Mar.Drugs 2014.12 260 The commonalities and differences in the pharmacological response of trabectedin and its close relatives,Zalypsis and lurbinectedin (videnfra)have been discussed recently with respect to their experimental effect upon the Fanconi anemia pathway.Martinez et al.[25]demonstrated that these three agents inhibited the Fanconi anemia pathway in the cell lines tested,increasing their sensitivity to mitomycin C.in contrast to mitomycin C which always activated that pathway in the same cell lines.The authors suggested that as a result of these findings these three agents might be useful clinically in "Fanconizing"cancer cells in order to gain sensitivity against other anti-tumor drugs.In another paper the same year.Romano et al.26 reported that inin vitro and in vivo models.no relationship was found between the in vitro cytotoxic potency and in vivo antitumor activity in syngeneic mouse models, suggesting that there might well be a host response in these models.In addition,the pharmacokinetic differ.even between the quite similar trabectedin and lurbinectedin in humans.and as expected due to the differences in structure,Zalypsis has been shown to differ in pharmacokinetics in humans [27]. As of the end of October 2013,there were 15 studies found for ET743 in the NIH clinical trials database,12 at Phase II and three at Phase I,all being listed as completed,with cancer types covering breast,prostate.soft tissue sarcoma and osteosarcoma,plus general carcinomas.Searching the corresponding EU Clinical Trials Register,19 trials were listed ranging from 2005 to 2013 with three being Phase IlI trials not found on the NIH site.These were two trials against refractory ovarian cancer with liposomal doxorubicin,and the third was for patients with translocation-related sarcomas.Again these listings demonstrates that once a compound has been approved for treatment of one type of cancer, it will be placed in clinical trials for many others,either individually or as part of a new drug regimen. A discussion of the probabilities of ET743 and its congeners being produced by as yet uncultured microbes associated with the source tunicate was recently published by Giddings and Newman [28] which should be consulted for further details. 3.2.1.PM-10450(Zalypsis:PhasesI-II,Figure2.6) This compound,another variation on the basic structure of the dimeric isoquinoline alkaloids,was derived from the structure of jorumycin,a compound isolated from the skin and mucin of the nudibranch Joruna 29]and renieramycin J from a species of the marine sponge Netropsia.Zalypsis was synthesized by workers at PharmaMar(Madrid,Spain)using methodologies related to the ET743 synthesis from safracin B [30].The initial report of the molecular pharmacology of this agent was described by Leal eral.in 2009 [31]and even though it has a close resemblance to ET743,it does not activate the DNA damage checkpoint response. Currently both the NIH and EU clinical trials sites show three clinical trials at Phase II/I levels with one in Spain showing as still continuing.There are eleven reports to date in the literature with recent results from Phase I studies being reported in 2012 from work in the UK [27].These were then followed by further reports in 2013,where objective responses,mainly stable disease,were seen in a small number of patients [32.33].In contrast.also in 2013.a report was published demonstrating a lack of response and termination of the Phase II trial of this compound in a heavily pretreated population with advanced and/or metastatic endometrial or cervical cancers34]
Mar. Drugs 2014, 12 260 The commonalities and differences in the pharmacological response of trabectedin and its close relatives, Zalypsis® and lurbinectedin (vide infra) have been discussed recently with respect to their experimental effect upon the Fanconi anemia pathway. Martinez et al. [25] demonstrated that these three agents inhibited the Fanconi anemia pathway in the cell lines tested, increasing their sensitivity to mitomycin C, in contrast to mitomycin C which always activated that pathway in the same cell lines. The authors suggested that as a result of these findings these three agents might be useful clinically in “Fanconizing” cancer cells in order to gain sensitivity against other anti-tumor drugs. In another paper the same year, Romano et al. [26] reported that in in vitro and in vivo models, no relationship was found between the in vitro cytotoxic potency and in vivo antitumor activity in syngeneic mouse models, suggesting that there might well be a host response in these models. In addition, the pharmacokinetics differ, even between the quite similar trabectedin and lurbinectedin in humans, and as expected due to the differences in structure, Zalypsis® has been shown to differ in pharmacokinetics in humans [27]. As of the end of October 2013, there were 15 studies found for ET743 in the NIH clinical trials database, 12 at Phase II and three at Phase I, all being listed as completed, with cancer types covering breast, prostate, soft tissue sarcoma and osteosarcoma, plus general carcinomas. Searching the corresponding EU Clinical Trials Register, 19 trials were listed ranging from 2005 to 2013 with three being Phase III trials not found on the NIH site. These were two trials against refractory ovarian cancer with liposomal doxorubicin, and the third was for patients with translocation-related sarcomas. Again these listings demonstrates that once a compound has been approved for treatment of one type of cancer, it will be placed in clinical trials for many others, either individually or as part of a new drug regimen. A discussion of the probabilities of ET743 and its congeners being produced by as yet uncultured microbes associated with the source tunicate was recently published by Giddings and Newman [28] which should be consulted for further details. 