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Rationale for Phase I Study of UFT Plus Leucovorin and Oral JM-216

Rationale for Phase I Study of UFT Plus Leucovorin and Oral JM-216

ABSTRACT: Both cisplatin (Platinol) and fluorouracil (5-FU) have demonstrated single-agent clinical efficacy in a variety of solid neoplasms. The combination of these agents has revealed synergistic cytotoxicity in models in vitro and in vivo, which may explain the clinical effectiveness of 5-FU-cisplatin regimens. UFT (tegafur and uracil) and bis-aceto-ammine-dichloro-cyclohexyl-amine platinum (IV) (JM-216) are novel oral analogues of 5-FU and cisplatin, respectively. In preclinical models, JM-216 has demonstrated equivalent cytotoxicity to cisplatin, while phase I trials suggest its dose-limiting toxicity is myelosuppression. In contrast to cisplatin, JM-216 has not demonstrated significant neurotoxicity or nephrotoxicity. UFT has been used extensively in Japan, where phase II data suggest disease response rates similar to single-agent 5-FU in colorectal, gastric, and breast carcinomas. Combination studies of prolonged administration UFT and single-dose cisplatin have shown efficacy, but also significant hematologic toxicity. We propose a phase I study of UFT and JM-216 administered daily over 14 consecutive days with leucovorin (90 mg/d). Ease of administration and continuous drug exposure are potential advantages of this regimen. Several disease specific investigations may be warranted given demonstrated feasibility in this phase I study.[ONCOLOGY 11(Suppl 10):26-29, 1997]


Introduction

Cisplatin (Platinol) and fluorouracil (5-FU) represent two broad-spectrum, high-efficacy antineoplastic agents. As such, they are widely used in solid tumor oncology. In combination regimens, cisplatin and 5-FU are active against refractory head and neck, lung, and gastric cancers and against squamous cell skin carcinomas. Preclinical models confirming a synergism between coadministered cisplatin and 5-FU support this broad clinical efficacy. In a human squamous cell carcinoma cell line (HST-1) model, Esaki et al[1] demonstrated synergistic cytotoxicity when 5-FU was administered 24 hours before cisplatin. The same investigators subsequently showed that 5-FU pretreatment enhances cisplatin cytotoxicity even in cell lines previously selected for cisplatin resistance.[2] In vivo HST-1 xenograft and primary murine colon tumor models have also substantiated the 5-FU/cisplatin sequence-dependent synergism.[3,4]

At least three different mechanisms of 5-FU/cisplatin synergism have been suggested in these preclinical investigations. Esaki et al[2] suggested that cisplatin resistance is linked to cellular glutathione levels, noting increased intracellular levels in resistance-selected lines. Glutathione levels were markedly reduced in 5-FU–pretreated cells, which were then highly susceptible to cisplatin.[2] 5-FU is known to modulate the repair of platinum–DNA adducts. 5-FU misincorporation into nuclear RNA may subsequently impair transcription of ERCC1, a nuclear enzyme critical to excisional repair of cisplatin-DNA adduct damage.[5] Using an ovarian cell line model, Scanlon et al[6] observed that cisplatin administered before 5-FU produced synergistic cytotoxicity. In this sequence, cisplatin notably increased intracellular reduced folate, thus enhancing 5-fluoro-2'-deoxyuridylate–deoxythymidine monophosphate (FdUMP-dTMP) synthase binding and 5-FU cytotoxicity.

Cisplatin and 5-FU therefore represent an efficacious combination regimen, based on both preclinical synergy and durable responses in various clinical studies. UFT and bis-aceto-ammine-dichloro-cyclohexyl-amine-platinum (IV) (JM-216) represent novel oral analogues of 5-FU and cisplatin, respectively. As discussed below, preclinical and phase I/II data for both single-agent UFT and JM-216 suggest efficacy, acceptable toxicity, and convenient administration. We therefore propose a phase I study of concomitantly administered UFT and JM-216.

