Phase I study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients

T C Chang, H S Shiah, C H Yang, K H Yeh, A L Cheng, B N Shen, Y W Wang, C G Yeh, N J Chiang, J Y Chang, L T Chen, T C Chang, H S Shiah, C H Yang, K H Yeh, A L Cheng, B N Shen, Y W Wang, C G Yeh, N J Chiang, J Y Chang, L T Chen

Abstract

Purpose: To define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02, a novel liposome-encapsulated irinotecan, in patients with advanced refractory solid tumors.

Methods: Patients were enrolled in cohorts of one to three to receive escalating dose of PEP02 in a phase I trial. PEP02, from 60 to 180 mg/m(2), was given as a 90-min intravenous infusion, every 3 weeks.

Results: A total of 11 patients were enrolled into three dose levels: 60 (one patient), 120 (six patients) and 180 mg/m(2) (four patients). DLT was observed in three patients, one at 120 mg/m(2) (grade 3 catheter-related infection) and two at 180 mg/m(2) (grade 4 neutropenia lasting for >3 days in one, grade 4 hematological toxicities and grade 4 diarrhea in the other). MTD was determined as 120 mg/m(2). Comparing with those after free-form irinotecan in the literature, the dose-normalized PK of SN-38 (the active metabolite) after PEP02 was characterized by lower C max, prolonged terminal half-life and higher AUC but with significant inter-individual variation. One patient who died of treatment-related toxicity had significantly higher C max and AUC levels of SN-38 than those of the other three patients at 180 mg/m(2). Post hoc pharmacogenetic study showed that the patient had a combined heterozygosity genotype of UGT1A1*6/*28. Two patients had objective tumor response.

Conclusions: PEP02 apparently modified the PK parameters of irinotecan and SN-38 by liposome encapsulation. The MTD of PEP02 monotherapy at 3-week interval is 120 mg/m(2), which will be the recommended dose for future studies.

Figures

Fig. 1
Fig. 1
Plasma concentration–time profiles of a encapsulated CPT-11 (PEP02) and b SN-38 at 60, 120 and 180 mg/m2 dose level of PEP02
Fig. 2
Fig. 2
Plasma concentration–time profiles of encapsulated CPT-11 (PEP02) and total CPT-11 at 120 mg/m2 dose level of PEP02
Fig. 3
Fig. 3
Plasma concentration–time profiles of a total CPT-11 and b SN-38 in subjects at 180 mg/m2 dose level of PEP02

References

    1. Costin D, Potmesil M. Preclinical and clinical development of camptothecins. Adv Pharmacol. 1994;29B:51–72. doi: 10.1016/S1054-3589(08)61131-X.
    1. Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest. 1998;101:847–854. doi: 10.1172/JCI915.
    1. Zamboni WC, Jung LL, Egorin MJ, Hamburger DR, Joseph E, Jin R, Strychor S, Ramanathan RK, Eiseman JL. Relationship between plasma exposure of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite and antitumor response in mice bearing human colon carcinoma xenografts. Clin Cancer Res. 2005;11:4867–4874. doi: 10.1158/1078-0432.CCR-05-0144.
    1. Drummond DC, Noble CO, Guo Z, Hong K, Park JW, Kirpotin DB. Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Cancer Res. 2006;66:3271–3277. doi: 10.1158/0008-5472.CAN-05-4007.
    1. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997;89:1138–1147. doi: 10.1093/jnci/89.15.1138.
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Glabbeke MV, Oosterom ATV, Christian MC, Gwyther SG, European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205–216. doi: 10.1093/jnci/92.3.205.
    1. Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413–1418. doi: 10.1016/S0140-6736(98)02309-5.
    1. Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003;21:807–814. doi: 10.1200/JCO.2003.08.058.
    1. Rowinsky EK, Grochow LB, Ettinger DS, Sartorius SE, Lubejko BG, Chen TL, Rock MK, Donehower RC. Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11) administered as a ninety-minute infusion every 3 weeks. Cancer Res. 1994;54:427–436.
    1. Harel M, Hyatt JL, Brumshtein B, Morton CL, Yoon KJ, Wadkins RM, Silman I, Sussman JL, Potter PM. The crystal structure of the complex of the anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica acetylcholinesterase provides a molecular explanation for its cholinergic action. Mol Pharmacol. 2005;67:1874–1881. doi: 10.1124/mol.104.009944.
    1. Blandizzi C, De Paolis B, Colucci R, Lazzeri G, Baschiera F, Del Tacca M. Characterization of a novel mechanism accounting for the adverse cholinergic effects of the anticancer drug irinotecan. Br J Pharmacol. 2001;132:73–84. doi: 10.1038/sj.bjp.0703766.
    1. Rothenberg ML, Kuhn JG, Burris HA, 3rd, Nelson J, Eckardt JR, Tristan-Morales M, Hilsenbeck SG, Weiss GR, Smith LS, Rodriguez GI. Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol. 1993;11:2194–2204.
    1. Rivory LP, Haaz MC, Canal P, Lokiec F, Armand JP, Robert J. Pharmacokinetic interrelationships of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials. Clin Cancer Res. 1997;3:1261–1266.
    1. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Elferink RP, Chowdhury NR. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med. 1995;333:1171–1175. doi: 10.1056/NEJM199511023331802.
    1. Palomaki GE, Bradley LA, Douglas MP, Kolor K, Dotson WD. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan: an evidence-based review. Genet Med. 2009;11:21–34. doi: 10.1097/GIM.0b013e31818efd77.
    1. Camptosar brand of irinotecan hydrochloride injection [package insert]. Pfizer, 2012
    1. Araki K, Fujita K, Ando Y, Nagashima F, Yamamoto W, Endo H, Miya T, Kodama K, Narabayashi M, Sasaki Y. Pharmacogenetic impact of polymorphisms in the coding region of the UGT1A1 gene on SN-38 glucuronidation in Japanese patients with cancer. Cancer Sci. 2006;97:1255–1259. doi: 10.1111/j.1349-7006.2006.00321.x.
    1. Minami H, Sai K, Saeki M, Saito Y, Ozawa S, Suzuki K, Kaniwa N, Sawada J, Hamaguchi T, Yamamoto N, Shirao K, Yamada Y, Ohmatsu H, Kubota K, Yoshida T, Ohtsu A, Saijo N. Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. Pharmacogenet Genomics. 2007;17:497–504. doi: 10.1097/FPC.0b013e328014341f.
    1. Infante JR, Keedy VL, Jones SF, Zamboni WC, Chan E, Bendell JC, Lee W, Wu H, Ikeda S, Kodaira H, Rothenberg ML, Burris HA., III Phase I and pharmacokinetic study of IHL-305 (PEGylated liposomal irinotecan) in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2012;5:699–705. doi: 10.1007/s00280-012-1960-5.
    1. Kraut EH, Fishman MN, Lorusso PM, Gordon MS, Rubin EH, Haas A, Fetterly GJ, Cullinan P, Dul JL, Steinberg JL (2005) Final results of a phase I study of liposome encapsulated SN-38 (LE-SN38): safety, pharmacogenomics, pharmacokinetics, and tumor response [abstract 2017]. ASCO annual meeting
    1. Ocean AJ, Niedzwiecki D, Atkins JN, Parker B, O’Neil BH, Lee JW, Wadler S, Goldberg RM (2008) LE-SN38 for metastatic colorectal cancer after progression on oxaliplatin: results of CALGB 80402 [abstract 4109]. ASCO annual meeting

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe