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Phase I Trial of Oral 2'-Deoxy-2'-methylidenecytidine: On a Daily x 14-day Schedule¹

Department of Internal Medicine, Osaka Prefectural Habikino Hospital, Osaka 583-8588 [N. M., K. M.]; Department of Internal Medicine, Kinki University School of Medicine, Osaka 589-0014 [N. Y., T. N., K. N., M. F.]; Department of Respiratory Disease, Osaka City General Hospital, Osaka 534-0021 [S. Neg., K. T., N. T.]; 1st Department of Internal Medicine, Osaka City University School of Medicine, Osaka 545-0051 [M. Y., S. K.]; and Pharmaceutical Development Division, Nippon Roche K. K., Tokyo 105-8532, Japan [T. O., S. Nem., K. O., H. M., S. Ni.]

	ABSTRACT

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2'-deoxy-2'-methylidenecytidine (DMDC) is a potent deoxycytidine analogue. Preclinical studies of DMDC demonstrated activity against a variety of murine and human tumors in cell cultures and murine models and indicate enhanced antitumor activity of DMDC when it was administered in a manner that provided prolonged systemic exposure. In view of this observation, this study was designed to determine the toxicities, maximum-tolerated dose, and pharmacokinetic profile of DMDC. DMDC was given p.o. under fasting conditions for 14 consecutive days every 4 weeks in patients with advanced solid tumors. The starting dose was 12 mg/m²/day. Pharmacokinetic studies were carried out on days 1 and 14 of the first cycle. Fourteen patients received 22 courses of DMDC. The dose-limiting toxicities were anorexia, leukopenia, thrombocytopenia, and anemia. General fatigue was the common nonhematological toxicity. The maximum-tolerated dose was 18 mg/m²/day, at which two of six patients developed grade 3 toxicities. This dose level could also be considered for Phase II testing with this schedule. At the 18-mg/m²/day dose level, the mean terminal half-life, maximum plasma concentration (C_max), the area under the plasma drug concentration-time curve (AUC_0-) on day 1 were 1.7496 h, 112.9 ng/ml, and 399.8 ng·h/ml, respectively. Forty to 50% of the administered dose was recovered in the urine, indicating a good bioavailability and resulting significant systemic exposure to the drug, which may enable chronic oral treatment.

	INTRODUCTION

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DMDC³ , synthesized by Dr. K. Takenuki et al. (1) , is a novel deoxycytidine analogue with structural similarity to ara-C and gemcitabine (Fig. 1) . DMDC is activated by deoxycytidine kinase to the diphosphate and triphosphate metabolites. DMDC triphosphate inhibits human DNA polymerases with resultant inhibition of additional elongation of DNA (2 , 3) . DMDC diphosphate inhibits ribonucleotide reductase, which is a key enzyme involved in DNA synthesis and, therefore, a potential target for cancer chemotherapy (2 , 4) .

View larger version (16K): [in this window] [in a new window]   Fig. 1. Chemical structure of 2'-deoxy-2'-methylidenecytidine dihydrate (DMDC).

In contrast to gemcitabine and ara-C, which are susceptible to cytidine deaminase, DMDC is highly resistant, so that it is minimally converted to an inactive metabolite, DMDU (1 , 6) . In tumors with high cytidine deaminase activity, the enzyme converts 2'-deoxycytidine to 2'-deoxyuridine and lowers intracellular 2'-deoxycytidine concentrations. Because 2'-deoxycytidine competitively inhibits the activation of DMDC by deoxycytidine kinase, DMDC is phosphorylated more effectively because of the decreased level of intracellular 2'-deoxycytidine. DMDC was highly effective in human cancer xenograft models with high levels of cytidine deaminase activity, whereas gemcitabine was less effective in such tumors (7 , 8) . These features distinguish DMDC from other deoxycytidine analogues such as ara-C and gemcitabine. Therefore, non-small cell lung cancer, colon cancer, esophageal cancer, pancreas cancer, and cervical cancer, which show high cytidine deaminase activity, seem to be rational targets for therapy with DMDC.