Drug Formulations and Pharmacokinetics

UFT

UFT is a combined oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil, complexed in a 1:4 molar ratio. Fujii et al[7] noted that coadministration of uracil with tegafur significantly increased intratumoral levels of 5-FU. UFT is a prodrug, metabolized to the 5-FU by both hepatic cytochrome P-450 and the target tissues themselves.[8]

Anttila et al[9] examined the pharmacokinetics of tegafur after both oral and intravenous administration. Following an oral dose, distribution and elimination half-lives of 0.7 and 9.2 hours, respectively, were observed. The volume of distribution was essentially that of body water. Excellent oral bioavailability was observed, with an oral/intravenous area under the concentration-time curve ratio of 115 ± 8%.[9]

JM-216

JM-216 represents a unique platinum compound with excellent oral bioavailability. The chemical structure of JM-216 relative to cisplatin and carboplatin (Paraplatin) is depicted in Figure 1.[10] A phase I study examined the pharmacokinetics of single-dose JM-216 at doses ranging from 60 to 700 mg/m2.[11] Linear pharmacokinetics with only moderate interpatient variability were observed at doses £ 120 mg/m2. Absorption was notably saturable at doses exceeding 200 mg/m2, and pharmacokinetics demonstrated significant variability (coefficient of variance for maximum concentration, 21% to 63%; for area under the concentration-time curve, 26% to 63%). No hematologic or nonhematologic toxicities greater than grade 2 were noted at doses £ 200 mg/m2. In preclinical models, a single JM-216 dose was well distributed throughout liver, kidney, lung, skin, cardiac, and skeletal tissues.[12] The liver was the major tissue depot for single-dose JM-216 in this study; hepatic concentrations were more than fivefold greater than observed for equitoxic doses of intravenous cisplatin and carboplatin.[12]

Raynaud et al[13] have examined the biotransformation of JM-216 following a single oral administration. Quantitation by high-performance liquid chromatography and atomic absorption spectrophotometry (AA) revealed six biotransformation species. JM-118, JM-383, and JM-518 represent the major species, while virtually no parent JM-216 was present in ultrafiltrate obtained 20 minutes following drug administration. With ovarian carcinoma cell lines, JM-118 was identified as the major cytotoxic species.[13]

Preclinical, Phase I and II Studies: JM-216 and UFT as Single Agents

JM-216

In preclinical studies, JM-216 has displayed cytotoxicity equal or superior to cisplatin and carboplatin. Kelland et al[14] noted similar median inhibiting concentration cytotoxicity between JM-216 and cisplatin in seven ovarian carcinoma cell lines. JM-216 retained cytotoxicity in vitro against ovarian, testicular, and cervical cisplatin-resistant cell lines. Compared with equitoxic dosages of cisplatin, carboplatin, and tetraplatin (Ormaplatin), JM-216 maintained equal or superior activity against murine plasmacytoma and ovarian xenograft models in vivo.[14] JM-216 efficacy in cisplatin-resistant cervical carcinoma cell lines was correlated with the increased intracellular accumulation of JM-216.[15] In contrast to other platinum derivatives, a schedule-dependent effect is suggested for JM-216.[16] In ADJ/PC6 plasmacytoma and ovarian xenograft models, a superior therapeutic index was noted when JM-216 was administered for 5 days.

Raynaud et al[17] have examined the 5-consecutive day schedule in a phase I trial. A maximum tolerated dose of 140 mg/m2/day × 5 was observed in therapy-naive patients. Neutropenia and thrombocytopenia were the observed dose-limiting toxicities. A 14-consecutive-day schedule has been examined by Pagani et al.[18] Thirty-three patients were treated at doses ranging from 10 to 45 mg/m2/day. One grade 3 neutropenia and two grade 4 thrombocytopenias were noted among seven patients treated at the 40 mg/m2/day dose level. Nadirs were noted 4 and 5 weeks after treatment, consistent with the prolonged terminal half-life of this platinum species.[18] Significant cardiac, pulmonary, renal, or neurologic toxicities were not observed.[18]

Groen et al[19] conducted a phase II study of single-agent JM-216 in therapy-naive patients with small cell lung cancer. At a dosage of 120 to 140 mg/m2/day ×5, a 31% response rate was noted without significant renal toxicity or neurotoxicity. Phase II studies in patients with refractory ovarian, cervical, or prostate cancer are currently accruing participants at multiple investigation sites.

UFT

As extensive preclinical and clinical data exist for single-agent UFT, our discussion will be limited to phase I studies with relevant administration schedules and selected phase II data. Meropol et al[20] examined 28-day UFT administration with concomitant leucovorin (150 mg/day in three divided doses). Previously untreated patients experienced dose-limiting diarrhea, nausea, and emesis at doses exceeding 350 mg/m2/day in three divided doses.[20] Saltz et al[21] evaluated a 28-day schedule with concomitant low-dose leucovorin (15 mg/day), and demonstrated acceptable toxicity at UFT doses of 350 mg/m2/day in three divided doses.[21] Fourteen-day UFT administration schedules are currently being investigated.

