There is a paucity of literature on the referral outcome of patients seen in phase I trial clinics in academic oncology centres. This study aims to provide information on the accrual rate and to ...identify obstacles in the recruitment process.
A retrospective chart review was performed for all new patients referred and seen in the phase I clinic at the Princess Margaret Hospital between January 2000 and June 2005. Data on their demographics, medical history, and details of trial participation or non-entry were recorded.
A total of 667 new phase I referrals were seen during the stated period. Of these patients, 197 (29.5%) patients were enrolled into a phase I trial, and 64.5% of them started trial within 1 month of the initial visit. About a quarter (165 of 667) of the patients referred were deemed ineligible at their first visit, with the most frequent reasons for ineligibility being poor performance status, unacceptable bloodwork, too many prior treatments and rapid disease progression. The remaining 305 patients (45.7%) were potentially eligible at their initial visit, but never entered a phase I trial. The main reasons for their non-entry were patient refusal, other treatment recommended first, and lack of available trials or trial spots.
This study provides information on the clinical realities underlying a referral to a phase I clinic and eventual trial enrollment. Better selection of patients, appropriate education of referring physicians, and opening phase I trials with fewer restrictions on some criteria such as prior therapy may enhance their recruitment rates.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ruthenium-p-cymene complexes (p-cymene)Ru(1,2,3,4-Me4-NUPHOS)ClSbF6 (2a) and (p-cymene)Ru(1,4-Et2-2,3-cyclo-C6H8-NUPHOS)ClSbF6 (2b) have been prepared by reaction of (p-cymene)RuCl22 with the ...corresponding NUPHOS diphosphine in the presence of NaSbF6. The chloro ligand can be abstracted from these monocations to afford (p-cymene)Ru(P,P,η2(C)-1,2,3,4-Me4-NUPHOS)SbF62 (3a) and (p-cymene)Ru(P,P,η2(C)-1,4-Et2-2,3-cyclo-C6H8-NUPHOS)SbF62 (3b), respectively, in which the diphosphine coordinates as a six-electron donor, bonded through both diphenylphosphino groups and one of the double bonds of the butadiene tether. In stark contrast, it proved markedly more difficult to abstract the chloro ligand from either the BIPHEP or the MeO-BIPHEP monocations (p-cymene)Ru(BIPHEP)ClSbF6 (4a) and (p-cymene)Ru(MeO-BIPHEP)ClSbF6 (4b), and even after prolonged reaction times at elevated temperature (p-cymene)Ru(BIPHEP)SbF62 (5a) and (p-cymene)Ru(MeO-BIPHEP)SbF62 (5b) formed as a 30% mixture with unreacted 4a and 4b, respectively. The structures of 2a, as its perchlorate salt, and 2b have been determined by single-crystal X-ray crystallography and are compared with that of their BIPHEP counterpart 4a. Unfortunately, it has not been possible to prepare the corresponding dppb complex (p-cymene)Ru(dppb)ClSbF6 to undertake a comparative study, since (p-cymene)RuCl22 reacts with dppb under the same conditions as those used to prepare 2a,b to afford the bridged dimer {(p-cymene)RuCl2}2(μ-dppb) (6), the identity of which has been confirmed by a single-crystal X-ray study. Interestingly, 3a undergoes rapid hydrolysis in the presence of pyridine to give (p-cymene)Ru{Ph2(O)PC(H)MeCMeCMeCMePPh2}SbF6 (7), which contains an unusual unsymmetrical bisphosphine monoxide pincer ligand formed by oxidation of one of the diphenylphosphino groups of 1,2,3,4-Me4-NUPHOS and a highly regioselective syn addition of Ru and H across the butadiene double bond proximate to the phosphine oxide. Dications 3a,b catalyze the regioselective anti-Markovnikov addition of benzoic acid to 1-pentyne and 1-octyne to give the corresponding alk-1-en-1-yl esters with cis-to-trans ratios as high as 95:5, while the corresponding BIPHEP and MeO-BIPHEP complexes were significantly less selective, catalyst mixtures formed from 4b giving a 70:30 mixture of cis and trans alk-1-en-1-yl ester. In contrast, selectivity was reversed with catalyst mixtures generated from 6, which were 90% selective for Markovnikov addition to 1-octyne, as might have been predicted for a ruthenium catalyst coordinated by a single phosphine, albeit one-half of a bidentate diphosphine. Catalysts based on NUPHOS diphosphines are also highly active and selective for anti-Markovnikov addition of benzoic acid to phenylacetylene and give (Z)-styryl benzoate in yields of up to 85% and selectivities as high as 99:1 with no evidence for the formation of terminal olefin. In our hands, solutions formed by activation of 4a,b with AgSbF6 catalyze the regio- and stereoselective anti-Markovnikov hydrocarboxylation of phenylacetylene, which was somewhat surprising considering that an earlier report has claimed that 5b reacts with phenylacetylene to form a stable catalytically inactive cyclometalation/insertion product.