Preclinical features of DMDC were high potency, a broad spectrum of antitumor activity against murine tumors as well as the xenografts of human tumors in nude mice, and increased activity with prolonged exposure (5 , 7) . The availability of a p.o. active drug would provide significant advantages for administration of chronic dosing regimens and the opportunity for cost-effective outpatient treatment. These data led to the selection of an oral daily schedule for 14 consecutive days for the clinical trial.

The objectives of this Phase I study were (a) to determine the maximum tolerated dose of DMDC on this schedule; (b) to describe and quantify the clinical toxicities; (c) to determine the pharmacokinetics of DMDC and DMDU and to evaluate whether there is a relationship between pharmacokinetic parameters and clinical toxicities; and (d) to obtain preliminary evidence of therapeutic activity in patients with advanced solid tumors.

	PATIENTS AND METHODS

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Patient Selection.
Patients were enrolled in this study if they met the following criteria: histological or cytological evidence of a malignant solid tumor that was no longer amenable to established forms of treatment or for which no such standard therapy exists; no therapy within 4 weeks before entry (within 6 weeks for nitrosourea or mitomycin C); no whole blood, blood constituent transfusions, or administration of hematopoietic factors, including recombinant human granulocyte colony-stimulating factor within 2 weeks before enrollment; life expectancy of at least 12 weeks; age of 20–74 years; performance status of 2 by the Eastern Cooperative Oncology Group scale; adequate bone marrow function (leukocyte count, 4,000–120,000/µl; granulocyte count, 2,000/µl; platelet count, 100,000/µl; and hemoglobin concentration, 10.0 g/dl), normal hepatic function (bilirubin, 1.5 mg/dl; transaminases, 2.5 x upper limit of normal), and renal function (creatinine, 1.5 mg/dl; serum uric acid, 1.25 x upper limit of normal; and serum calcium, 11.5 mg/dl); free of any concurrent active malignancy; no medical problem sufficiently severe to prevent compliance with the study requirements or that exposes the patients to excessive risk; and informed consent of the patient. Patients were ineligible if they had a history of congestive heart failure (cases rated as New York Heart Association Functional Classification of grade III or IV) or acute myocardial infarction within the previous 6 months; had a history of drug allergy; had a diagnosis of serious obstructive pulmonary disease; were lactating or pregnant women or those willing to be pregnant; had a history of gastrointestinal disorders or kidney diseases assumed to influence the pharmacokinetics of the investigational product; had a history of hepatocellular carcinoma or hepatitis B (hepatitis B antigen-positive) or hepatitis C (hepatitis C virus antibody-positive); not willing to use contraception; had a history of organ allografts (except autologous bone marrow transplant); were treated with other investigational drugs within 6 weeks before the initiation of this study; had symptomatic brain metastases; had massive pleural effusion or ascitic fluid; and had serious infectious diseases including HIV infection. Patients receiving systemic corticosteroid therapy were also ineligible. The study was approved in advance by the Institutional Review Board and by the Hospital Ethics Committee.

Drug Formulation and Administration.
DMDC was supplied by Nippon Roche Co., Ltd. (Tokyo, Japan) as light-red, film-coated tablets containing 5 and 20 mg of product. Patients received once daily oral DMDC for 14 consecutive days 1 h before breakfast, followed by a 14-day rest period. Because the smallest DMDC tablet size available was 5 mg, it was necessary to make some approximations in the calculated daily dose. For example, if the patient, whose body surface area was from 1.25 to 1.66 m², should be treated at 12 mg/m²/day, the drug was administered at 15 mg/day for 14 days.

Study Design.
A starting dose of 12 mg/m²/day, corresponding to one-third of the oral dose at which there was no observable adverse event in monkeys in the 4-week toxicity study (9) , was used. Then the dose was planned to be increased in increments of 6 mg/m² for successive patient cohorts until the MTD was reached, and at least three patients were to be included at each dose level (see Table 2 ). The MTD was defined as the dose causing grade 3–4 adverse reactions (grade 4 in case of granulocytopenia) in two or more of six patients (or two or more of three patients). No intrapatient dose escalation was allowed in this trial.

Pharmacokinetics.
Pharmacokinetic studies were performed during the first cycle. Heparinized blood samples (3 ml) for the pharmacokinetic study were obtained before and at 30 and 60 min as well as 2, 3, 4, 5, 6, 8, 12, and 24 h after oral administration on days 1 and 14. The blood was centrifuged immediately, and the plasma thus obtained was stored at -20°C until analysis.

Urine samples were collected at intervals of 0–4, 4–8, 8–12, and 12–24 h after drug administration on day 1 and at intervals of 0–4, 4–8, 8–12, 12–24, and 24–28 h after drug administration on day 14. Aliquots of 10 ml were stored at -20°C in cryotubes until analysis.

Pharmacokinetic Analyses.
The following noncompartmental pharmacokinetic parameters of DMDC and DMDU were estimated by WinNonlin Version 2.1 (WinNonlin Version SCI 1998, Apex, NC). C_max is the maximum drug concentration after oral administration; T_max is the time of maximum plasma drug concentration; the AUC to the last measurable concentration (AUC_t) was estimated by log-linear trapezoidal rule and extrapolated to infinity (AUC_0-) by the addition of C_t/_z, where _z is the terminal rate constant and C_t is the drug concentration at the last measurable sampling time. Terminal half-life (t_1/2) was calculated as ln2/_z. AUC_0–24 was defined as follows: if the concentration at 24 h was measurable, it was defined as AUC_t, and otherwise the concentration at the next time was substituted by 0 and extrapolated to this point. AUC_0–24 was calculated as AUC_t including this extrapolated point. Urinary excretion rate was calculated by Ae₂₄/dose, where Ae₂₄ was the cumulative amount recovered in urine until 24 h. The compartmental model was also fitted simultaneously to the plasma DMDC and DMDU concentration-time profiles using WinNonlin Version 2.1. The compartmental model was fitted to the mean values at each time.

Analytical Assay Methods.
Concentrations of DMDC and DMDU in plasma and urine were determined by validated column switching reverse-phase high-performance liquid chromatography assay with the UV detection at 275 nm. The plasma sample pretreated with 2 M perchloric acid and 2 M potassium hydroxide was applied to a precolumn (column A) Capsel Pak C₁₈ UG-120 (Shiseido, Tokyo, Japan). L-column (CITI, Tokyo, Japan) was used as an analytical column (column B) for determination of both DMDC and DMDU. The mobile phases for the columns A and B were 50 mM phosphate buffer (pH 2.2)/methanol (98:2, v/v) and 0.1 M phosphate buffer (pH 7.0)/methanol (98:2, v/v) for DMDC and 50 mM phosphate buffer (pH 2.2)/methanol (94:6, v/v) and 0.1 M phosphate buffer (pH 4.0)/methanol (95: 5, v/v) for DMDU, respectively. In the determination of DMDC and DMDU in urine, the sample pretreatment was conducted by Bond Elut C₁₈ (Varian, Sunnyvale, CA) and by ethylacetate/methanol (9:1, v/v), respectively. For DMDC analysis, column A was Capsel Pak C₁₈ UG-120, and the tandemly aligned column B was STR ODS II (Shimadzu, Kyoto, Japan) and TSK-gel (TOSOH, Tokyo, Japan). The mobile phases for the columns A and B were 50 mM ammonium acetate (pH 9.0)/methanol (98:2, v/v) and 0.1 M phosphate buffer (pH 2.2)/methanol (98:2, v/v/), respectively. For DMDU, columns A and B were the same as those for the plasma sample analysis. The mobile phases applied to the columns A and B consisted of 50 mM phosphate buffer (pH 2.2)/methanol (94:6, v/v) and 0.1 M phosphate buffer (pH 6.0)/methanol (95:5, v/v), respectively. The lower limits of quantification of DMDC and DMDU were 0.02 µg/ml in plasma and 0.5 µg/ml in urine. The intra- and interday variability for both DMDC and DMDU were <10% in plasma and urine assay.

