A Phase I Study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in Adult Patients with Refractory or Metastatic Solid Malignancies

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2010 Jan 14

PMID 20068096

Citations 7

Authors

Susanne M Arnold

John J Rinehart

Eleftheria Tsakalozou

John R Eckardt

Scott Z Fields

Brent J Shelton

Philip A Desimone

Bryan K Kee

Jeffrey A Moscow

Markos Leggas

Affiliations

Soon will be listed here.

Abstract

Purpose: 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a novel third generation camptothecin selected for development based on the blood stability of its pharmacologically active lactone form and its high potency in preclinical models. Here, we report the initial phase I experience with i.v. AR-67 in adults with refractory solid tumors. EXPERIMENTAL DESIGN AND METHODS: AR-67 was infused over 1 hour daily five times, every 21 days, using an accelerated titration trial design. Plasma was collected on the 1st and 4th day of cycle 1 to determine pharmacokinetic parameters.

Results: Twenty-six patients were treated at nine dosage levels (1.2-12.4 mg/m(2)/d). Dose-limiting toxicities were observed in five patients and consisted of grade 4 febrile neutropenia, grade 3 fatigue, and grade 4 thrombocytopenia. Common toxicities included leukopenia (23%), thrombocytopenia (15.4%), fatigue (15.4%), neutropenia (11.5%), and anemia (11.5%). No diarrhea was observed. The maximum tolerated dosage was 7.5 mg/m(2)/d. The lactone form was the predominant species in plasma (>87% of area under the plasma concentration-time curve) at all dosages. No drug accumulation was observed on day 4. Clearance was constant with increasing dosage and hematologic toxicities correlated with exposure (P < 0.001). A prolonged partial response was observed in one subject with non-small cell lung cancer. Stable disease was noted in patients with small cell lung cancer, non-small cell lung cancer, and duodenal cancer.

Conclusions: AR-67 is a novel, blood-stable camptothecin with a predictable toxicity profile and linear pharmacokinetics. The recommended phase II dosage is 7.5 mg/m(2)/d five times every 21 days.

Citing Articles

Design and Synthesis of Mycophenolic Acid Analogues for Osteosarcoma Cancer Treatment.

Silalai P, Teeyakasem P, Pruksakorn D, Saeeng R ACS Bio Med Chem Au. 2025; 5(1):106-118.

PMID: 39990949 PMC: 11843339. DOI: 10.1021/acsbiomedchemau.4c00079.

Phytochemical-Based Nanomedicine for Advanced Cancer Theranostics: Perspectives on Clinical Trials to Clinical Use.

Dhupal M, Chowdhury D Int J Nanomedicine. 2020; 15:9125-9157.

PMID: 33244231 PMC: 7683832. DOI: 10.2147/IJN.S259628.

Population pharmacokinetic analysis of AR-67, a lactone stable camptothecin analogue, in cancer patients with solid tumors.

Tang F, Tsakalozou E, Arnold S, Ng C, Leggas M Invest New Drugs. 2019; 37(6):1218-1230.

PMID: 30820810 PMC: 6713628. DOI: 10.1007/s10637-019-00744-0.

The effect of breast cancer resistance protein, multidrug resistant protein 1, and organic anion-transporting polypeptide 1B3 on the antitumor efficacy of the lipophilic camptothecin 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) in vitro.

Tsakalozou E, Adane E, Kuo K, Daily A, Moscow J, Leggas M Drug Metab Dispos. 2013; 41(7):1404-13.

PMID: 23620484 PMC: 3684821. DOI: 10.1124/dmd.112.050021.

Pharmacokinetic modeling to assess factors affecting the oral bioavailability of the lactone and carboxylate forms of the lipophilic camptothecin analogue AR-67 in rats.

Adane E, Liu Z, Xiang T, Anderson B, Leggas M Pharm Res. 2011; 29(7):1722-36.

PMID: 22068278 DOI: 10.1007/s11095-011-0617-0.