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The quality of informed consent in phase I trials is controversial, partially due to gaps in patient understanding. We assessed an educational DVD's impact on knowledge and satisfaction in cancer ...patients newly referred to a phase I clinic.
Forty-nine patients were randomly assigned to view an educational DVD (n = 22) which explained phase I trials or a placebo DVD (n = 27). Patients completed a questionnaire assessing knowledge of phase I studies and satisfaction with the DVD. The blinded interviewing physician (n = 8) rated the patient's understanding of phase I trials.
The mean patient age was 56; 61% were male. Patients who viewed the educational DVD were less likely to believe that phase I trials determine drug efficacy (p = 0.019), more likely to know that phase I drugs have not been thoroughly studied in humans (p = 0.003), and less likely to believe that these agents have proven activity against human cancers (p = 0.008). More patients who viewed the educational DVD agreed/strongly agreed that the DVD provided useful information (p < 0.001), were confident in their knowledge of phase I trials (p = 0.031), felt aided in their decision to enter a phase I study (p = 0.011), and would have more questions for their physicians because of the DVD (p = 0.017). No statistically significant difference in physician perception of patient understanding or phase I trial accrual was observed between the educational and placebo DVD groups.
An educational DVD increased patient knowledge and satisfaction regarding participation in phase I clinical trials.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, ODKLJ, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Palladium and platinum complexes of conformationally flexible 1,3-butadiene-bridged diphosphines NUPHOS can be resolved with (S)-BINOL at elevated temperatures to afford diastereopure ...δ-(NUPHOS)M{(S)-BINOL} (M = Pd, Pt). The homochiral Lewis acid complexes δ-(NUPHOS)MOTf2, generated by protonation of δ-(NUPHOS)M{(S)-BINOL} with trifluoromethanesulfonic acid, catalyze the Diels−Alder reaction between acryloyl-N-oxazolidinones and cyclopentadiene to give ee values up to 96%. The corresponding enantiopure dichlorides δ-(NUPHOS)PtCl2 react with AgClO4 to form highly efficient catalysts that give good endo/exo selectivities and high endo enantioselectivity.