Statistical Analysis.
The significance of difference of dose-independent pharmacokinetic parameters between 12 and 18 mg/m² was determined using one-way ANOVA.

	RESULTS

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Between November 1997 and September 1998, 14 patients participated in this four-center trial and received a total of 22 courses of therapy. Five patients were women and nine were men, and the median age was 61 years (range, 44–66 years; Table 1 ). Most patients received prior chemotherapy. The number of DMDC cycles administered per patient ranged from 1 to 4 (one cycle in 8 patients, two in 5 patients, and four in 1 patient).

Toxicity.
Two patients were not fully assessable for toxicity. One patient at dose level 1 was nonevaluable because scheduled laboratory tests on day 22 were missing. Another patient at dose level 2 was also not fully assessable for anemia because he suffered from massive hematuria attributable to multiple renal metastases. Because one patient treated with the starting dose level of 12 mg/m²/day experienced grade 3 anorexia, three more fully assessable patients were accrued (Table 2) . No other toxicities were seen, and escalation continued. One patient at dose level 2 had grade 3 leukopenia and neutropenia, and, therefore, three more patients were entered.

Hematological Toxicity.
At 12 mg/m²/day, no patients experienced grade 3 or worse myelosuppression (Table 2) . A patient treated at 18 mg/m²/day had grade 3 leukopenia, grade 3 neutropenia, and grade 3 anemia. Another patient experienced grade 3 thrombocytopenia. The onsets of neutropenia and thrombocytopenia were relatively late, with neutrophil and platelet nadirs observed on days 22–25 and 15–22, respectively. Because two of six fully evaluable patients of the 18-mg/m²/day dose level had DLTs, defining the MTD as 18 mg/m²/day for 14 days, no additional dose escalation was carried out in this trial.

Nonhematological Toxicity.
The nonhematological toxicities were relatively mild. Only one patient experienced grade 3 anorexia during the first cycle. Other documented toxicities were grade 2 or less. The most frequent toxicity was malaise of grade 2 occurring in 9 of 22 cycles (41%; Table 3 ). Anorexia was observed in eight (36%) cycles (grade 2 in 7 courses and grade 3 in one). Stomatitis of grade 2 was observed in five (23%) courses. Other gastrointestinal toxicity, including nausea and vomiting, gastric pain, and constipation, was very mild and transient. Fever was a minor problem, occurring in three patients. Increase in C-reactive protein was observed in three cycles. There was no evidence of hepatic or renal toxicity or alopecia in any of the patients. One patient at dose level 2 died on day 15 during the second cycle from pulmonary artery thrombosis, which was unlikely to be related to the study drug.

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View larger version (22K): [in this window] [in a new window]   Fig. 2. Schematic presentation of the compartmental model simultaneously fitted to the mean values of DMDC and DMDU.

View larger version (19K): [in this window] [in a new window]   Fig. 3. Observed and simulated mean plasma concentrations after oral administrations of DMDC in patients at a dose of 18 mg/m2/day. The simulated plasma concentrations were calculated based on compartmental model.

	DISCUSSION

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This article describes a Phase I trial of the novel deoxycytidine analogue, DMDC, administered p.o. once a day for 14 days and repeated at 4-week intervals. DMDC given on this schedule was generally well tolerated. The DLTs of DMDC were anorexia and myelosuppression (anemia and thrombocytopenia). Because the MTD was defined as the dose at which one-third or more of the patients experienced DLT during course 1 therapy, it was reached at the 18-mg/m²/day level, with DLTs observed in two of six patients (Table 2) . This dose (18 mg/m²/day) could also be considered appropriate for Phase II testing of DMDC administered for 14 days p.o., because these DLTs were short-lasting, predictable, and easily manageable. The observed toxicity pattern was quite different from that in preclinical studies of monkeys. With prolongation of exposure time, dermatitis characterized by erythema, pain, bullae, and desquamation prevailed, and there were only mild hematological toxicities in monkeys (9) . Gemcitabine, another deoxycytidine analogue in a well-advanced stage of clinical development, frequently induces flu-like symptoms (12, 13, 14, 15, 16, 17) . However, in this study flu-like syndrome and fever were not frequent nonhematological toxicities. Other toxicities were relatively mild, and no episodes of toxicities grade 3 or worse were noted (Table 3) .

