A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors
Purpose Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal formulation of a 24-base DNA oligonucleotide called PNT100. Methods Patients with malignant solid tumors were assigned sequentially to one of ten...
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| Published in | Cancer chemotherapy and pharmacology Vol. 73; no. 2; pp. 363 - 371 |
|---|---|
| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Berlin/Heidelberg
Springer Berlin Heidelberg
01.02.2014
Springer Springer Nature B.V |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Purpose
Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal formulation of a 24-base DNA oligonucleotide called PNT100.
Methods
Patients with malignant solid tumors were assigned sequentially to one of ten dose-escalation cohorts of PNT2258 at 1, 2, 4, 8, 16, 32, 64, 85, 113, and 150 mg/m
2
administered intravenously on days 1 through 5 of each 21-day cycle. Pharmacokinetics were determined on days 1 and 5 of the first cycle. Lymphocyte and platelets concentrations were measured for evidence of BCL2-targeted effect. CT scans were used to identify radiologic evidence of anti-tumor effect.
Results
Twenty-two subjects received PNT2258, and the maximum tolerated dose for PNT2258 was not reached. Doses at or above 32 mg/m
2
resulted in exposure to PNT2258 above the exposure level required for anti-tumor activity in preclinical xenograft testing of 22,377 ng h/ml (PK analysis
2012
). Fatigue was the most commonly reported adverse event. Dose-limiting toxicity, manifesting as a transient increase in aspartate aminotransferase, occurred at 150 mg/m
2
, the highest dose tested. Four subjects, two each with diagnosis of non-small-cell lung cancer and sarcoma, treated at doses of 64 mg/m
2
or higher, remained on study for 5–8 cycles.
Conclusions
PNT2258 was safe and well tolerated at the doses tested up to 150 mg/m
2
. Exposure to PNT2258 resulted in clinically manageable decreases in lymphocyte and platelet concentrations. |
|---|---|
| AbstractList | Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal formulation of a 24-base DNA oligonucleotide called PNT100. Patients with malignant solid tumors were assigned sequentially to one of ten dose-escalation cohorts of PNT2258 at 1, 2, 4, 8, 16, 32, 64, 85, 113, and 150 mg/m^sup 2^ administered intravenously on days 1 through 5 of each 21-day cycle. Pharmacokinetics were determined on days 1 and 5 of the first cycle. Lymphocyte and platelets concentrations were measured for evidence of BCL2-targeted effect. CT scans were used to identify radiologic evidence of anti-tumor effect. Twenty-two subjects received PNT2258, and the maximum tolerated dose for PNT2258 was not reached. Doses at or above 32 mg/m^sup 2^ resulted in exposure to PNT2258 above the exposure level required for anti-tumor activity in preclinical xenograft testing of 22,377 ng h/ml (PK analysis 2012 ). Fatigue was the most commonly reported adverse event. Dose-limiting toxicity, manifesting as a transient increase in aspartate aminotransferase, occurred at 150 mg/m^sup 2^, the highest dose tested. Four subjects, two each with diagnosis of non-small-cell lung cancer and sarcoma, treated at doses of 64 mg/m^sup 2^ or higher, remained on study for 5-8 cycles. PNT2258 was safe and well tolerated at the doses tested up to 150 mg/m^sup 2^. Exposure to PNT2258 resulted in clinically manageable decreases in lymphocyte and platelet concentrations.