3.2.1. PM-10450 (Zalypsis®; Phases I–II; Figure 2, 6) This compound, another variation on the basic structure of the dimeric isoquinoline alkaloids, was derived from the structure of jorumycin, a compound isolated from the skin and mucin of the nudibranch Joruna funebris [29], and renieramycin J from a species of the marine sponge, Netropsia. Zalypsis® was synthesized by workers at PharmaMar (Madrid, Spain) using methodologies related to the ET743 synthesis from safracin B [30]. The initial report of the molecular pharmacology of this agent was described by Leal et al. in 2009 [31] and even though it has a close resemblance to ET743, it does not activate the DNA damage checkpoint response. Currently both the NIH and EU clinical trials sites show three clinical trials at Phase II/I levels with one in Spain showing as still continuing. There are eleven reports to date in the literature with recent results from Phase I studies being reported in 2012 from work in the UK [27]. These were then followed by further reports in 2013, where objective responses, mainly stable disease, were seen in a small number of patients [32,33]. In contrast, also in 2013, a report was published demonstrating a lack of response and termination of the Phase II trial of this compound in a heavily pretreated population with advanced and/or metastatic endometrial or cervical cancers [34]
Mar.Drugs 2014,12 261 3.2.2.Lurbinectedin (PM-01183:Phases I-II:Figure 2,7) This compound is another variation on the basic structure of the dimeric isoquinoline alkaloids,but has a tetrahydro-B-carboline moiety instead of the tetrahydroisoquinoline present in ring C.and binds in the DNA minor groove [35].The compound was shown to have different pharmacokinetics in patients and also like trabectedin,to attenuate nuclear excision repair (NER).It also demonstrated synergy with platinum-based agents in vitro thus suggesting a possible treatment regimen since it also demonstrated activity against platinum-resistant cell lines [36].Two Phase II clinical trials with lurbinectedin are shown on the NIH clinical trials site.one recruiting and one approved but not yet recruiting,with two Phase I trials recruiting and one approved but not yet recruiting.On the European clinical trials site,one Phase II trial corresponding to the"not yet recruiting trial"listed on the NIH site in the USA,is on-going in Spain,and the other is a two year old trial against metastatic pancreatic cancer in Spain and the UK 3.3.Eribulin (Halaven":Phases I-IV:Figure 2.8) The story of the discovery of this compound (a totally synthetic variation on halichondrin B has been given in a variety of formats over the years,from the chapter by the Eisai scientists in Woburn. MA that showed the progression from the synthesis of halichondrin B to the initial synthesis of eribulin [37].to two recent papers on the industrial methodologies that enabled the production of this molecule,certainly the most complex synthetic drug to date [38.39]. As with the other approved compounds mentioned earlier,Halaven is currently shown as being in 28 trials that are recruiting patients with 27 being Phase I or II or I/II.The one Phase III trial is a physician's choice model with Halaven being one of the three drugs to choose from.In addition,of the other 43 trials shown,21 are active but not recruiting with the majority being at Phase I or II, though two are at Phase III and one (Phase IV)is a post market surveillance.One trial in the list was terminated with no reason given.In addition.a new liposomal formulation of eribulin mesilate is currently in a Phase I clinical trial (NCTO1945710)in the United Kingdom under the auspices of Eisai The geographic areas of these trials effectively cover the world.but the majority are either in the USA or Europe.Summation of the figures on the map in the Clinicaltrials web site always gives a higher figure as a significant number of trials cross geographic boundaries within the one trial 3.4.Brentuximab Vedotin (Adcetris":Phases 0 to IV:Figure 2.9) This immunoconjugate with a "warhead"derived from dolastatin 10,monomethylauristatin E (vedotin;Figure 2,10),a secondary metabolite from a Symploca species of cyanophyte,was approved in the USA in 2011 for treatment of CD30 positive lymphoproliferative disorders such as Hodgkin's lymphoma.This combination was the second immunoglobulin-warhead combination to be approved for leukemias following the initial approval of mylotarg by the FDa in 2000. Subsequently Mylotarg was withdrawn in the USA in 2010 due to concerns about the product's safety that were raised by a confirmatory study conducted after approval,as patients on the preparation and also receiving chemotherapy had a higher death rate and no objective increase in life when compared to a group using just chemotherapy.This combination is still in use in other countries