A phase II, 28-day UFT study (300 to 350 mg/m2/day) in previously untreated patients with colon carcinoma revealed a response rate of 42%.[22] Ota et al[23] reported phase II response data for patients with several advanced solid tumors given UFT bid or tid at doses ranging from 300 to 600 mg/d. Response rates ranged from 25% to 32% in patients with colorectal cancer, cholangiocarcinoma, gastric cancer, or breast cancer.

Combined Clinical Experience with Cisplatin and UFT

Various combination trials using oral UFT in combination with cisplatin have been conducted. In non–small-cell lung cancer, UFT has been administered over 14 and 21 days with single-dose cisplatin.[24,25] Feliu et al[24] noted a response rate of 12% with UFT 390 mg/m2/day ×14 days, but significant hematologic toxicities necessitated dose reduction in 17 of 25 patients. [24] Ichinose et al[25] noted a 35% response rate in therapy-naive patients treated bid with UFT 400 mg/m2/day × 21 days, combined with single-dose cisplatin. Grade 4 myelosuppression was noted in two (6%) of 31 patients. UFT was studied in combination with cisplatin in an etoposide (VePesid)/doxorubicin (Adriamycin)/cisplatin regimen by Hayakawa et al.[26] Patients with advanced gastric carcinoma received UFT 400 mg/m2/day × 28 days with weekly etoposide, doxorubicin, and cisplatin. An overall response rate of 47% was observed, although toxicities were substantial (grade 3 or greater leukopenia in 44.1% of patients).[26]

Overview: Combination UFT and JM-216

Our planned phase I study will determine the feasibility and maximally tolerated doses of concomitantly administered oral UFT and JM-216. To maximize synergism, JM-216 will be administered each day with UFT over a 14-day interval. Pagani et al[18] have demonstrated the feasibility of JM-216 administration over this protracted schedule. A maximum tolerated dose of 40 mg/m2/day was noted by these investigators; 40 mg/m2/day ×14 will thus be employed as the maximal JM-216 dose in our combination study.

The combination maximum tolerated doses for UFT and JM-216 will be determined by the dose escalation schema outlined in Table 1. At all dose levels, 90 mg/day leucovorin (30 mg tid × 14 days) will be administered with UFT. Frequent objective assessments for gastrointestinal and hematologic toxicities will be undertaken throughout the study period.

Phase II Applications

Both platinum and 5-FU are widely used to treat gastric and head and neck carcinomas. Patient convenience and continuous-exposure pharmacokinetics represent potential advantages of an all-oral regimen for these carcinomas. Preliminary single-agent JM-216 phase II data are encouraging for refractory prostate, ovarian, and cervical carcinomas. Potentiation of JM-216 cytotoxicity with combined UFT administration may therefore have phase II applications in these solid tumors. The radiosensitizing effects of continuous infusion 5-FU are established in head and neck, pancreatic, bladder, and anal carcinomas. A regimen of concomitant oral UFT/JM-216 and radiation may therefore deserve investigation in these clinical settings.

References

1. Esaki T, Nakano S, Tatsumoto T, et al: Inhibition by 5-fluorouracil of cis-diamminedichloroplatinum (II) induced DNA interstrand cross-link removal in a HST-1 human squamous carcinoma cell line. Cancer Res 52:6501-6506, 1992.

2. Esaki T, Nakano S, Matsumoto N, et al: Schedule-dependent reversion of acquired cisplatin resistance by 5-fluorouracil in a newly established cisplatin-resistant HST-1 human squamous carcinoma cell line. Int J Cancer 65:479-484, 1996.

3. Kuroki M, Nakano S, Mitsugi K, et al: In vivo comparative therapeutic study of optimal administration of 5-fluorouracil and cisplatin using a newly established HST-1 human squamous-carcinoma cell line. Cancer Chemother Pharmacol 29:273-276, 1992.

4. Pratesi G, Gianni L, Manzotti C, et al: Sequence dependence of the antitumor and toxic effects of 5-fluorouracil and cis-diamminedichloroplatinum combination on primary colon tumors in mice. Cancer Chemother Pharmacol 21:237-240, 1988.