[PUBLICATION ABSTRACT] Purpose Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal formulation of a 24-base DNA oligonucleotide called PNT100. Methods Patients with malignant solid tumors were assigned sequentially to one of ten dose-escalation cohorts of PNT2258 at 1, 2, 4, 8, 16, 32, 64, 85, 113, and 150 mg/m 2 administered intravenously on days 1 through 5 of each 21-day cycle. Pharmacokinetics were determined on days 1 and 5 of the first cycle. Lymphocyte and platelets concentrations were measured for evidence of BCL2-targeted effect. CT scans were used to identify radiologic evidence of anti-tumor effect. Results Twenty-two subjects received PNT2258, and the maximum tolerated dose for PNT2258 was not reached. Doses at or above 32 mg/m 2 resulted in exposure to PNT2258 above the exposure level required for anti-tumor activity in preclinical xenograft testing of 22,377 ng h/ml (PK analysis 2012 ). Fatigue was the most commonly reported adverse event. Dose-limiting toxicity, manifesting as a transient increase in aspartate aminotransferase, occurred at 150 mg/m 2 , the highest dose tested. Four subjects, two each with diagnosis of non-small-cell lung cancer and sarcoma, treated at doses of 64 mg/m 2 or higher, remained on study for 5–8 cycles. Conclusions PNT2258 was safe and well tolerated at the doses tested up to 150 mg/m 2 . Exposure to PNT2258 resulted in clinically manageable decreases in lymphocyte and platelet concentrations. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal formulation of a 24-base DNA oligonucleotide called PNT100.PURPOSEMaximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal formulation of a 24-base DNA oligonucleotide called PNT100.Patients with malignant solid tumors were assigned sequentially to one of ten dose-escalation cohorts of PNT2258 at 1, 2, 4, 8, 16, 32, 64, 85, 113, and 150 mg/m(2) administered intravenously on days 1 through 5 of each 21-day cycle. Pharmacokinetics were determined on days 1 and 5 of the first cycle. Lymphocyte and platelets concentrations were measured for evidence of BCL2-targeted effect. CT scans were used to identify radiologic evidence of anti-tumor effect.METHODSPatients with malignant solid tumors were assigned sequentially to one of ten dose-escalation cohorts of PNT2258 at 1, 2, 4, 8, 16, 32, 64, 85, 113, and 150 mg/m(2) administered intravenously on days 1 through 5 of each 21-day cycle. Pharmacokinetics were determined on days 1 and 5 of the first cycle. Lymphocyte and platelets concentrations were measured for evidence of BCL2-targeted effect. CT scans were used to identify radiologic evidence of anti-tumor effect.Twenty-two subjects received PNT2258, and the maximum tolerated dose for PNT2258 was not reached. Doses at or above 32 mg/m(2) resulted in exposure to PNT2258 above the exposure level required for anti-tumor activity in preclinical xenograft testing of 22,377 ng h/ml (PK analysis 2012). Fatigue was the most commonly reported adverse event. Dose-limiting toxicity, manifesting as a transient increase in aspartate aminotransferase, occurred at 150 mg/m(2), the highest dose tested. Four subjects, two each with diagnosis of non-small-cell lung cancer and sarcoma, treated at doses of 64 mg/m(2) or higher, remained on study for 5-8 cycles.RESULTSTwenty-two subjects received PNT2258, and the maximum tolerated dose for PNT2258 was not reached. Doses at or above 32 mg/m(2) resulted in exposure to PNT2258 above the exposure level required for anti-tumor activity in preclinical xenograft testing of 22,377 ng h/ml (PK analysis 2012). Fatigue was the most commonly reported adverse event. Dose-limiting toxicity, manifesting as a transient increase in aspartate aminotransferase, occurred at 150 mg/m(2), the highest dose tested. Four subjects, two each with diagnosis of non-small-cell lung cancer and sarcoma, treated at doses of 64 mg/m(2) or higher, remained on study for 5-8 cycles.PNT2258 was safe and well tolerated at the doses tested up to 150 mg/m(2). Exposure to PNT2258 resulted in clinically manageable decreases in lymphocyte and platelet concentrations.CONCLUSIONSPNT2258 was safe and well tolerated at the doses tested up to 150 mg/m(2). Exposure to PNT2258 resulted in clinically manageable decreases in lymphocyte and platelet concentrations. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal formulation of a 24-base DNA oligonucleotide called PNT100. Patients with malignant solid tumors were assigned sequentially to one of ten dose-escalation cohorts of PNT2258 at 1, 2, 4, 8, 16, 32, 64, 85, 113, and 150 mg/m(2) administered intravenously on days 1 through 5 of each 21-day cycle. Pharmacokinetics were determined on days 1 and 5 of the first cycle. Lymphocyte and platelets concentrations were measured for evidence of BCL2-targeted effect. CT scans were used to identify radiologic evidence of anti-tumor effect. Twenty-two subjects received PNT2258, and the maximum tolerated dose for PNT2258 was not reached. Doses at or above 32 mg/m(2) resulted in exposure to PNT2258 above the exposure level required for anti-tumor activity in preclinical xenograft testing of 22,377 ng h/ml (PK analysis 2012). Fatigue was the most commonly reported adverse event. Dose-limiting toxicity, manifesting as a transient increase in aspartate aminotransferase, occurred at 150 mg/m(2), the highest dose tested. Four subjects, two each with diagnosis of non-small-cell lung cancer and sarcoma, treated at doses of 64 mg/m(2) or higher, remained on study for 5-8 cycles. PNT2258 was safe and well tolerated at the doses tested up to 150 mg/m(2). Exposure to PNT2258 resulted in clinically manageable decreases in lymphocyte and platelet concentrations. |
| Author | Gaylor, Shari K. Woolliscroft, Michael J. Tolcher, Anthony W. Patnaik, Amita Messmann, Richard A. Rodrigueza, Wendi V. Sooch, Mina P. Rasco, Drew W. Bisgaier, Charles L. Amaya, Alex Papadopoulos, Kyriakos P. Moore, Timothy D. |
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| Keywords | BCL2 Liposome DNAi PNT2258 Phase I Deoxyribonucleic acid inhibitor Human Solid tumor Targeting Drug carrier Malignant tumor Target DNA C-Onc gene Phase I trial Advanced stage Inhibitor Protooncogene Cancer |
| Language | English |
| License | http://creativecommons.org/licenses/by/2.0 CC BY 4.0 Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
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| PublicationTitleAbbrev | Cancer Chemother Pharmacol |
| PublicationTitleAlternate | Cancer Chemother Pharmacol |
| PublicationYear | 2014 |
| Publisher | Springer Berlin Heidelberg Springer Springer Nature B.V |
| Publisher_xml | – name: Springer Berlin Heidelberg – name: Springer – name: Springer Nature B.V |
| References | http://www.eortc.be/recist TanNMalekMZhaJYuePKasseesRBerryLFairbrotherWJSampathDBelmontLDNavitoclax enhances the efficacy of taxanes in non-small cell lung cancer modelsClin Cancer Res2011176139414041:CAS:528:DC%2BC3MXjtFChs7o%3D2122047810.1158/1078-0432.CCR-10-2353 DavidsMSLetaiATargeting the B-cell lymphoma/leukemia 2 family in cancerJ Clin Oncol20123025312731351:CAS:528:DC%2BC38XhsVKlsLnE2264914410.1200/JCO.2011.37.0981 AdamsJMCorySBcl-2-regulated apoptosis: mechanism and therapeutic potentialCurr Opin Immunol20071954884961:CAS:528:DC%2BD2sXhtFSmu7vN27543081762946810.1016/j.coi.2007.05.004 (2010) PNT100 Expression in preclinical murine samples. Internal document (ProNAi Therapeutics) Technical Report 2-ProNAi Research Protocol 236: efficacy evaluation of PNT2258 stored frozen and stored refrigerated in WSU-DLCL2 xenograft bearing CB-17 SCID mice in combination with rituximab. Kalamazoo, MI WalenskyLDFrom mitochondrial biology to magic bullet: navitoclax disarms BCL-2 in chronic lymphocytic leukemiaJ Clin Oncol20123055545571:CAS:528:DC%2BC38XkvVCit7g%3D2218438910.1200/JCO.2011.37.9339 TseCShoemakerARAdickesJAndersonMGChenJJinSJohnsonEFMarshKCMittenMJNimmerPRobertsLTahirSKXiaoYYangXZhangHFesikSRosenbergSHElmoreSWABT-263: a potent and orally bioavailable Bcl-2 family inhibitorCancer Res2008689342134281:CAS:528:DC%2BD1cXltlSltrs%3D1845117010.1158/0008-5472.CAN-07-5836 SethSJohnsRTemplinMVDelivery and biodistribution of siRNA for cancer therapy: challenges and future prospectsTher deliv2012322452611:CAS:528:DC%2BC38Xhslyjtbk%3D2283420010.4155/tde.11.155 ThurmanRERynesEHumbertRVierstraJMauranoMTHaugenESheffieldNCStergachisABWangHVernotBGargKJohnSSandstromRBatesDBoatmanLCanfieldTKDiegelMDunnDEbersolAKFrumTGisteEJohnsonAKJohnsonEMKutyavinTLajoieBLeeBKLeeKLondonDLotakisDNephSNeriFNguyenEDQuHReynoldsAPRoachVSafiASanchezMESanyalAShaferASimonJMSongLVongSWeaverMYanYZhangZZhangZLenhardBTewariMDorschnerMOHansenRSNavasPAStamatoyannopoulosGIyerVRLiebJDSunyaevSRAkeyJMSaboPJKaulRFureyTSDekkerJCrawfordGEStamatoyannopoulosJAThe