Mar. Drugs 2014, 12 261 3.2.2. Lurbinectedin (PM-01183; Phases I–II; Figure 2, 7) This compound is another variation on the basic structure of the dimeric isoquinoline alkaloids, but has a tetrahydro-β-carboline moiety instead of the tetrahydroisoquinoline present in ring C, and binds in the DNA minor groove [35]. The compound was shown to have different pharmacokinetics in patients and also like trabectedin, to attenuate nuclear excision repair (NER). It also demonstrated synergy with platinum-based agents in vitro thus suggesting a possible treatment regimen since it also demonstrated activity against platinum-resistant cell lines [36]. Two Phase II clinical trials with lurbinectedin are shown on the NIH clinical trials site, one recruiting and one approved but not yet recruiting, with two Phase I trials recruiting and one approved but not yet recruiting. On the European clinical trials site, one Phase II trial corresponding to the” not yet recruiting trial” listed on the NIH site in the USA, is on-going in Spain, and the other is a two year old trial against metastatic pancreatic cancer in Spain and the UK. 3.3. Eribulin (Halaven®; Phases I–IV; Figure 2, 8) The story of the discovery of this compound (a totally synthetic variation on halichondrin B has been given in a variety of formats over the years, from the chapter by the Eisai scientists in Woburn, MA that showed the progression from the synthesis of halichondrin B to the initial synthesis of eribulin [37], to two recent papers on the industrial methodologies that enabled the production of this molecule, certainly the most complex synthetic drug to date [38,39]. As with the other approved compounds mentioned earlier, Halaven® is currently shown as being in 28 trials that are recruiting patients with 27 being Phase I or II or I/II. The one Phase III trial is a physician’s choice model with Halaven® being one of the three drugs to choose from. In addition, of the other 43 trials shown, 21 are active but not recruiting with the majority being at Phase I or II, though two are at Phase III and one (Phase IV) is a post market surveillance. One trial in the list was terminated with no reason given. In addition, a new liposomal formulation of eribulin mesilate is currently in a Phase I clinical trial (NCT01945710) in the United Kingdom under the auspices of Eisai. The geographic areas of these trials effectively cover the world, but the majority are either in the USA or Europe. Summation of the figures on the map in the Clinicaltrials web site always gives a higher figure as a significant number of trials cross geographic boundaries within the one trial. 3.4. Brentuximab Vedotin (Adcetris®; Phases 0 to IV; Figure 2, 9) This immunoconjugate with a “warhead” derived from dolastatin 10, monomethylauristatin E (vedotin; Figure 2, 10), a secondary metabolite from a Symploca species of cyanophyte, was approved in the USA in 2011 for treatment of CD30 positive lymphoproliferative disorders such as Hodgkin’s lymphoma. This combination was the second immunoglobulin-warhead combination to be approved for leukemias following the initial approval of Mylotarg® by the FDA in 2000. Subsequently Mylotarg® was withdrawn in the USA in 2010 due to concerns about the productʼs safety that were raised by a confirmatory study conducted after approval, as patients on the preparation and also receiving chemotherapy had a higher death rate and no objective increase in life when compared to a group using just chemotherapy. This combination is still in use in other countries
Mar.Drugs 2014.12 262 A relationship to marine sources for the "warhead endiyne molecule"was established when investigators at the Scripps Oceanographic Institution (La Jolla,CA.USA)showed the presence of endiyne cryptic clusters in marine bacteria of the genus Salinospora [40]. Adcetris is the product of extensive work by Seattle Genetics (Seattle,WA,USA),first in optimizing the vedotin warhead(10)and then developing the linkers that couple the antibody to the compound [41].Some of these,discussed later,are designed to release the warhead (vedotin)by simple hydrolysis of a linker bond,whereas others require the enzymatic digestion of the antibody. releasing the warhead plus appendages.It was approved by the FDA in 2011 and subsequently approval was given in the EU late in 2012 and launched in the UK in early 2013,all for CD30 positive leukemias.Full explanations of the methodologies used and the utility of this agent against a variety of lymphomas have been published in the last three vears and should be consulted by the interested reader [42-45].In addition,a recent report from Takeda(Osaka,Japan)shows the strategy that this company is adopting,including the further development of this agent [46]. Currently,this agent is in 37 trials mainly in the USA from Phase 0 to Phase IV where the latter trial is listed as recruiting on the NIH clinical trials site.Six more are listed in the EU clinical trials site covering Phase II to Phase IV 3.4.1.Glembatumumab Vedotin (Phase II) This is monomethvlauristatin E (MMAE)linked to a fully human monoclonal antibody CROll (an anti-CG56972)via a stable valine-citrulline dipeptide linker.It was targeted against patients with unresectable melanomas at stage III or IV who have failed one cytotoxic chemotherapy regimen and has expanded to include metastatic breast cancer as well.The combination has a variety of names during its early days including CDX-011.CR-011 and CR011-veMMAE,so searching for data can be a trifle challenging. The initial report of the use of this combination was given by investigators from CuraGen in 2006[47].followed by a report of xenograft activity in 2007 from the same group [4].The value of the monoclonal's target in triple negative breast cancer was described in 2010 by Rose et al.