Annals of Oncology Advance Access originally published online on December 8, 2006
Annals of Oncology 2007 18(3):576-580; doi:10.1093/annonc/mdl440
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 European Society for Medical Oncology
phase I and pharmacokinetics |
A phase I trial of fixed dose rate gemcitabine plus capecitabine in metastatic cancer patients
Medical Oncology, University Campus Bio-Medico, Rome, Italy
* Correspondence to: Dr D. Santini, Medical Oncology, University Campus Bio-Medico, Via Emilio Longoni, 69, 00155 Rome, Italy. Tel: +39-06-22541737; Fax: +39-06-22541520; E-mail: d.santini{at}unicampus.it
 |
Abstract |
|---|
 Top Abstract backgroundpatients and methodsresultsdiscussionReferences |
|---|
Background: Capecitabine and gemcitabine given as fixed dose rate (FDR) has not been demonstrated to be well tolerated in phase I previous studies. The goals of this phase I study were to determine the maximum-tolerated dose of this combination and to describe the dose-limiting toxic effects (DLT) and the safety profile of this way of administration.
Patients and methods: Patients with advanced solid tumors were eligible for this study. Capecitabine was administered orally at a dose of 650 mg/m2 bis in die (b.i.d.) for 14 consecutive days. Gemcitabine was administered at FDR of 10 mg/m2 per min in escalating durations of infusion on days 1 and 8. The cycles were repeated every 21 days.
Results: All 20 patients enrolled into the study were assessable for toxicity. Only one out of the first six patients treated at FDR gemcitabine dose of 800 mg/m2 met protocol-specified DLT criteria (grade 4 neutropenia lasting 
7 days) during the first two cycles. At these doses the majority of cycles of therapy were, however, delivered without dose reduction or delay. Another similar episode of DLT was observed at the same dose step among the following eight included patients. The dose of FDR gemcitabine 800 mg/m2 in 80 min on days 1 and 8 plus capecitabine 650 mg/m2 b.i.d., for 14 consecutive days followed by 1 week of rest is recommended for further study.
Conclusion: The combination of FDR gemcitabine plus capecitabine can be administered with acceptable toxicity. The evidence of antitumor activity deserves further investigation in phase II combination chemotherapy studies.
Key words: capecitabine, fixed dose rate, gemcitabine, phase I study
|
background |
|---|
|
TopAbstractbackgroundpatients and methodsresultsdiscussionReferences |
|---|
Gemcitabine is an antimetabolite that has demonstrated activity in pancreatic, lung, breast, and bladder carcinomas [1, 2]. Gemcitabine also appears to modulate the activity of 5-fluorouracil (5-FU) in renal and gastrointestinal (GI) malignancies, presumably by inhibiting ribonucleoside reductase and other enzymes critical to DNA synthesis [1, 2]. To enhance the cytotoxic activity of gemcitabine, an alternative infusion regimen has been explored. As the active metabolite of gemcitabine, 2',2'-difluordeoxycytidine triphosphate (dFdCTP) has a long intracellular half-life, a fixed dose rate (FDR) infusion of 10 mg/m2 per min has been shown to lead to maximal intracellular accumulation. In particular, it has been demonstrated that increasing the infusion time while holding the dose rate constant at 10 mg/m2/min could result in increased intracellular levels of dFdCTP, thus enhancing the activity of Gemcitabine [3, 4]. One randomized phase II study indicated that gemcitabine monotherapy administered by FDR may be superior to standard 30-min infusion gemcitabine in patients with advanced pancreatic cancer [5]. These results have been recently confirmed in a phase III trial comparing 30-min infusion gemcitabine (Eli Lilly, IN, USA) versus FDR gemcitabine versus gemcitabine + oxaliplatin in patients with advanced pancreatic cancer [6].
Capecitabine (Hoffman La Roche, Basel, Switzerland), a carbamate derivative of 5'-deoxy-5-fluorouridine (DFUR), is absorbed through the GI mucosa as an intact molecule and thereby it avoids the GI toxicity associated with 5'-DFUR [7]. It is sequentially activated by carboxylesterase, cytidine deaminase, and pyrimidine nucleoside phosphorylase. This cascade results in the formation of 5'-deoxy-5-fluorocytidine, 5'-DFUR, and finally the intratumoral release of 5-FU [7]. Thymydilate phosphorylase catalyses the final step of capecitabine activation from the intermediate metabolite 5-deoxyfluorouracil to fluorouracil. 5-FU derived from the conversion acts on thymidylate synthase and it is catalyzed by dihydropyrimidine dehydrogenase. So its pharmacodynamic is similar to intravenous 5-FU [7].