accessible chromatin landscape of the human genomeNature2012489741475821:CAS:528:DC%2BC38XhtlGns7bL37213482295561710.1038/nature11232 Legakis HC, Tran P, Rodrigueza WV, Bisgaier C (2012) Development and validation of a hybridization-ligation assay for the quantitative measurement of PNT100, the oligonucleotide component present in liposomal formulation PNT2258, in human plasma. Paper presented at the 14th annual TIDES conference: oligonucleotide and peptide therapeutics from research through commercialization, Las Vegas SouersAJLeversonJDBoghaertERAcklerSLCatronNDChenJDaytonBDDingHEnschedeSHFairbrotherWJHuangDCHymowitzSGJinSKhawSLKovarPJLamLTLeeJMaeckerHLMarshKCMasonKDMittenMJNimmerPMOleksijewAParkCHParkCMPhillipsDCRobertsAWSampathDSeymourJFSmithMLSullivanGMTahirSKTseCWendtMDXiaoYXueJCZhangHHumerickhouseRARosenbergSHElmoreSWABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing plateletsNat Med20131922022081:CAS:528:DC%2BC3sXjslagtQ%3D%3D2329163010.1038/nm.3048 (2010) A 4-Week (2-Cycle) Intravenous Toxicity and Pharmacokinetic/Tissue Distribution Study of PNT2258 in Rats. ProNAi Therapeutics report number MPI (MPI Research) 1208-002 DavidsMSLetaiAABT-199: taking dead aim at BCL-2Cancer Cell20132321391411:CAS:528:DC%2BC3sXisVSqtbg%3D36939522341097110.1016/j.ccr.2013.01.018 WilsonWHO’ConnorOACzuczmanMSLaCasceASGerecitanoJFLeonardJPTulpuleADunleavyKXiongHChiuYLCuiYBusmanTElmoreSWRosenbergSHKrivoshikAPEnschedeSHHumerickhouseRANavitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activityLancet Oncol20101112114911591:CAS:528:DC%2BC3cXhsVyhsLbN30254952109408910.1016/S1470-2045(10)70261-8 Basit F, Cristofanon S, Fulda S (2013) Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranes. Cell Death Differ. doi:10.1038/cdd.2013.45 LightfootHLHallJTarget mRNA inhibition by oligonucleotide drugs in manNucleic Acids Res2012402110585105951:CAS:528:DC%2BC38Xhslalu7fE35105002298970910.1093/nar/gks861 WongMTanNZhaJPealeFVYuePFairbrotherWJBelmontLDNavitoclax (ABT-263) reduces Bcl-x(L)-mediated chemoresistance in ovarian cancer modelsMol Cancer Ther2012114102610351:CAS:528:DC%2BC38Xltl2ntLg%3D2230209810.1158/1535-7163.MCT-11-0693 Analysis of pharmacokinetic data CRL 345764. Clinical Reference Laboratory, Lenexa, Kansas 66215 USA ChenJJinSAbrahamVHuangXLiuBMittenMJNimmerPLinXSmithMShenYShoemakerARTahirSKZhangHAcklerSLRosenbergSHMaeckerHSampathDLeversonJDTseCElmoreSWThe Bcl-2/Bcl-X(L)/Bcl-w inhibitor, navitoclax, enhances the activity of chemotherapeutic agents in vitro and in vivoMol Cancer Ther20111012234023491:CAS:528:DC%2BC3MXhsFylurbL2191485310.1158/1535-7163.MCT-11-0415 (2010) A 4-Week (2-Cycle) Intravenous Toxicity and Pharmacokinetic/Tissue Distribution Study of PNT2258 and an Active Analogue in Cynomolgus Monkeys. ProNAi Therapeutics report number MPI (MPI Research) 1208-003 AdamiRCSethSHarviePJohnsRFamRFosnaughKZhuTFarberKMcCutcheonMGoodmanTTLiuYChenYKwangETemplinMVSeversonGBrownTVaishNChenFCharmleyPPoliskyBHoustonMEJrAn amino acid-based amphoteric liposomal delivery system for systemic administration of siRNAMol Ther J Am Soc Gene Ther2011196114111511:CAS:528:DC%2BC3MXkvVOjsrY%3D10.1038/mt.2011.56 RascoDWPatnaikAAmayaAGaylorSMooreTIzbickaEStreeperRRodriguezaWMessmannRTolcherAA study of PNT2258 (DNA-targeted Blocker of BCL2 Expression) in patients with advanced solid tumorsEur J Cancer201248Suppl 6191 SeniorJHFate and behavior of liposomes in vivo: a review of controlling factorsCrit Rev Ther Drug Carrier Syst1987321231931:CAS:528:DyaL2sXptVSitw%3D%3D3542245 SakumaYTsunezumiJNakamuraYYoshiharaMMatsukumaSKoizumeSMiyagiYABT-263, a Bcl-2 inhibitor, enhances the susceptibility of lung adenocarcinoma cells treated with Src inhibitors to anoikisOncol Rep20112536616671:CAS:528:DC%2BC3MXjvVWgtrk%3D2120697610.3892/or.2010.11232010.1123 