Preclinical analyses and phase I evaluation of LY2603618 administered in combination with Pemetrexed and cisplatin in patients with advanced cancer
- 941 Downloads
LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122) and NCI-H441 (H441) xenograft tumors. These data informed the clinical assessment of LY2603618 in a seamless phase I/II study, which administered pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) and escalating doses of LY2603618: 130–275 mg. Patients were assessed for safety, toxicity, and pharmacokinetics. In phase I, 14 patients were enrolled, and the most frequently reported adverse events included fatigue, nausea, pyrexia, neutropenia, and vomiting. No DLTs were reported at the tested doses. The systemic exposure of LY2603618 increased in a dose-dependent manner. Pharmacokinetic parameters that correlate with the maximal pharmacodynamic effect in nonclinical xenograft models were achieved at doses ≥240 mg. The pharmacokinetics of LY2603618, pemetrexed, and cisplatin were not altered when used in combination. Two patients achieved a confirmed partial response (both non-small cell lung cancer), and 8 patients had stable disease. LY2603618 administered in combination with pemetrexed and cisplatin demonstrated an acceptable safety profile. The recommended phase II dose of LY2603618 was 275 mg.
KeywordsCHK1 Cancer LY2603618 Cell cycle Lung cancer Pharmacokinetics
The authors acknowledge Justin Meyer, Rita Bowers and Lisa Green at Covance Laboratory for their help with the flow cytometry, Ignacio Garcias-Ribas and Eric Westin for their contributions to the CHK1 clinical program, and Suzanne R.L. Young of Eli Lilly and Company for writing assistance.
Conflict of interest
M.S. reports the following: Advisory Board: Lilly, Boehringer Ingelheim, Pfizer, TEVA Lectures: Novartis, Roche, Pfizer, Abbott, Amgen, Lilly, Boehringer Ingelheim. E.K. is an employee of inVentiv HealthClinical.
M.M., V.C., U.O., S.M.H., H.B.D., D.B., F.F.M., L.H., L.K., P.I., and A.B.L. are all employees and shareholders of Eli Lilly and Company.
This study was conducted in accordance with applicable laws and regulations, GCPs, and the ethical principles that have their origin in the Declaration of Helsinki.
- 3.Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C (2012) Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 13(3):247–255CrossRefPubMedGoogle Scholar
- 4.Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clini Oncol 26(21):3543–3551CrossRefGoogle Scholar
- 6.Shepherd FA, Dancey J, Arnold A, Neville A, Rusthoven J, Johnson RD, Fisher B, Eisenhauer E (2001) Phase II study of Pemetrexed disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced nonsmall cell lung carcinoma: a study of the national cancer institute of Canada clinical trials group. Cancer 92(3):595–600CrossRefPubMedGoogle Scholar
- 8.Karnitz LM, Flatten KS, Wagner JM, Loegering D, Hackbarth JS, Arlander SJ, Vroman BT, Thomas MB, Baek YU, Hopkins KM, Lieberman HB, Chen J, Cliby WA, Kaufmann SH (2005) Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival. Mol Pharmacol 68(6):1636–1644PubMedGoogle Scholar
- 9.Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA, Elledge SJ (2000) Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev 14(12):1448–1459PubMedCentralPubMedGoogle Scholar
- 15.Kortmansky J, Shah MA, Kaubisch A, Weyerbacher A, Yi S, Tong W, Sowers R, Gonen M, O’Reilly E, Kemeny N, Ilson DI, Saltz LB, Maki RG, Kelsen DP, Schwartz GK (2005) Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with Fluorouracil in patients with advanced solid tumors. J Clin Oncol 23(9):1875–1884CrossRefPubMedGoogle Scholar