Gemcitabine is the only agent that abates symptoms and confers a modest survival advantage in pancreatic cancer patients [8]. Several randomized phase III trials have been conducted to compare gemcitabine-containing regimens with gemcitabine monotherapy since gemcitabine became available clinically [9, 10]. The combination of gemcitabine given at a fixed dose of 1000 mg/m2 with a fixed infusion duration plus capecitabine has demonstrated a survival advantage over gemcitabine with acceptable levels of toxicity in pancreatic cancer patients [11]. To determine the toxicity of the combination between FDR gemcitabine plus capecitabine, a phase I trial in metastatic renal cell carcinoma (RCC) was conducted by Rini et al. [12]. In this trial, the enrolled patients received FDR gemcitabine on days 1, 8, and 15 in combination with capecitabine, given on days 1–21 of a 28-day cycle. This combination produced unacceptable toxicity and the authors did not recommend further development of this schedule [12].
On the basis of this phase I trial and on the above considerations, we conducted a phase I study aimed to determine the maximum-tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of a combination of FDR gemcitabine on days 1 and 8 plus capecitabine given on days 1–14 every 21 days administered for two courses.
|
patients and methods |
|---|
|
TopAbstractbackgroundpatients and methodsresultsdiscussionReferences |
|---|
patient selection
All patients had a baseline history and full physical examination with radiologic and laboratory evaluation. Patients with measurable or clinically assessable histologically confirmed advanced solid tumors were eligible for this study. An age between 18 and 80 years, an Eastern Cooperative Oncology Group (ECOG) performance status of one or less, and a life expectancy >3 months were required. Bone marrow function requirements included an absolute neutrophil count
1500/mm3, a platelet count 100 000/mm3, and hemoglobin 10.0 g/100 ml. Preserved renal function (serum creatinine 
1.6 mg/dl, normal creatinine clearance), hepatic function (total bilirubin 1.5 mg/dl, aspartate aminotransferase and alanine aminotransferase 2.5 x normal without hepatic metastasis, and 4 x normal with hepatic metastasis; serum alkaline phosphatase <2.5 x the upper limit of normal or <5 x the upper limit of normal if liver metastases were present or <10 x the upper limit of normal if bone metastases were present), and cardiac function were required. Major exclusion criteria included cytotoxic or radiotherapy treatment within the previous 4 weeks (6 weeks if the previous therapy included a nitrosourea or mitomycin C). Concomitant use of amiodarone, ketoconazole, itraconazole, diltiazem, verapamil, barbiturates, and warfarin was not permitted. Pregnant or breast-feeding woman or patients with uncontrolled severe disease were excluded. Patients with significant stomach, small intestine, liver, or kidney disease likely to affect drug absorption or metabolism were excluded from the study. Patients with history of coagulopathy or with central nervous system tumor or metastasis were excluded too. All patients were required to provide written informed consent before initiation of treatment, after a complete and opportune explanation. Local ethics committee approval was obtained. The trial was conducted in accordance with the declaration of Helsinki. Patients were excluded if adequate follow-up was not possible (environmental or geographic difficulties, no compliance to undergo necessary clinical-instrumental investigations, etc).
study design
This is an open-label, single-center, nonrandomized, dose-escalating phase I study.
Capecitabine (Xeloda®, Hoffman La Roche Laboratories, Basel, Switzerland) was administered orally at a dose of 1300 mg/m2 per day, divided into two equal doses, for 14 consecutive days followed by 1 week of rest. Capecitabine was supplied as film-coated Xeloda tablets in two dosage strengths, 150-mg and 500-mg tablets, administered in non-fasting conditions, swallowed with water. Gemcitabine was administered at a FDR of 10 mg/m2 per min in escalating durations of infusion on days 1 and 8 every 21 days. Each treatment cycle was repeated every 21 days. Gemcitabine was commercially available as Gemzar (Eli Lilly, Indianapolis, IN) in 20-mg/ml vials, 10- and 50-ml sizes. The drug was prepared for administration according to directions in the package labeling. No specific premedication for nausea and/or vomiting was provided. A preventive protonic pump inhibitor was advised.