ShiJZhouYHuangHCMitchisonTJNavitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xLCancer Res20117113451845261:CAS:528:DC%2BC3MXotlertr8%3D31294522154657010.1158/0008-5472.CAN-10-4336 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf Rasco DW, Papadopoulos K, Wick M, Amaya A, Izbicka E, Streeper R, Louden C, Woolliscroft M, Sooch M, Messmann RA, Rodrigueza WV (2013) Effect of PNT2258, an anti-BCL2 DNA-interference drug, on tumor growth and immunological markers in mice and humans. In: American association of cancer research annual meeting, Washington, DC, 18 January 2013 Nicolaou AE (2009) Mode of action of PNT100 (trans: Department P). Internal document (ProNAi Therapeutics) conducted by Novosom AG VoglerMDickensDDyerMJOwenAPirmohamedMCohenGMThe B-cell lymphoma 2 (BCL2)-inhibitors, ABT-737 and ABT-263, are substrates for P-glycoproteinBiochem Biophys Res Commun201140823443491:CAS:528:DC%2BC3MXlvVynsbg%3D2151427810.1016/j.bbrc.2011.04.043 Rodrigueza WV, Mohammad R, McGovern JP, Wick MJ, Rasco D, Tolcher AW, Bisgaier CL (2012) Effect of PNT2258 combinations with docetaxel, dacarbazine, or vemurafenib on the A375 melanoma xenograft. In: AACR 103rd Annual Meeting 2012, Chicago, IL, 31 Mar–4 Apr, 2012 The SMARTICLES® technology: enabling systemic DNA therapeutics. http://pharmalicensing.com/public/outlicensing/view/12158/the-smarticles-technology-enabling-systemic-dna-therapeutics Mattoo AR, Fitzgerald DJ (2012) Combination treatments with ABT-263 and an immunotoxin produce synergistic killing of ABT-263-resistant small cell lung cancer cell lines. Int J Cancer. doi:10.1002/ijc.27732 Ackler S, Mitten MJ, Chen J, Clarin J, Foster K, Jin S, Phillips DC, Schlessinger S, Wang B, Leverson JD, Boghaert ER (2012) Navitoclax (ABT 263) and bendamustine ± rituximab induce enhanced killing of non-Hodgkin’s lymphoma tumors in vivo. Br J Pharmacol. doi:10.1111/j.1476-5381.2012.02048.x CorySAdamsJMKilling cancer cells by flipping the Bcl-2/Bax switchCancer Cell200581561:CAS:528:DC%2BD2MXntVejs74%3D1602359310.1016/j.ccr.2005.06.012 (2010) A Repeat-Dose Safety Pharmacology Study (with evaluation of cardiovascular, respiratory, and central nervous systems) of PNT2258 Administered to Cynomolgus Monkeys by Intravenous Infusion. ProNAi Therapeutics report number CRL (Charles River Labs) LLF00001 (2012) PK analysis for a phase 1 study of PNT2258 in patients with advanced solid tumors. Internal document (ProNAi Therapeutics) conducted by VEEDA Clinical Research, Brussels, Belgium SethSMatsuiYFosnaughKLiuYVaishNAdamiRHarviePJohnsRSeversonGBrownTTakagiABellSChenYChenFZhuTFamRMaciagiewiczIKwangEMcCutcheonMFarberKCharmleyPHoustonMEJrSoATemplinMVPoliskyBRNAi-based therapeutics targeting survivin and PLK1 for treatment of bladder cancerMol Ther J Am Soc Gene Ther20111959289351:CAS:528:DC%2BC3MXisFKlt7g%3D10.1038/mt.2011.21 HerbstRSFrankelSROblimersen sodium (Genasense bcl-2 antisense oligonucleotide): a rational therapeutic to enhance apoptosis in therapy of lung cancerClin Cancer Res20041012 Pt 24245s4248s1:CAS:528:DC%2BD2cXltFWlsrY%3D1521796710.1158/1078-0432.CCR-040018 SchmitzRRenneCRosenquistRTinguelyMDistlerVMenestrinaFLestaniMStankovicTAustenBBrauningerAHansmannMLKuppersRInsights into the multistep transformation process of lymphomas: IgH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin’s and non-Hodgkin’s lymphomasLeukemia2005198145214581:CAS:528:DC%2BD2MXmtlSjsLs%3D1597345510.1038/sj.leu.2403841 SchoenwaelderSMJacksonSPBcl-xL-inhibitory BH3 mimetics (ABT-737 or ABT-263) and the modulation of cytosolic calcium flux and platelet functionBlood20121195132013211:CAS:528:DC%2BC38XisFOitb4%3D2230828510.1182/blood-2011-10-387399(author reply 1321-1322) GandhiLCamidgeDRRibeiro de OliveiraMBonomiPGandaraDKhairaDHannCLMcKeeganEMLitvinovichEHemkenPMDiveCEnschedeSHNolanCChiuYLBusmanTXiongHKrivoshikAPHumerickhouseRShapiroGIRudinCMPha 2361_CR1 S Cory (2361_CR3) 2005; 8 SM Schoenwaelder (2361_CR29) 2012; 119 J Shi (2361_CR30) 2011; 71 MS Davids (2361_CR4) 2012; 30 M Vogler (2361_CR33) 2011; 