A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors

Anthony W Tolcher, Wendi V Rodrigueza, Drew W Rasco, Amita Patnaik, Kyriakos P Papadopoulos, Alex Amaya, Timothy D Moore, Shari K Gaylor, Charles L Bisgaier, Mina P Sooch, Michael J Woolliscroft, Richard A Messmann, Anthony W Tolcher, Wendi V Rodrigueza, Drew W Rasco, Amita Patnaik, Kyriakos P Papadopoulos, Alex Amaya, Timothy D Moore, Shari K Gaylor, Charles L Bisgaier, Mina P Sooch, Michael J Woolliscroft, Richard A Messmann

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.

Figures

Fig. 1
Fig. 1
a A representation of the PNT2258 molecule. The PNT100 oligonucleotide is encapsulated in liposomes of MOCHOL/CHEMS/DOPE/POPC, particle size ~130 nm. PNT2258 has an overall pKa of ~6.5, containing pH responsive lipids that are cationic during manufacturing (in order to attract the negatively charged PNT100 oligonucleotide) and anionic during systemic circulation. Charge and lipid components are similar to circulating lipoproteins The pH “tunability” is designed to enhance endosomal escape following cellular uptake. b Diagrammatic representation of the DNA “target” for PNT100 binding located on chromosome 18. The PNT100 oligonucleotide sequence is designed to hybridize (i.e., bind) to a region 5′ upstream of the BCL2 gene start site
Fig. 2
Fig. 2
Days on study for each subject as a function of dose of PNT2258 administered. Patient cancer diagnosis is shown to the right of the bars
Fig. 3
Fig. 3
a First-cycle lymphocyte nadir (i.e., percent maximum decline from baseline) as a function of dose. b Cycle 1 platelet levels

