1 Centre Hospitalier de l'Université de Montréal, St-Luc Hospital, Montreal, Canada; 2 Leicester Royal Infirmary, Leicester; 3 Christie Hospital, Manchester, UK; 4 Jewish General Hospital, Montreal; 5 London Regional Cancer Center, London; 6 Sacré-Coeur Hospital, Montreal, Canada; 7 Belfast City Hospital, Belfast, UK; 8 Shire Pharmaceutical Development, Rockville, MD, USA; 9 Princess Margaret Hospital, Toronto, Canada
* Correspondence to: Dr M. Moore, Department of Medical Oncology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Tel: +1-416-946-2263; Fax: +1-416-946-2082; Email: malcolm.moore{at}uhn.on.ca
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Abstract |
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Patients and methods: Troxacitabine 1.5 mg/m2 was administered by 30-min infusions daily x5 every 4 weeks to 54 patients with advanced pancreatic cancer. Patients were evaluated for objective tumor response, time to tumor progression (TTP), changes in tumor marker CA 19-9, survival, safety, pain, analgesic consumption, Karnofsky performance status and weight change.
Results: Median TTP was 3.5 months (95% CI 2.03.8), median survival 5.6 months (95% CI 4.97.4), and the 1 year survival rate 19%. Best responses were stable disease in 24 patients with eight patients having stable disease for at least 6 months (15%). A 50% or greater decrease in CA 19-9 was seen in seven of 44 assessed patients (16%). Grade 3 and 4 neutropenia were observed in 37% and 30% of patients with one episode of febrile neutropenia. The most common drug-related non-hematological toxic effects reported were cutaneous, with 22% and 6% of patients reporting grade 2 and 3 skin rash, respectively and 4% grade 2 handfoot syndrome.
Conclusion: Troxacitabine administered by a bolus daily x5 monthly regimen has modest activity in advanced pancreatic adenocarcinoma.
Key words: nucleoside analog, pancreatic cancer, phase II, troxacitabine
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Introduction |
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Naturally occurring nucleosides and nucleoside analogs developed to date as anticancer therapeutics, such as gemcitabine, are in the D stereochemical configuration. Until recently, corresponding unnatural L-enantiomers have largely been considered to be unrecognizable by cellular enzymes and therefore biologically inactive. However, the discovery that the L-()-SddC (2'-deoxy-3'-thiacytidine; lamivudine; 3TC®) stereoisomer was more potent than its corresponding D-enantiomer against human immunodeficiency [3] and hepatitis B [4
] viruses led to the identification of L-()-OddC (2'-deoxy-3'-oxacytidine; troxacitabine; TroxatylTM), a nucleoside analog with significant preclinical anticancer activity [5
]. The different isomeric configurations confer to troxacitabine different mechanistic properties relative to gemcitabine: its cellular membrane permeation is non-carrier mediated [6
] and it is resistant to deamination [5
], phosphorylated from diphosphate to triphosphate by 3-phosphoglycerate kinase [7
] and excised from DNA by human apurinic/apyrimidinic DNA endonuclease [8
]. Troxacitabine causes chain termination after it is incorporated into DNA since it lacks a hydroxyl group and is a potent inhibitor of DNA polymerases [9
]. Troxacitabine has significant activity in pancreatic cancer xenograft models, where it was more active than gemcitabine in the Panc-01 model and has moderate activity in the gemcitabine refractory MiaPaCa model [10
].
Three phase I studies of troxacitabine using different bolus administration schedules (every 3 weeks; daily x5 monthly and weekly x3 every 4 weeks) were carried out in patients with solid tumors and a fourth phase I study using the daily x5 schedule was carried out in acute leukemia [1115
]. Granulocytopenia and skin rash were dose-limiting in the solid tumor studies and stomatitis and handfoot syndrome in the acute leukemia trial. The pharmacokinetics of troxacitabine were linear and consistent across the phase I trials with urinary excretion of unchanged troxacitabine accounting for most drug elimination [11
, 12
, 14
]. Pilot solid tumor phase II clinical trials were carried out in prostate, colorectal, pancreatic, renal cell [16
], non-small-cell lung cancer [17
] and malignant melanoma. In the pancreatic cancer trial, one of the seven patients with no prior chemotherapy had a partial response. There was no evidence of troxacitabine activity in eight patients previously treated with gemcitabine. The most commonly observed toxic effects in the phase II studies were hematological (neutropenia) and cutaneous (skin rash, dry skin, pruritus and handfoot syndrome).
On the basis of the preclinical and clinical results and the activity of other nucleoside analogs in pancreatic adenocarcinoma, it was decided to study the activity of troxacitabine in advanced pancreatic cancer in patients with no prior chemotherapy using the daily x5 every 4 weeks schedule.
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Patients and methods |
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Study design and treatment
This was a phase II, single-arm, open-label, multicenter study of troxacitabine administered as a 30-min infusion at 1.5 mg/m2 daily x5 every 4 weeks. The primary objective was to determine the progression-free survival of chemotherapy-naïve patients treated with troxacitabine. Secondary objectives were overall survival, objective response rate, toxicity and assessment of pain, analgesic consumption, Karnofsky performance status and weight change. Doses were reduced for hematological and other toxic effects, as graded using the NCI Common Toxicity Criteria (CTC) version 2.0. If patients experienced grade 2 or higher skin rash, treatment was delayed until the skin rash had recovered to at least grade 1. Retreatment was carried out at the same dose but administered with prednisone at 25 mg orally daily for the first 5 to 7 days, starting the first day of treatment. Treatment was delayed in the event of grade 2 or 3 handfoot syndrome until recovery to at least grade 1 with subsequent cycles administered at a 25% dose reduction. Study treatment was continued until there was evidence of disease progression, unacceptable toxicity, the patient requested discontinuation of study treatment, or the investigator felt the patient could not benefit from further treatment. Treatments administered after patients progressed and went off therapy were not documented.