5. Dabholker M, Vionnet J, Bostick-Bruton F, et al: Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Invest 94:703-708, 1994.

6. Scanlon KJ, Newman EM, Lu Y, et al: Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci U S A 83:8923-8925, 1986.

7. Fujii S, Ikenaka K, Fukushima M, et al: Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil. Jpn J Cancer Res 69:763-772, 1978.

8. Au JL, Sadee W: Activation of Ftorafur to 5-fluorouracil and gamma-butyrolactone. Cancer Res 40:2814-2819, 1980.

9. Anttila MI, Sotaniemi EA, Kairaluoma MI, et al: Pharmacokinetics of Ftorafur after intravenous and oral administration. Cancer Chemother Pharmacol 10:150-153, 1983.

10. MeKeage MJ: Comparative adverse effect profiles of platinum drugs. Drug Safety 13:228-244, 1995.

11. McKeage MJ, Mistry P, Ward J, et al: A phase I and pharmacology study of an oral platinum complex, JM-216: Dose-dependent pharmacokinetics with single dose administration. Cancer Chemother Pharmacol 36:451-458, 1995.

12. McKeage MJ, Morgan SE, Boxall FE, et al: Preclinical toxicology and tissue platinum distribution of novel oral antitumor platinum complexes: Ammine/amine platinum (IV) dicarboxylates. Cancer Chemother Pharmacol 33:497-503, 1994.

13. Raynaud FI, Mistry P, Donaghue A, et al: Biotransformation of the platinum drug JM-216 following oral administration to cancer patients. Cancer Chemother Pharmacol 38:155-162, 1996.

14. Kelland LR, Abel G, McKeage MJ, et al: Preclinical antitumor evaluation of bis-aceto-ammine-dichloro-cyclo-hexylamine platinum (IV): An orally active platinum drug. Cancer Res 53:2581-2586, 1993.

15. Mellish KJ, Kelland LR, Harrap KR: In vitro platinum drug chemosensitivity of human cervical squamous cell carcinoma cell lines with intrinsic and acquired resistance to cisplatin. Br J Cancer 68:240-250, 1993.

16. McKeage MJ, Kelland LR, Boxall FE, et al: Schedule dependency of orally administered bis-aceto-ammine-dichlorocyclohexylamine-platinum, (IV) in vivo. Cancer Res 54:4118-4122, 1994.

17. McKeage MJ, Raynaud F, Ward J, et al: Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer. J Clin Oncol 15:2691-2700, 1997.

18. Pagani O, Bauer J, Bomer M, et al: Phase I study of the oral platinum derivative JM-216 given daily for 14 days (abstract). 21st Congress ESMO, November 1-5, 1996.

19. Groen HJM, Smit EF, Bauer J, et al: A phase II study of oral platinum JM-216 as first-line treatment in small cell lung cancer (abstract). Proc Am Soc Clin Oncol 15:1128, 1996.

20. Meropol NJ, Rustum YM, Petrelli NJ, et al: A phase I and pharmacokinetic study of oral uracil, Ftorafur, and leucovorin in patients with advanced cancer. Cancer Chemother Pharmacol 37:581-586, 1996.

21. Saltz LB, Leichman CG, Young CW, et al: A fixed-ratio combination of uracil and Ftorafur (UFT) with low dose leucovorin: An active oral regimen for advanced colon cancer. Cancer 75:782-785, 1995.

22. Pazdur R, Lassere Y, Rhodes V, et al: Phase II trial of uracil and tegafur plus oral leucovorin: An effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol 12:2296-2300, 1994.

23. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmacol 22:333-338, 1988.

24. Feliu J, Gonzalez-Baron M, Espinosa E, et al: Cisplatin and UFT modulated with leucovorin for the treatment of advanced non-small cell lung cancer. Am J Clin Oncol 19:121-124, 1996.

25. Ichinose Y, Takanashi N, Yano T, et al: A phase II trial of oral tegafur and uracil plus cisplatin in patients with inoperable non-small cell lung cancer. Cancer 75:2677-2680, 1995.

26. Hayakawa M, Morise K, Chin K, et al: Combination chemotherapy with tegafur-uracil (UFT) etoposide, Adriamycin and cisplatin (UFT-EAP) for advanced gastric cancer. Jpn J Clin Oncol 24:282-288, 1994.

 
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