- 16.Lara PN Jr, Mack PC, Synold T, Frankel P, Longmate J, Gumerlock PH, Doroshow JH, Gandara DR (2005) The cyclin-dependent kinase inhibitor UCN-01 plus cisplatin in advanced solid tumors: a California cancer consortium phase I pharmacokinetic and molecular correlative trial. Clin Cancer Res 11(12):4444–4450CrossRefPubMedGoogle Scholar
- 17.Blasina A, Hallin J, Chen E, Arango ME, Kraynov E, Register J, Grant S, Ninkovic S, Chen P, Nichols T, O’Connor P, Anderes K (2008) Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1. Mol Cancer Ther 7(8):2394–2404CrossRefPubMedGoogle Scholar
- 20.Morgan MA, Parsels LA, Zhao L, Parsels JD, Davis MA, Hassan MC, Arumugarajah S, Hylander-Gans L, Morosini D, Simeone DM, Canman CE, Normolle DP, Zabludoff SD, Maybaum J, Lawrence TS (2010) Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. Cancer Res 70(12):4972–4981PubMedCentralCrossRefPubMedGoogle Scholar
- 21.Tse AN, Rendahl KG, Sheikh T, Cheema H, Aardalen K, Embry M, Ma S, Moler EJ, Ni ZJ, Lopes de Menezes DE, Hibner B, Gesner TG, Schwartz GK (2007) CHIR-124, a novel potent inhibitor of Chk1, potentiates the cytotoxicity of topoisomerase I poisons in vitro and in vivo. Clini Cancer Res 13(2 Pt 1):591–602CrossRefGoogle Scholar
- 22.Walton MI, Eve PD, Hayes A, Valenti M, De Haven BA, Box G, Boxall KJ, Aherne GW, Eccles SA, Raynaud FI, Williams DH, Reader JC, Collins I, Garrett MD (2010) The preclinical pharmacology and therapeutic activity of the novel CHK1 inhibitor SAR-020106. Mol Cancer Ther 9(1):89–100CrossRefPubMedGoogle Scholar
- 23.Zabludoff SD, Deng C, Grondine MR, Sheehy AM, Ashwell S, Caleb BL, Green S, Haye HR, Horn CL, Janetka JW, Liu D, Mouchet E, Ready S, Rosenthal JL, Queva C, Schwartz GK, Taylor KJ, Tse AN, Walker GE, White AM (2008) AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Mol Cancer Ther 7(9):2955–2966CrossRefPubMedGoogle Scholar
- 25.Bartucci M, Svensson S, Romania P, Dattilo R, Patrizii M, Signore M, Navarra S, Lotti F, Biffoni M, Pilozzi E, Duranti E, Martinelli S, Rinaldo C, Zeuner A, Maugeri-Sacca M, Eramo A, De Maria R (2012) Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy. Cell Death Differ 19(5):768–778PubMedCentralCrossRefPubMedGoogle Scholar
- 26.Gadhikar MA, Sciuto MR, Ortega Alves MV, Pickering CR, Osman AA, Neskey DM, Zhao M, Fitzgerald AL, Myers JN, Frederick MJ (2013) Chk1/2 inhibition overcomes the cisplatin resistance of head and neck cancer cells secondary to the loss of functional p53. Mol Cancer Ther 12(9):1860–1873PubMedCentralCrossRefPubMedGoogle Scholar
- 29.King C, Diaz H, Barnard D, Barda D, Clawson D, Blosser W, Cox K, Guo S, Marshall M (2013) Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Investigational New DrugsGoogle Scholar
- 30.Marshall M, Barda D, Barnard D, Cox K, Diaz HB, King C, Nutter S, Westin E (2009) Characterization and preclinical development of LCI-1, a selective and potent Chk1 inhibitor in phase 1 clinical trials. Mol Cancer Ther (presented) 8 (B248) Google Scholar
- 31.Weiss GJ, Donehower RC, Iyengar T, Ramanathan RK, Lewandowski K, Westin E, Hurt K, Hynes SM, Anthony SP, McKane S (2013) Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer. Investig New Drugs 31(1):136–144CrossRefGoogle Scholar
- 32.Cristy M, Eckerman K (1987) Specific absorbed fractions of energy at various ages from internal photon sources. I. Methods. ORNL/TM-8381 V 1:1987Google Scholar
- 33.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, national cancer institute of the united states, national cancer institute of Canada. J Natl Cancer Inst 92(3):205–216CrossRefPubMedGoogle Scholar
- 35.Chen VJ, Bewley JR, Andis SL, Schultz RM, Iversen PW, Shih C, Mendelsohn LG, Seitz DE, Tonkinson JL (1998) Preclinical cellular pharmacology of LY231514 (MTA): a comparison with methotrexate, LY309887 and raltitrexed for their effects on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Br J Cancer 78(Suppl 3):27–34PubMedCentralCrossRefPubMedGoogle Scholar