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In chloroform, RuCl2(nbd)(py)2 (1) (nbd = norbornadiene; py = pyridine) reacts with 1,4-bis(diphenylphosphino)-1,2,3,4-tetramethyl-1,3-butadiene (1,2,3,4-Me4-NUPHOS) to give the dimer ...Ru2Cl3(η4-1,2,3,4-Me4-NUPHOS)2Cl (2a), whereas, in THF RuCl2(1,2,3,4-Me4-NUPHOS)(py)2 (3) is isolated as the sole product of reaction. Compound 2 exists as a 4:1 mixture of two noninterconverting isomers, the major with C 1 symmetry and the minor with either C s or C 2 symmetry. A single-crystal X-ray analysis of Ru2Cl3(η4-1,2,3,4-Me4-NUPHOS)2SbF6 (2b), the hexafluoroantimonate salt of 2a, revealed that the diphosphine coordinates in an unusual manner, as a η4-six-electron donor, bonded through both P atoms and one of the double bonds of the butadiene tether. Compounds 2a and 3 react with 1,2-ethylenediamine (en) in THF to afford RuCl2(1,2,3,4-Me4-NUPHOS)(en) (4), which rapidly dissociates a chloride ligand in chloroform to give RuCl(η4-1,2,3,4-Me4-NUPHOS)(en)Cl (5a). Complexes 4 and 5a cleanly and quantitatively interconvert in a solvent-dependent equilibrium, and in THF 5a readily adds chloride to displace the η2-interaction and re-form 4. A single-crystal X-ray structure determination of RuCl(η4-1,2,3,4-Me4-NUPHOS)(en)ClO4 (5b) confirmed that the diphosphine coordinates in an η4-manner as a facial six-electron donor with the η2-coordinated double bond occupying the site trans to chloride. The η4-bonding mode can be readily identified by the unusually high-field chemical shift associated with the phosphorus atom adjacent to the η2-coordinated double bond. Complexes 2a, 2b, 4, and 5a form catalysts that are active for transfer hydrogenation of a range of ketones. In all cases, catalysts formed from precursors 2a and 2b are markedly more active than those formed from 4 and 5a.
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Conformationally flexible NUPHOS-type diphosphines have been resolved as their diastereopure platinum BINOLate complexes δ- and λ-(NUPHOS)Pt{(S)-BINOL} and the corresponding enantiopure Lewis acids ...δ- and λ-(NUPHOS)Pt(OTf)2, being generated by protonation with trifluoromethanesulfonic acid, act as highly efficient catalysts for the hetero-Diels−Alder reaction of nonactivated conjugated dienes with aryl glyoxals and glyoxylate esters, giving ee's as high as 99%.
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A thorough and detailed study of diastereointerconversion in the chiral platinum complexes (NUPHOS)Pt{(S)-BINOL} (3a−e) has been undertaken and compared with the results of a similar study with ...(BIPHEP)Pt{(S)-BINOL}. Rate data revealed that this process obeys first-order relaxation kinetics, and rate constants for conversion of the minor to the major diastereoisomer have been obtained. Eyring analysis of the data gave ΔH ⧧ and ΔS ⧧ values of 22−25 kcal mol-1 and −1 to −16 eu, respectively. In combination with computational analysis, these studies indicate that atropinversion most likely occurs via an on-metal pathway involving a planar seven-membered transition state. Substitution of (S)-BINOL for (S,S)-DPEN results in a marked reduction in the barrier to atropinversion; a ΔH ⧧ value of 17 kcal mol-1 has been determined for the conversion of δ-(Ph4-NUPHOS)Pt{(S,S)-DPEN}Cl2 to λ-(Ph4-NUPHOS)Pt{(S,S)-DPEN}Cl2, which could indicate that an alternative mechanism operates.
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Several novel phosphoramidites have been prepared by reaction of the primary amines
para-vinylaniline,
ortho-anisidine, 2-methoxyphenyl(4-vinylbenzyl)amine, 8-aminoquinoline and ...3-vinyl-8-aminoquinoline with (
S)-1,1′-bi-2-naphthylchlorophosphite, in the presence of base. Rhodium(I) complexes of these phosphoramidites catalyse the asymmetric hydrogenation of dimethylitaconate and dehydroamino acids and esters giving ee values up to 95%. Soluble non-cross linked polymers of the
para-vinylaniline and 3-vinyl-8-aminoquinoline-based phosphoramidites have been prepared by free radical co-polymerisation with styrene in the presence of AIBN as initiator. The corresponding Rh(COD)
+ complexes serve as recyclable catalysts for the asymmetric hydrogenation dimethylitaconate and dehydroamino acids and esters to give ee values up to 80%.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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