References

    1. (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
    1. Adams JM, Cory S. Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol. 2007;19(5):488–496. doi: 10.1016/j.coi.2007.05.004.
    1. Cory S, Adams JM. Killing cancer cells by flipping the Bcl-2/Bax switch. Cancer Cell. 2005;8(1):5–6. doi: 10.1016/j.ccr.2005.06.012.
    1. Davids MS, Letai A. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012;30(25):3127–3135. doi: 10.1200/JCO.2011.37.0981.
    1. The SMARTICLES® technology: enabling systemic DNA therapeutics.
    1. Adami RC, Seth S, Harvie P, Johns R, Fam R, Fosnaugh K, Zhu T, Farber K, McCutcheon M, Goodman TT, Liu Y, Chen Y, Kwang E, Templin MV, Severson G, Brown T, Vaish N, Chen F, Charmley P, Polisky B, Houston ME., Jr An amino acid-based amphoteric liposomal delivery system for systemic administration of siRNA. Mol Ther J Am Soc Gene Ther. 2011;19(6):1141–1151. doi: 10.1038/mt.2011.56.
    1. Seth S, Johns R, Templin MV. Delivery and biodistribution of siRNA for cancer therapy: challenges and future prospects. Ther deliv. 2012;3(2):245–261. doi: 10.4155/tde.11.155.
    1. 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
    1. (2010) PNT100 Expression in preclinical murine samples. Internal document (ProNAi Therapeutics)
    1. Nicolaou AE (2009) Mode of action of PNT100 (trans: Department P). Internal document (ProNAi Therapeutics) conducted by Novosom AG
    1. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, Sheffield NC, Stergachis AB, Wang H, Vernot B, Garg K, John S, Sandstrom R, Bates D, Boatman L, Canfield TK, Diegel M, Dunn D, Ebersol AK, Frum T, Giste E, Johnson AK, Johnson EM, Kutyavin T, Lajoie B, Lee BK, Lee K, London D, Lotakis D, Neph S, Neri F, Nguyen ED, Qu H, Reynolds AP, Roach V, Safi A, Sanchez ME, Sanyal A, Shafer A, Simon JM, Song L, Vong S, Weaver M, Yan Y, Zhang Z, Zhang Z, Lenhard B, Tewari M, Dorschner MO, Hansen RS, Navas PA, Stamatoyannopoulos G, Iyer VR, Lieb JD, Sunyaev SR, Akey JM, Sabo PJ, Kaul R, Furey TS, Dekker J, Crawford GE, Stamatoyannopoulos JA. The accessible chromatin landscape of the human genome. Nature. 2012;489(7414):75–82. doi: 10.1038/nature11232.
    1. Schmitz R, Renne C, Rosenquist R, Tinguely M, Distler V, Menestrina F, Lestani M, Stankovic T, Austen B, Brauninger A, Hansmann ML, Kuppers R. Insights 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 lymphomas. Leukemia. 2005;19(8):1452–1458. doi: 10.1038/sj.leu.2403841.
    1. 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
    1. (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
    1. (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
    1. 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
    1. (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
    1. Senior JH. Fate and behavior of liposomes in vivo: a review of controlling factors. Crit Rev Ther Drug Carrier Syst. 1987;3(2):123–193.
    1. Analysis of pharmacokinetic data CRL 345764. Clinical Reference Laboratory, Lenexa, Kansas 66215 USA
    1. Seth S, Matsui Y, Fosnaugh K, Liu Y, Vaish N, Adami R, Harvie P, Johns R, Severson G, Brown T, Takagi A, Bell S, Chen Y, Chen F, Zhu T, Fam R, Maciagiewicz I, Kwang E, McCutcheon M, Farber K, Charmley P, Houston ME, Jr, So A, Templin MV, Polisky B. RNAi-based therapeutics targeting survivin and PLK1 for treatment of bladder cancer. Mol Ther J Am Soc Gene Ther. 2011;19(5):928–935. doi: 10.1038/mt.2011.21.
    1. 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
    1. Chen J, Jin S, Abraham V, Huang X, Liu B, Mitten MJ, Nimmer P, Lin X, Smith M, Shen Y, Shoemaker AR, Tahir SK, Zhang H, Ackler SL, Rosenberg SH, Maecker H, Sampath D, Leverson JD, Tse C, Elmore SW. The Bcl-2/Bcl-X(L)/Bcl-w inhibitor, navitoclax, enhances the activity of chemotherapeutic agents in vitro and in vivo. Mol Cancer Ther. 2011;10(12):2340–2349. doi: 10.1158/1535-7163.MCT-11-0415.
    1. 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
    1. Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, Ranson MR, Dive C, McKeegan EM, Chyla BJ, Dowell BL, Chakravartty A, Nolan CE, Rudersdorf N, Busman TA, Mabry MH, Krivoshik AP, Humerickhouse RA, Shapiro GI, Gandhi L. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res. 2012;18(11):3163–3169. doi: 10.1158/1078-0432.CCR-11-3090.
    1. Sakuma Y, Tsunezumi J, Nakamura Y, Yoshihara M, Matsukuma S, Koizume S, Miyagi Y. ABT-263, a Bcl-2 inhibitor, enhances the susceptibility of lung adenocarcinoma cells treated with Src inhibitors to anoikis. Oncol Rep. 2011;25(3):661–667. doi: 10.3892/or.2010.1123.
    1. Schoenwaelder SM, Jackson SP. Bcl-xL-inhibitory BH3 mimetics (ABT-737 or ABT-263) and the modulation of cytosolic calcium flux and platelet function. Blood. 2012;119(5):1320–1321. doi: 10.1182/blood-2011-10-387399.
    1. Shi J, Zhou Y, Huang HC, Mitchison TJ. Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL. Cancer Res. 2011;71(13):4518–4526. doi: 10.1158/0008-5472.CAN-10-4336.
    1. Tan N, Malek M, Zha J, Yue P, Kassees R, Berry L, Fairbrother WJ, Sampath D, Belmont LD. Navitoclax enhances the efficacy of taxanes in non-small cell lung cancer models. Clin Cancer Res. 2011;17(6):1394–1404. doi: 10.1158/1078-0432.CCR-10-2353.
    1. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421–3428. doi: 10.1158/0008-5472.CAN-07-5836.
    1. Vogler M, Dickens D, Dyer MJ, Owen A, Pirmohamed M, Cohen GM. The B-cell lymphoma 2 (BCL2)-inhibitors, ABT-737 and ABT-263, are substrates for P-glycoprotein. Biochem Biophys Res Commun. 2011;408(2):344–349. doi: 10.1016/j.bbrc.2011.04.043.
    1. Walensky LD. From mitochondrial biology to magic bullet: navitoclax disarms BCL-2 in chronic lymphocytic leukemia. J Clin Oncol. 2012;30(5):554–557. doi: 10.1200/JCO.2011.37.9339.
    1. Wilson WH, O’Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, Tulpule A, Dunleavy K, Xiong H, Chiu YL, Cui Y, Busman T, Elmore SW, Rosenberg SH, Krivoshik AP, Enschede SH, Humerickhouse RA. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010;11(12):1149–1159. doi: 10.1016/S1470-2045(10)70261-8.
    1. Wong M, Tan N, Zha J, Peale FV, Yue P, Fairbrother WJ, Belmont LD. Navitoclax (ABT-263) reduces Bcl-x(L)-mediated chemoresistance in ovarian cancer models. Mol Cancer Ther. 2012;11(4):1026–1035. doi: 10.1158/1535-7163.MCT-11-0693.
    1. Davids MS, Letai A. ABT-199: taking dead aim at BCL-2. Cancer Cell. 2013;23(2):139–141. doi: 10.1016/j.ccr.2013.01.018.
    1. Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM. Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol. 2011;29(7):909–916. doi: 10.1200/JCO.2010.31.6208.
    1. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30(5):488–496. doi: 10.1200/JCO.2011.34.7898.
    1. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–208. doi: 10.1038/nm.3048.
    1. 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
    1. Herbst RS, Frankel SR. Oblimersen sodium (Genasense bcl-2 antisense oligonucleotide): a rational therapeutic to enhance apoptosis in therapy of lung cancer. Clin Cancer Res. 2004;10(12 Pt 2):4245s–4248s. doi: 10.1158/1078-0432.CCR-040018.
    1. Rasco DW, Patnaik A, Amaya A, Gaylor S, Moore T, Izbicka E, Streeper R, Rodrigueza W, Messmann R, Tolcher A (2012) A study of PNT2258 (DNA-targeted Blocker of BCL2 Expression) in patients with advanced solid tumors. Eur J Cancer 48(Suppl 6):191. doi:10.1016/S0959-8049(12)72417-6
    1. 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
    1. Lightfoot HL, Hall J. Target mRNA inhibition by oligonucleotide drugs in man. Nucleic Acids Res. 2012;40(21):10585–10595. doi: 10.1093/nar/gks861.

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