les (R)(+) et (S)(-) méthyl-2 succinates de méthyle, préparés par résolution enzymatique à l'aide de la lipase du pancréas de porc, sont cyclisés par réaction du type acyloïne en (R) et (S) méthyl-3 disiloxycyclobutènes respectivement. Ceux-ci par régression de cycle stéréosélective C4 → C3 en milieu basique, donnent accès sans altération du centre chiral à des hydroxy-1 cyclopropanecarbo­ xaldéhydes, utilisés pour préparer des (vinylcarbinol)-1 cyclopropanols optiquement actifs. Une extension de cycle C3→C4 régio- et stéréospécifique conduit alors aux vinyl-2 cyclobutanones avec une très bonne énantiosélectivité. Ces composés ont été utilisés pour préparer la (S)(+) méthyl-5 cyclohexène-2-one et un buténolide : la quercus lactone b. Les vinyl-2 cyclobutanones sont des précurseurs de cycle en C5, C6 et C8, cette méthodologie, ne mettant pas en jeu d'ions cyclopropylcarbinyl vrais comme le prouve la stéréospécificité des réarrangements, permet donc, à partir de succinates chiraux, d'envisager la synthèse totale de produits naturels de structures variées
The aim of this thesis is the preparation and study of the synthetic potential of chiral cyclopropanols. The 1-hydroxy 2-methyl cyclopropanecarboxaldehyde available from 2-methylsuccinate, is used to prepare 1-(vinylcarbinol} cyclopropanols which, undergo acid induced C3 C4 regiospecific ring expansion into 2-vinyl cyclobutanones (BF3-Et20) or C3 -+ C4 --+- C5 ring expansion into cyclopenten-2- ones (CH3S03H-P205). The thermal rearrangement of 2-methyl vinylcyclopropanes leads by an ene-reaction to ring-opened products ; therefore the limitation of the thermal vinylcyclopropane-cyclopentene ring enlargement is removed by this new approach. (R)(+) and (S)(-). Dimethyl 2-methylsuccinates, now available from enantiose­ lective hydrolysis by porcine pancreatic lipase, undergo acyloin type cyclization into (R) and (S) 3-methyl-1,2-disiloxycyclobutene, respectively. Base-induced stereoselective C4 C3 ring contraction of these cyclobutenes provides 1-hydroxycyclopropanecarboxaldehydes which are used to prepare optically active 1-alkenylcyclopropanols. Then, acid-induced regio- and stereospecific C3---+ C4 ring enlargement leads to 2-vinylcyclobutanones with high enantiomeric excesses. These compounds are used to synthetize (S) 5-methyl cyclohexen-2-one and abutenolide ; i. E. The quercus lactone b2-Vinylcyclobutanones are efficient precursors of 5-, 6- and 8-membered rings. Therefore, this new methodology, which does not involve cyclopropylcarbiny1 cations as proven by the stereospecificity of the rearrangements, allows one to prepare from chiral succinates natural compounds bearing different frameworks

Les travaux exposés dans cette thèse sont relatifs : 1) à l'éthoxy-l cyclopropanol : sa condensation avec les acétyléniques métallés conduit aux cyclopropanols propargyliques qui, après réduction et silylation permettent d'obtenir des silo­xy-l vinyl-l cyclopropanes subissant par thermolyse l'extension de cycle C3 ---> C5 en éthers d ‘énols silyliques de cyclopentanones alkylables en cyclopentanones α, ʓ-disubstituées. Selon ce schéma réactionnel, nous avons pu réaliser la synthèse totale de la désoxy-ll prostaglandine E₂, produit naturel à propriétés hypotensives ; 2) à l'hydroxy-l cyclopropanecarboxaldéhyde : protégé sous forme d'éther silylique ou tétrahydropyrannylique, ce synthon permet un accès relativement aisé aux siloxy-l vinyl-l cyclopropanes alkylés sur la double liaison du vinyle et pouvant donc par thermolyse puis par simple hydrolyse ou déhydrosilylation conduire respectivement à des cyclopentanones et cyclopenténones α, ʓ-disubsti­ tuées en évitant ainsi l'alkylation délicate des éthers d’énols silyliques de cyclopentanones. Une application à la synthèse de la Dicranénone A, cyclopenténone α’, ʓ’-disubstituée, produit naturel possédant des activités antibiotiques a été réalisée à partir de ce synthon
The aim of this thesis is the synthetic applications of two peculiar cyclopropanols : l) The l-ethoxycyclopropanol, is converted into propargylic cyclopropanols upon treatment with acetylenic magnesium bromide or lithium. Hydride reduction and O-silylation lead to l-siloxy l-vinylcyclopropanes which undergo thermal C3 ---> C5 ring enlargement into l-siloxycyclopentenes ; then , these enol ethers are regiospecifically alkylated into 2, 3-disubstituted cyclopentanones. This scheme is illustrated by the total synthesis of ± ll-deoxypros­taglandin E₂ methyl ester. 2) The l-hydroxycyclopropanecarboxaldehyde tetrahydropyranyl and silylated ethers provide l-siloxy-l-vinylcyclopropanes which, after thermal rearrangement lead directly to 2,3-disubstituted cyclopentanones and cyclopentenones upon hydrolysis or dehydrosilylation, so avoiding the quite delicate enol ether alkylation. Dicranenones, new fatty acids structurally similar to prostanoids and jasmanoids, having antimicrobial activity, are prepared from this new synthon