dose escalation and definition of study end points
In this phase I study, gemcitabine was administered at a FDR of 10 mg/m2 per min in escalating durations of infusion (60–90 min) on days 1 and 8 every 21 days. The starting dose of gemcitabine was 600 mg/m2, which was substantially lower than the dose in the previous phase I trial with standard infusion rate gemcitabine [13]. Treatment was administered on an outpatient basis. Gemcitabine doses were to be increased in increments of 100 mg/m2 per week until the MTD was established, not to exceed 900 mg/m2. No modification of the capecitabine dose was planned initially and no intrapatient dose escalation was allowed. In the absence of dose-limiting toxic effects, only three patients were to be treated at the first two dose levels. At the third and subsequent dose levels, it was planned to treat at least six patients because it was anticipated that these dose levels may be associated with toxicity. Patients were seen weekly and toxicity was assessed by the National Cancer Institute of Canada Common Toxicity Criteria [14]. For purposes of determining the MTD, only DLTs occurring during the first two cycles of therapy were considered. The MTD was defined as the dose level at which no more than one out of six patients experienced a DLT. Once this dose level was established, additional patients were enrolled (maximum of 12) to gain additional experience with the combination. The MTD represents the dose recommended for further studies. DLTs were defined as any of the following: grade 4 neutropenia lasting 7 days or grade 3 or 4 neutropenia associated with fever 38.1°C; grade 4 thrombocytopenia lasting 7 days, grade 4 anemia; any grade 3 or 4 non-hematologic toxicity except alopecia, and palmar-plantar erythrodysesthesia (‘hand-foot’ syndrome); grade 3 or 4 nausea, vomiting, or mucositis; grade 3 and 4 diarrhea or a second occurrence of grade 2 diarrhea; grade 2 or 3 hand-foot syndrome not reduced to grade 1 before the start of cycle 2; delay of 14 days in initiating the second or the third cycle of therapy because of persistent toxicity of grade 2 or higher.
dose modifications
The capecitabine administration was interrupted or modified in spite of observed toxicity. There was no dose modification for grade 1 toxicity. For grade 2 toxicity that persisted despite symptomatic treatment, capecitabine was withheld until resolution to grade 0 or 1 and then restarted at the same dose. If the grade 2 toxicity recurred or any grade 3 toxicity, capecitabine was withheld until resolution to grade 0 or 1 and then restarted at the preceding dose. For grade 4 toxicity, capecitabine was discontinued unless considered by the investigator to be in the patient's best interests, e.g. a responding patient, to continue at a lower dose level. The gemcitabine administration was interrupted or modified in spite of observed toxicity. Dose adjustments and delays were allowed for each drug. Gemcitabine was reduced by 25% on all subsequent cycles for febrile neutropenia, grade 4 hematological toxicity lasting for >7 days, or bleeding-associated thrombocytopenia, and gemcitabine was reduced by 25% for grade 3 non-hematologic toxicity thought to be related to gemcitabine until recovery to grade 1 toxicity or baseline occurred. In any case, patients who experienced DLT could be continued on treatment at a modified dose at the discretion of the treating physician if they seemed to be benefiting from the therapy.
pretreatment and follow-up studies
All patients had a baseline history and full physical examination with radiologic and laboratory evaluations. History, physical examination, and laboratory tests were repeated on day 1 of each cycle of therapy. Assessment of toxicity and hematology tests were carried out weekly during each cycle of therapy (during and after the study period). Response was assessed after two cycles of treatment (day 43) according to RECIST response criteria [15]. Responding patients or those with stable disease (SD) could continue treatment of a further four cycles of FDR gemcitabine plus capecitabine with assessment of tumor response after six cycles. Patients who responded or had SD after six cycles could continue treatment at the discretion of the investigator.
|
results |
|---|
|
TopAbstractbackgroundpatients and methodsresultsdiscussionReferences |
|---|
patients
The characteristics of the 20 patients enrolled in this study are summarized in Table 1. The median age was 63 years (range 39–75 years) and the median ECOG performance status was zero (range 0–1). None of them except four patients had previously received chemotherapy. None of them except for five patients had previously received radiotherapy. All patients completed the first two cycles of therapy and were, therefore, assessable for toxicity.