408 L Gandhi (2361_CR38) 2011; 29 HL Lightfoot (2361_CR45) 2012; 40 2361_CR41 AW Roberts (2361_CR39) 2012; 30 2361_CR21 2361_CR43 JM Adams (2361_CR2) 2007; 19 2361_CR20 2361_CR22 2361_CR44 MS Davids (2361_CR37) 2013; 23 AJ Souers (2361_CR40) 2013; 19 2361_CR24 2361_CR26 CM Rudin (2361_CR27) 2012; 18 RS Herbst (2361_CR42) 2004; 10 WH Wilson (2361_CR35) 2010; 11 Y Sakuma (2361_CR28) 2011; 25 S Seth (2361_CR23) 2011; 19 LD Walensky (2361_CR34) 2012; 30 RE Thurman (2361_CR11) 2012; 489 C Tse (2361_CR32) 2008; 68 S Seth (2361_CR7) 2012; 3 J Chen (2361_CR25) 2011; 10 M Wong (2361_CR36) 2012; 11 2361_CR10 2361_CR14 2361_CR13 2361_CR16 2361_CR15 R Schmitz (2361_CR12) 2005; 19 N Tan (2361_CR31) 2011; 17 RC Adami (2361_CR6) 2011; 19 2361_CR17 2361_CR8 2361_CR9 2361_CR19 JH Senior (2361_CR18) 1987; 3 2361_CR5 |
| References_xml | – reference: ThurmanRERynesEHumbertRVierstraJMauranoMTHaugenESheffieldNCStergachisABWangHVernotBGargKJohnSSandstromRBatesDBoatmanLCanfieldTKDiegelMDunnDEbersolAKFrumTGisteEJohnsonAKJohnsonEMKutyavinTLajoieBLeeBKLeeKLondonDLotakisDNephSNeriFNguyenEDQuHReynoldsAPRoachVSafiASanchezMESanyalAShaferASimonJMSongLVongSWeaverMYanYZhangZZhangZLenhardBTewariMDorschnerMOHansenRSNavasPAStamatoyannopoulosGIyerVRLiebJDSunyaevSRAkeyJMSaboPJKaulRFureyTSDekkerJCrawfordGEStamatoyannopoulosJAThe accessible chromatin landscape of the human genomeNature2012489741475821:CAS:528:DC%2BC38XhtlGns7bL37213482295561710.1038/nature11232 – reference: Analysis of pharmacokinetic data CRL 345764. Clinical Reference Laboratory, Lenexa, Kansas 66215 USA – reference: HerbstRSFrankelSROblimersen sodium (Genasense bcl-2 antisense oligonucleotide): a rational therapeutic to enhance apoptosis in therapy of lung cancerClin Cancer Res20041012 Pt 24245s4248s1:CAS:528:DC%2BD2cXltFWlsrY%3D1521796710.1158/1078-0432.CCR-040018 – reference: SchmitzRRenneCRosenquistRTinguelyMDistlerVMenestrinaFLestaniMStankovicTAustenBBrauningerAHansmannMLKuppersRInsights into the multistep transformation process of lymphomas: IgH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin’s and non-Hodgkin’s lymphomasLeukemia2005198145214581:CAS:528:DC%2BD2MXmtlSjsLs%3D1597345510.1038/sj.leu.2403841 – reference: SeniorJHFate and behavior of liposomes in vivo: a review of controlling factorsCrit Rev Ther Drug Carrier Syst1987321231931:CAS:528:DyaL2sXptVSitw%3D%3D3542245 – reference: SchoenwaelderSMJacksonSPBcl-xL-inhibitory BH3 mimetics (ABT-737 or ABT-263) and the modulation of cytosolic calcium flux and platelet functionBlood20121195132013211:CAS:528:DC%2BC38XisFOitb4%3D2230828510.1182/blood-2011-10-387399(author reply 1321-1322) – reference: Rodrigueza WV, Mohammad R, McGovern JP, Wick MJ, Rasco D, Tolcher AW, Bisgaier CL (2012) Effect of PNT2258 combinations with docetaxel, dacarbazine, or vemurafenib on the A375 melanoma xenograft. In: AACR 103rd Annual Meeting 2012, Chicago, IL, 31 Mar–4 Apr, 2012 – reference: RudinCMHannCLGaronEBRibeiro de OliveiraMBonomiPDCamidgeDRChuQGiacconeGKhairaDRamalingamSSRansonMRDiveCMcKeeganEMChylaBJDowellBLChakravarttyANolanCERudersdorfNBusmanTAMabryMHKrivoshikAPHumerickhouseRAShapiroGIGandhiLPhase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancerClin Cancer Res20121811316331691:CAS:528:DC%2BC38XnvVOgu7g%3D37150592249627210.1158/1078-0432.CCR-11-3090 – reference: DavidsMSLetaiATargeting the B-cell lymphoma/leukemia 2 family in cancerJ Clin Oncol20123025312731351:CAS:528:DC%2BC38XhsVKlsLnE2264914410.1200/JCO.2011.37.0981 – reference: SakumaYTsunezumiJNakamuraYYoshiharaMMatsukumaSKoizumeSMiyagiYABT-263, a Bcl-2 inhibitor, enhances the susceptibility of lung adenocarcinoma cells treated with Src inhibitors to anoikisOncol Rep20112536616671:CAS:528:DC%2BC3MXjvVWgtrk%3D2120697610.3892/or.2010.11232010.1123 – reference: Technical Report 2-ProNAi Research Protocol 236: efficacy evaluation of PNT2258 stored frozen and stored refrigerated in WSU-DLCL2 xenograft bearing CB-17 SCID mice in combination with rituximab. Kalamazoo, MI – reference: (2010) A 4-Week (2-Cycle) Intravenous