In comparison, in a single i.v. administration Phase I trial, the dose was escalated from 200 to 450 mg/m². The MTD on this schedule was >400 mg/m², and no antitumor activity was noted on this schedule (18) . On a daily i.v. injection for 5-day schedule, the MTD was 40 mg/m²/day. Although no major responses were observed in this trial, a sign of the potential antitumor activity was observed in one patient with lung cancer who experienced some shrinkage of liver metastasis. The DLTs for both trials were leukopenia and neutropenia (18) . A Phase I trial with the drug given p.o. once a day for 10 consecutive days every 4 weeks revealed that the MTD was 40 mg/m²/day with the dose-limiting toxicities being neutropenia and thrombocytopenia (19) .

The pharmacokinetic study showed that after oral administration of DMDC, the drug was readily detected in plasma with a short lag time of 0.42–1.29 min and a peak at about 1.2–1.6 h, and rapid absorption [absorption rate constant (k12) = 0.74–0.93 h^-1]. The pharmacokinetic data, obtained on days 1 and 14 of the cycle 1, suggest that the pharmacokinetic parameters of DMDC were not changed by multiple dosing. Because the t_1/2 of DMDC was short relative to the dosing interval of 24 h, DMDC did not accumulate on repeated dosing (Fig. 3) . Furthermore, there was a trend toward an apparent time-dependent reduction in systemic exposure in some patients.

After oral administration of DMDC, 40–50% of the administered dose was recovered in the urine as DMDC and DMDU combined (Table 6) . In contrast, in another deoxycitidine analogue, (E)-2'-deoxy-2'-(fluoromethylene)cytidine only 3.2–4.8% of the total dose was found in the first 24-h urine (20) .

Although DMDC was about 700-fold more resistant to metabolic degradation by cytidine deaminase than gemcitabine (7) , the proportion of metabolite DMDU to parent compound DMDC was significant (Table 6) , indicating that the extensive metabolism of DMDC by cytidine deaminase occurred in vivo.

Although no major responses were observed in this trial, signs of the potential antitumor activity were observed in one patient with advanced non-small cell lung cancer who was heavily pretreated with cisplatin plus vindesine and thoracic radiotherapy.

In conclusion, this trial demonstrated that the MTD of DMDC and the recommended dose for an additional Phase II trial on this schedule were the same dose of 18 mg/m²/day. The DLTs were anorexia, leukopenia, anemia, and thrombocytopenia. General fatigue was the most frequent nonhematological toxic effect. Because there were signs of the antitumor activity, additional development of this drug is recommended.

	ACKNOWLEDGMENTS

 
We thank Satoshi Hattori and Dr. Tomoo Funaki for their help with the pharmacokinetic analysis.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Nippon Roche K.K. Company, Tokyo, Japan.

² To whom requests for reprints should be addressed, at Department of Internal Medicine, Osaka Prefectural Habikino Hospital, 3-7-1 Habikino, Habikino Osaka 583, Japan. Phone: 011-81-729-57-2121; Fax: 011-81-729-57-5708.

³ The abbreviations used are: DMDC, 2'-deoxy-2'-methylidenecytidine dihydrate; ara-C, 1-ß-D-arabinofuranoxylcytosine; DMDU, 2'-deoxy-2'-methylidineuridine; MTD, maximum tolerated dose; DLT, dose-limiting toxicity; AUC, the area under the (plasma drug concentration-time) curve.

Received 10/15/99; revised 2/28/00; accepted 3/ 9/00.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Masuda, N. Articles by Fukuoka, M. Search for Related Content PubMed PubMed Citation Articles by Masuda, N. Articles by Fukuoka, M.