[49],with the corresponding details in melanoma described in 2012 by a group from the People's Republic of China [50].Currently three completed studies at the Phase I/II levels are reported in the NIH clinical trials database with one preliminary report of clinical activity in breast cancer patients [51]. 3.4.2.ABT-414 (Phase I-II) This is an antibody-drug conjugate (ADC)linking the anti-Epidermal Growth Factor Receptor (EGFR)antibody ABT-806 to another variation on auristatin;in this case,monomethylaurisatin F (Figure 2,11)is used in place of the"E"variant.The ADC was designed to bind to a unique epitope of EGFR that is usually not accessible when EGFR is expressed at physiological levels.However,the ADC binds when tumors express EGFRde2-7(EGFRvIII)and in other tumors with amplified EGFR or excessive EGFR activation under"normal wild-type conditions"[521. Abbvie (North Chicago,IL.USA),which is the renamed Abbott Pharmaceutical Division,recently instituted two human clinical trials as trials in mice using human wild-type EGFR-overexpressing tumors gave complete regressions and"cures"[52].Phase I studies where patients must have a solid
Mar. Drugs 2014, 12 262 A relationship to marine sources for the “warhead endiyne molecule” was established when investigators at the Scripps Oceanographic Institution (La Jolla, CA, USA) showed the presence of endiyne cryptic clusters in marine bacteria of the genus Salinospora [40]. Adcetris® is the product of extensive work by Seattle Genetics (Seattle, WA, USA), first in optimizing the vedotin warhead (10) and then developing the linkers that couple the antibody to the compound [41]. Some of these, discussed later, are designed to release the warhead (vedotin) by simple hydrolysis of a linker bond, whereas others require the enzymatic digestion of the antibody, releasing the warhead plus appendages. It was approved by the FDA in 2011 and subsequently approval was given in the EU late in 2012 and launched in the UK in early 2013, all for CD30 positive leukemias. Full explanations of the methodologies used and the utility of this agent against a variety of lymphomas have been published in the last three years and should be consulted by the interested reader [42–45]. In addition, a recent report from Takeda (Osaka, Japan) shows the strategy that this company is adopting, including the further development of this agent [46]. Currently, this agent is in 37 trials mainly in the USA from Phase 0 to Phase IV where the latter trial is listed as recruiting on the NIH clinical trials site. Six more are listed in the EU clinical trials site covering Phase II to Phase IV. 3.4.1. Glembatumumab Vedotin (Phase II) This is monomethylauristatin E (MMAE) linked to a fully human monoclonal antibody CR011 (an anti-CG56972) via a stable valine-citrulline dipeptide linker. It was targeted against patients with unresectable melanomas at stage III or IV who have failed one cytotoxic chemotherapy regimen and has expanded to include metastatic breast cancer as well. The combination has a variety of names during its early days including CDX-011, CR-011 and CR011-vcMMAE, so searching for data can be a trifle challenging. The initial report of the use of this combination was given by investigators from CuraGen in 2006 [47], followed by a report of xenograft activity in 2007 from the same group [48]. The value of the monoclonal’s target in triple negative breast cancer was described in 2010 by Rose et al. [49], with the corresponding details in melanoma described in 2012 by a group from the People’s Republic of China [50]. Currently three completed studies at the Phase I/II levels are reported in the NIH clinical trials database with one preliminary report of clinical activity in breast cancer patients [51]. 3.4.2. ABT-414 (Phase I–II) This is an antibody-drug conjugate (ADC) linking the anti-Epidermal Growth Factor Receptor (EGFR) antibody ABT-806 to another variation on auristatin; in this case, monomethylaurisatin F (Figure 2, 11) is used in place of the “E” variant. The ADC was designed to bind to a unique epitope of EGFR that is usually not accessible when EGFR is expressed at physiological levels. However, the ADC binds when tumors express EGFRde2-7 (EGFRvIII) and in other tumors with amplified EGFR or excessive EGFR activation under “normal wild-type conditions” [52]. Abbvie (North Chicago, IL, USA), which is the renamed Abbott Pharmaceutical Division, recently instituted two human clinical trials as trials in mice using human wild-type EGFR-overexpressing tumors gave complete regressions and “cures” [52]. Phase I studies where patients must have a solid