References

Burke T, Mishra A, Wani M, Wall M . Lipid bilayer partitioning and stability of camptothecin drugs. Biochemistry. 1993; 32(20):5352-64. DOI: 10.1021/bi00071a010. View

van Riel J, van Groeningen C, Kedde M, Gall H, Leisink J, Gruia G . Continuous administration of irinotecan by hepatic arterial infusion: a phase I and pharmacokinetic study. Clin Cancer Res. 2002; 8(2):405-12. View

Miller A, Herndon 2nd J, Gu L, Green M . Phase II trial of karenitecin in patients with relapsed or refractory non-small cell lung cancer (CALGB 30004). Lung Cancer. 2005; 48(3):399-407. DOI: 10.1016/j.lungcan.2004.11.019. View

Crews K, Stewart C, Jones-Wallace D, Thompson S, Houghton P, Heideman R . Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy. Clin Cancer Res. 2002; 8(7):2202-9. View

Bom D, Curran D, Chavan A, Kruszewski S, Zimmer S, Fraley K . Novel A,B,E-ring-modified camptothecins displaying high lipophilicity and markedly improved human blood stabilities. J Med Chem. 1999; 42(16):3018-22. DOI: 10.1021/jm9902279. View

Zhu A, Ready N, Clark J, Safran H, Amato A, Salem N . Phase I and pharmacokinetic study of gimatecan given orally once a week for 3 of 4 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009; 15(1):374-81. DOI: 10.1158/1078-0432.CCR-08-1024. View

Sparreboom A, van Tellingen O, Nooijen W, Beijnen J . Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res. 1996; 56(9):2112-5. View

Bom D, Curran D, Kruszewski S, Zimmer S, Thompson Strode J, Kohlhagen G . The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J Med Chem. 2000; 43(21):3970-80. DOI: 10.1021/jm000144o. View

Burke T, Mi Z . Ethyl substitution at the 7 position extends the half-life of 10-hydroxycamptothecin in the presence of human serum albumin. J Med Chem. 1993; 36(17):2580-2. DOI: 10.1021/jm00069a020. View

10.

Hertzberg R, Caranfa M, Holden K, Jakas D, Gallagher G, Mattern M . Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J Med Chem. 1989; 32(3):715-20. DOI: 10.1021/jm00123a038. View

11.

Ziomkowska B, Cyrankiewicz M, Kruszewski S . Determination of hydroxycamptothecin affinities to albumin and membranes by steady-state fluorescence anisotropy measurements. Comb Chem High Throughput Screen. 2007; 10(6):486-92. DOI: 10.2174/138620707781996420. View

12.

Horn J, Jordan S, Song L, Roberts M, Anderson B, Leggas M . Validation of an HPLC method for analysis of DB-67 and its water soluble prodrug in mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2006; 844(1):15-22. DOI: 10.1016/j.jchromb.2006.06.022. View

13.

Mi Z, Burke T . Differential interactions of camptothecin lactone and carboxylate forms with human blood components. Biochemistry. 1994; 33(34):10325-36. DOI: 10.1021/bi00200a013. View

14.

Zamboni W, Bowman L, Tan M, Santana V, Houghton P, Meyer W . Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors. Cancer Chemother Pharmacol. 1999; 43(6):454-60. DOI: 10.1007/s002800050923. View

15.

Burke T, Mi Z . Preferential binding of the carboxylate form of camptothecin by human serum albumin. Anal Biochem. 1993; 212(1):285-7. DOI: 10.1006/abio.1993.1325. View

16.

Staker B, Hjerrild K, Feese M, Behnke C, Burgin Jr A, Stewart L . The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A. 2002; 99(24):15387-92. PMC: 137726. DOI: 10.1073/pnas.242259599. View

17.

Bom D, Curran D, Zhang J, Zimmer S, Bevins R, Kruszewski S . The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity. J Control Release. 2001; 74(1-3):325-33. DOI: 10.1016/s0168-3659(01)00343-1. View

18.

Du W, Kaskar B, Blumbergs P, Curran D . Semisynthesis of DB-67 and other silatecans from camptothecin by thiol-promoted addition of silyl radicals. Bioorg Med Chem. 2003; 11(3):451-8. DOI: 10.1016/s0968-0896(02)00437-6. View

19.

Curran D, Josien H, Bom D, Gabarda A, Du W . The cascade radical annulation approach to new analogues of camptothecins. Combinatorial synthesis of silatecans and homosilatecans. Ann N Y Acad Sci. 2001; 922:112-21. DOI: 10.1111/j.1749-6632.2000.tb07030.x. View

20.

Basili S, Moro S . Novel camptothecin derivatives as topoisomerase I inhibitors. Expert Opin Ther Pat. 2009; 19(5):555-74. DOI: 10.1517/13543770902773437. View