|
toxicity
The most common toxic effects observed during the first two cycles of chemotherapy are listed in Table 2. No episodes of DLT were observed at FDR gemcitabine doses of 600 mg/m2 and 700 mg/m2. Only one patient among the first six patients treated at FDR gemcitabine dose of 800 mg/m2 met protocol-specified DLT criteria (grade 4 neutropenia lasting
7 days). Fourteen patients were treated at FDR gemcitabine dose of 800 mg/m2 for a total of 75 cycles and median number of four cycles per patient (range 2–14) (Table 3). At this dose step (800 mg/m2) we did not observe any grade 3 or 4 toxicity (with the exception of two episodes of grade 4 neutropenia lasting 7 days, one with fever, five episodes of grade 3 neutropenia and one episode of grade 3 anemia) during the first two cycles. We observed two patients (14.3%) with grade 2 stomatitis, two patients (14.3%) with grade 2 thrombocytopenia, and three patients (21.4%) with grade 2 fatigue. All patients included in this dose step received the first two cycles at full doses without any dose reduction.
|
|
The hematologic and non-hematologic toxic effects cumulative over all cycles are reported in Table 4. At FDR gemcitabine dose level of 800 mg/m2 we observed the following severe toxic effects: two episodes of grade 3 liver toxicity (14.3%), one episode of grade 3 stomatitis (7.1%), and one case of grade 3 fatigue (7.1%), all resolved after dose reduction of gemcitabine. Hematologic toxicity was generally mild, with only three patients (21.4%) experiencing grade 4 neutropenia (the first two episodes lasting
7 days during the first two cycles as previously reported and the third lasting <7 days during the fourth cycle). Moreover, two patients required chemotherapy interruption because of severe or unresolved toxicity (one patient after three cycles for persistent grade 2 neutropenia and another patient after 14 cycles for persistent grade 2 hand-foot syndrome). At the same dose step (800 mg/m2) three patients (21.4%) of the 14 included required (cycle 3 or higher) dose reduction for treatment-related toxicity. No patients experienced clinically significant hand-foot syndrome (grade 2 or higher), no patients required platelet or red cells transfusion, and no patients reported episodes of severe nausea/vomiting or diarrhea (Table 4). The MTD was defined as the dose level at which no more than one of six patients experienced a DLT. Once MTD was established, additional patients were enrolled (eight patients) to gain additional experience with the combination. On the basis of the occurrence of only one episode of DLT among the first six patients (grade 4 neutropenia lasting 7 days) during the first two cycles and the ability to deliver the majority of successive cycles without dose modification or delay, we recommend evaluation in phase II studies FDR gemcitabine at the dose of 800 mg/m2 in 80 min on days 1 and 8 plus capecitabine at a dose of 1300 mg/m2 per day, divided into two equal doses, for 14 consecutive days followed by 1 week of rest.
|
Although assessment of tumor response was not a primary objective of this study, patients were evaluated for tumor response after the first two and six cycles of treatment. Of the nine pancreatic cancer patients with measurable disease, we observed one partial response (PR), six SD, and two progressive disease (PD); of the six periampullary cancer patients, one had complete response (CR), four had SD, and one had progressive disease (PD). PR is defined as 30% decrease in the sum of the longest diameter of target lesions; PD is defined as 20% increase and CR as disappearance of all target lesions. The patient with CR had a progressive metastatic cholangiocarcinoma and is disease-free surviving for 12+ months. In this small study, there was no apparent correlation between initial performance status and toxic effects or response.