Evaluation
Progression-free survival was defined as the time from the first day of treatment to the first documentation of clinical or radiological tumor progression. Overall survival was calculated from the first day of treatment until the date of death. Assessment of measurable lesions was based on computed tomography or magnetic resonance imaging scans. Imaging studies were carried out at baseline and following every two cycles of treatment. Objective tumor responses were evaluated according to WHO Response Criteria. CA 19-9 levels were measured at baseline and every two cycles using commercially available assays at each participating institution. Baseline was defined as the last measurement within 7 days before day 1 of cycle 1. Percent reduction was the minimum per cent change value in all evaluated study cycles from baseline for each patient.
Pain and analgesic consumption were assessed weekly and Karnofsky performance status and weight change assessed monthly. Each patient participated in a 27 day lead-in period before receiving study drug in order to stabilize and characterize analgesic consumption and pain intensity. To establish a baseline measurement before study drug administration, assessments of Karnofsky performance status by the investigator and weight were taken within 72 h before day 1 of cycle 1. For pain intensity, the patient baseline status was the mean pain intensity score of day 1 of cycle 1 using the Memorial Pain Assessment Card (MPAC) visual analog scale (assessed before troxacitabine administration) and the scores from the last 2 days of the pain stabilization period (i.e. days 2 and 1 before day 1 of cycle 1). For analgesic consumption, the patient's baseline status in morphine mg equivalents was determined from the last 2 days of the pain stabilization period (i.e. days 2 and 1 before day 1 of cycle 1). Each patient was classified as positive, stable or negative for pain intensity, analgesic consumption and performance status evaluation and globally as achieving overall clinical benefit as previously described [2]. Safety data from physical examinations, laboratory evaluations, and adverse events were assessed according to the revised NCI CTC version 2.0. Complete blood counts were carried out at baseline and weekly thereafter whereas, after baseline, renal and hepatic function tests were repeated on day 1 of each treatment cycle. CA 19-9 tumor marker levels were obtained at baseline and on day 1 of every second cycle thereafter.
Statistical methods
All patients who received at least one dose of troxacitabine were evaluated for toxicity and efficacy. Overall survival and progression-free survival were derived by KaplanMeier curves. After the first 25 patients were entered, the 2-month progression-free rate was assessed with a null hypothesis that the proportion of patients free of progression was 20% versus an alternative hypothesis of a proportion of 40%. The study would have been stopped if eight patients or less out of 25 were free of progression at 2 months. This stopping rule provided 72.6% power at a significance level of 0.047. Treatment administration, adverse events and laboratory abnormalities were summarized descriptively.
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Results |
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Thirty-one patients (57%) had a minimum analgesic consumption of 10 mg morphine equivalents per day at baseline and four of the 27 with follow-up data (15%) decreased their analgesic use by 50% for at least 4 weeks. Median pain score at baseline was 14 mm. Twenty-eight patients (52%) had a minimum pain score of
20 at baseline and three of the 24 (13%) with follow-up data decreased their pain intensity score by
50% for at least 4 weeks. Eight patients out of 53 with baseline data (15%) had a Karnofsky score <80 and none of these had a
20-point improvement during the trial. Forty-one patients (77%) had either a Karnofsky performance status PS <80, a minimum analgesic consumption of 10 mg morphine equivalents per day or a minimum pain score of
20 at baseline and were thus eligible for clinical benefit response evaluation. Four of the 34 (12%) with available follow-up data had a positive clinical benefit response. Two additional patients who were not sufficiently symptomatic to meet the criteria for clinical benefit response evaluation increased their weight by >7% on the study while receiving eight and 14 cycles of therapy, respectively.
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Discussion |
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The incidence of hematological toxicity was low with a single episode of febrile neutropenia observed and, as in previous studies, the most prevalent non-hematological toxic effects were cutaneous [16]. However, the severity of observed skin rashes and handfoot syndrome appeared lower than reported with the every 3-week schedule [16
].
Troxacitabine and cytarabine have been shown to have additive effects in vivo in a human acute leukemia xenograft model [25]. Recently, troxacitabine and gemcitabine were also demonstrated to be synergic in vitro in four human pancreatic adenocarcinoma cell lines and to be at least additive in an in vivo model [26
]. The mechanisms of additivity/synergy has not yet been elucidated but may involve different mechanisms of cellular drug uptake [6
] and DNA repair [8
]. A phase I trial is currently examining the feasibility of a troxacitabine/gemcitabine combination and early results indicate that both drugs can be safely combined at effective doses [27
].
This study indicates that bolus administration of troxacitabine daily x5 has modest activity in pancreatic adenocarcinoma, with survival data comparable to those reported with single-agent gemcitabine.
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Acknowledgements |
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Received for publication August 17, 2004. Revision received October 19, 2004. Accepted for publication October 20, 2004.
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References |
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