Toxicity and Pharmacokinetic/Tissue Distribution Study of PNT2258 and an Active Analogue in Cynomolgus Monkeys. ProNAi Therapeutics report number MPI (MPI Research) 1208-003 – reference: GandhiLCamidgeDRRibeiro de OliveiraMBonomiPGandaraDKhairaDHannCLMcKeeganEMLitvinovichEHemkenPMDiveCEnschedeSHNolanCChiuYLBusmanTXiongHKrivoshikAPHumerickhouseRShapiroGIRudinCMPhase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumorsJ Clin Oncol20112979099161:CAS:528:DC%2BC3MXktlelsbw%3D2128254310.1200/JCO.2010.31.6208 – reference: RobertsAWSeymourJFBrownJRWierdaWGKippsTJKhawSLCarneyDAHeSZHuangDCXiongHCuiYBusmanTAMcKeeganEMKrivoshikAPEnschedeSHHumerickhouseRSubstantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory diseaseJ Clin Oncol20123054884961:CAS:528:DC%2BC38XkvVCitrg%3D2218437810.1200/JCO.2011.34.7898 – reference: ChenJJinSAbrahamVHuangXLiuBMittenMJNimmerPLinXSmithMShenYShoemakerARTahirSKZhangHAcklerSLRosenbergSHMaeckerHSampathDLeversonJDTseCElmoreSWThe Bcl-2/Bcl-X(L)/Bcl-w inhibitor, navitoclax, enhances the activity of chemotherapeutic agents in vitro and in vivoMol Cancer Ther20111012234023491:CAS:528:DC%2BC3MXhsFylurbL2191485310.1158/1535-7163.MCT-11-0415 – reference: The SMARTICLES® technology: enabling systemic DNA therapeutics. http://pharmalicensing.com/public/outlicensing/view/12158/the-smarticles-technology-enabling-systemic-dna-therapeutics – reference: Mattoo AR, Fitzgerald DJ (2012) Combination treatments with ABT-263 and an immunotoxin produce synergistic killing of ABT-263-resistant small cell lung cancer cell lines. Int J Cancer. doi:10.1002/ijc.27732 – reference: (2012) PK analysis for a phase 1 study of PNT2258 in patients with advanced solid tumors. Internal document (ProNAi Therapeutics) conducted by VEEDA Clinical Research, Brussels, Belgium – reference: ShiJZhouYHuangHCMitchisonTJNavitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xLCancer Res20117113451845261:CAS:528:DC%2BC3MXotlertr8%3D31294522154657010.1158/0008-5472.CAN-10-4336 – reference: TanNMalekMZhaJYuePKasseesRBerryLFairbrotherWJSampathDBelmontLDNavitoclax enhances the efficacy of taxanes in non-small cell lung cancer modelsClin Cancer Res2011176139414041:CAS:528:DC%2BC3MXjtFChs7o%3D2122047810.1158/1078-0432.CCR-10-2353 – reference: WilsonWHO’ConnorOACzuczmanMSLaCasceASGerecitanoJFLeonardJPTulpuleADunleavyKXiongHChiuYLCuiYBusmanTElmoreSWRosenbergSHKrivoshikAPEnschedeSHHumerickhouseRANavitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activityLancet Oncol20101112114911591:CAS:528:DC%2BC3cXhsVyhsLbN30254952109408910.1016/S1470-2045(10)70261-8 – reference: TseCShoemakerARAdickesJAndersonMGChenJJinSJohnsonEFMarshKCMittenMJNimmerPRobertsLTahirSKXiaoYYangXZhangHFesikSRosenbergSHElmoreSWABT-263: a potent and orally bioavailable Bcl-2 family inhibitorCancer Res2008689342134281:CAS:528:DC%2BD1cXltlSltrs%3D1845117010.1158/0008-5472.CAN-07-5836 – reference: Nicolaou AE (2009) Mode of action of PNT100 (trans: Department P). Internal document (ProNAi Therapeutics) conducted by Novosom AG – reference: CorySAdamsJMKilling cancer cells by flipping the Bcl-2/Bax switchCancer Cell200581561:CAS:528:DC%2BD2MXntVejs74%3D1602359310.1016/j.ccr.2005.06.012 – reference: SouersAJLeversonJDBoghaertERAcklerSLCatronNDChenJDaytonBDDingHEnschedeSHFairbrotherWJHuangDCHymowitzSGJinSKhawSLKovarPJLamLTLeeJMaeckerHLMarshKCMasonKDMittenMJNimmerPMOleksijewAParkCHParkCMPhillipsDCRobertsAWSampathDSeymourJFSmithMLSullivanGMTahirSKTseCWendtMDXiaoYXueJCZhangHHumerickhouseRARosenbergSHElmoreSWABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing plateletsNat Med20131922022081:CAS:528:DC%2BC3sXjslagtQ%3D%3D2329163010.1038/nm.3048 – reference: SethSMatsuiYFosnaughKLiuYVaishNAdamiRHarviePJohnsRSeversonGBrownTTakagiABellSChenYChenFZhuTFamRMaciagiewiczIKwangEMcCutcheonMFarberKCharmleyPHoustonMEJrSoATemplinMVPoliskyBRNAi-based therapeutics targeting survivin and PLK1 for treatment of bladder cancerMol Ther J Am Soc Gene Ther20111959289351:CAS:528:DC%2BC3MXisFKlt7g%3D10.1038/mt.2011.21 – reference: VoglerMDickensDDyerMJOwenAPirmohamedMCohenGMThe B-cell lymphoma 2 (BCL2)-inhibitors, ABT-737 and ABT-263, are substrates for P-glycoproteinBiochem Biophys Res Commun201140823443491:CAS:528:DC%2BC3MXlvVynsbg%3D2151427810.1016/j.bbrc.2011.04.043 – reference: SethSJohnsRTemplinMVDelivery and biodistribution of siRNA for cancer therapy: challenges and future prospectsTher deliv2012322452611:CAS:528:DC%2BC38Xhslyjtbk%3D2283420010.4155/tde.11.155 – reference: (2010) A 4-Week (2-Cycle) Intravenous Toxicity and Pharmacokinetic/Tissue Distribution Study of PNT2258 in Rats. ProNAi Therapeutics report number MPI (MPI Research) 1208-002 – reference: AdamiRCSethSHarviePJohnsRFamRFosnaughKZhuTFarberKMcCutcheonMGoodmanTTLiuYChenYKwangETemplinMVSeversonGBrownTVaishNChenFCharmleyPPoliskyBHoustonMEJrAn amino acid-based amphoteric liposomal delivery system for systemic administration of siRNAMol Ther J Am Soc Gene Ther2011196114111511:CAS:528:DC%2BC3MXkvVOjsrY%3D10.1038/mt.2011.56 – reference: Legakis HC, Tran P, Rodrigueza WV, Bisgaier C (2012) Development and validation of a hybridization-ligation assay for the quantitative measurement of PNT100, the oligonucleotide component present in liposomal formulation PNT2258, in human plasma. Paper presented at the 14th annual TIDES conference: oligonucleotide and peptide therapeutics from research through commercialization, Las Vegas – reference: AdamsJMCorySBcl-2-regulated apoptosis: mechanism and therapeutic potentialCurr Opin Immunol20071954884961:CAS:528:DC%2BD2sXhtFSmu7vN27543081762946810.1016/j.coi.2007.05.004 – reference: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf – reference: WalenskyLDFrom mitochondrial biology to magic bullet: navitoclax disarms BCL-2 in chronic lymphocytic leukemiaJ Clin Oncol20123055545571:CAS:528:DC%2BC38XkvVCit7g%3D2218438910.1200/JCO.2011.37.9339 – reference: DavidsMSLetaiAABT-199: taking dead aim at BCL-2Cancer Cell20132321391411:CAS:528:DC%2BC3sXisVSqtbg%3D36939522341097110.1016/j.ccr.2013.01.018 – reference: WongMTanNZhaJPealeFVYuePFairbrotherWJBelmontLDNavitoclax (ABT-263) reduces Bcl-x(L)-mediated chemoresistance in ovarian cancer modelsMol Cancer Ther2012114102610351:CAS:528:DC%2BC38Xltl2ntLg%3D2230209810.1158/1535-7163.MCT-11-0693 – reference: (2010) PNT100 Expression in preclinical murine samples. Internal document (ProNAi Therapeutics) – reference: RascoDWPatnaikAAmayaAGaylorSMooreTIzbickaEStreeperRRodriguezaWMessmannRTolcherAA study of PNT2258 (DNA-targeted Blocker of BCL2 Expression) in patients with advanced solid tumorsEur J Cancer201248Suppl 6191 – reference: Rasco DW, Papadopoulos K, Wick M, Amaya A, Izbicka E, Streeper R, Louden C, Woolliscroft M, Sooch M, Messmann RA, Rodrigueza WV (2013) Effect of PNT2258, an anti-BCL2 DNA-interference drug, on tumor growth and immunological markers in mice and humans. 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Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal... Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal formulation... |
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| SubjectTerms | Adult Aged Aged, 80 and over Antineoplastic agents Biological and medical sciences Cancer Research DNA - antagonists & inhibitors Female Humans Liposomes - administration & dosage Male Maximum Tolerated Dose Medical sciences Medicine Medicine & Public Health Middle Aged Molecular Targeted Therapy Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Neoplasms - drug therapy Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology Oligodeoxyribonucleotides - administration & dosage Oligonucleotides - administration & dosage Oligonucleotides - adverse effects Oligonucleotides - pharmacokinetics Oncology Original Original Article Pharmacology. Drug treatments Pharmacology/Toxicology Proto-Oncogene Proteins c-bcl-2 - genetics Treatment Outcome Tumors |
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| Title | A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors |
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