|
discussion |
|---|
|
TopAbstractbackgroundpatients and methodsresultsdiscussionReferences |
|---|
Despite advances in chemotherapy for many solid tumors, most noticeably in breast and lung cancers, there has been little progress over the last decade in the treatment of advanced periampullary carcinomas. Gemcitabine continues to be the mainstay of chemotherapy for patients with advanced pancreatic carcinoma. Several controlled trials have indicated improvements in the objective tumor response rate combining gemcitabine with other cytotoxic agents [9]; no statistically significant improvement in survival has been observed in multiple phase III trials when doublets of gemcitabine plus a cytotoxic drug have been compared with single-agent gemcitabine [9]. FDR administration has also been evaluated to improve the efficacy of gemcitabine. One randomized phase II study indicated that gemcitabine monotherapy administered by FDR may be superior to standard infusion gemcitabine in patients with advanced pancreatic cancer [5]. The current study reports the first positive phase I trial combining FDR administration of gemcitabine plus capecitabine. On the basis of the occurrence of only one episode of DLT among the first six patients (grade 4 neutropenia lasting
7 days) during the first two cycles and the ability to deliver the majority of successive cycles without dose modification or delay, we recommend for further evaluation in phase II studies FDR gemcitabine at the dose of 800 mg/m2 in 80 min on days 1 and 8 plus capecitabine at a dose of 1300 mg/m2 per day, divided into two equal doses, for 14 consecutive days followed by 1 week of rest. The only previous experience evaluating this type of combination has been recently published by Rini et al. [12]. The authors conducted a phase I trial aimed to determine the toxicity of this combination therapy in RCC. Patients received FDR gemcitabine on days 1, 8, and 15 in combination with capecitabine, given on days 1–21 of a 28-day cycle. The initial dose level (gemcitabine 600 mg/m2 plus capecitabine 830 mg/m2 twice per day) produced DLT, including prominent palmar-plantar erythrodysesthesia (hand-foot syndrome). As stated by the authors, this study shows several limitations: initial chemotherapy doses were chosen on the basis of the phase I study of capecitabine and standard infusion gemcitabine [12] and on the demonstrated effects in metastatic RCC of 21-day 5-FU dosing [16]. Clearly, prolonged infusion of gemcitabine has a different toxicity profile, and starting doses in this study resulted in unacceptable toxicity. Moreover, the authors chosen to administer gemcitabine for three consecutive weeks every 28 days and capecitabine continuously for 21 days. Probably, this schedule contributed to increase the risk of toxicity; in particular the weekly FDR infusion of gemcitabine appeared to enhance the hand-foot syndrome toxicity of continuous capecitabine.
On the contrary, our phase I study demonstrated a cumulative favorable toxicity profile of the regimen at the recommended dose step with only three patients (21.4%) experiencing grade 4 neutropenia (the first two episodes lasting 7 days during the first two cycles as previously reported and the third lasting <7 days during the fourth cycle). Moreover, the main non-hematological drug-related toxic effects at the same dose step were two episodes of grade 3 liver toxicity (14.3%), one episode grade 3 stomatitis (7.1%), and one case of grade 3 fatigue (7.1%), all of which were reversible and manageable with appropriate dose interruptions and modifications. The high degree of tolerability of this schedule was also confirmed with a median number of six cycles (range 2–18) (i.e. 126 days) in patients who received the recommended dose step.
We were encouraged to observe a significant number of patients with disease control, both in periampullary carcinoma and in pancreatic carcinoma. Pharmacologic studies were not carried out in this study, but it is likely that such studies would have contributed much information at this point in the development of this regimen. For this reason, a pharmacological study is strongly suggested. Phase II studies are now being planned for patients with pancreatic cancer and biliary cancer to further define the antitumor activity and tolerability of this regimen.
In conclusion, these results clearly and, for the first time, show the feasibility of a regimen that combines FDR infusion of gemcitabine plus capecitabine.
Received for publication September 7, 2006. Revision received October 24, 2006. Accepted for publication October 31, 2006.
|
References |
|---|
|
TopAbstractbackgroundpatients and methodsresultsdiscussionReferences |
|---|
1. Heinemann V, Xu YZ, Chubb S, et al. (1990) Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine. Mol Pharmacol 38:567–572.[Abstract]
2. Ren Q, Kao V, Grem JL. (1998) Cytotoxicity and DNA fragmentation associated with sequential gemcitabine and 5-fluoro-2'-deoxyuridine in HT-29 colon cancer cells. Clin Cancer Res 4:2811–2818.[Abstract]
3. Grunewald R, Kantarjian H, Keating MJ, et al. (1990) Pharmacologically directed design of the dose rate and schedule of 2',2'-difluorodeoxycytidine (gemcitabine) administration in leukemia. Cancer Res 50:6823–6826.
4. Abbruzzese JL, Grunewald R, Weeks EA, et al. (1991) A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498.[Abstract]
5. Tempero M, Plunkett W, Ruiz van Haperen V. (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21:3402–3408.
6. Poplin E, Levy DE, Berlin J, et al. Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion [FDR]) versus gemcitabine + oxaliplatin (GEMOX) in patients with advanced pancreatic cancer (E6201). ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Suppl); 2006: LBA4004.
7. Reigner B, Blesch K, Weidekamm E. (2001) Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet 40:85–104.[CrossRef][Web of Science][Medline]
8. Burris HA III, Moore MJ, Andersen J, et al. (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413.
9. Kindler HL. (2005) Front-line therapy of advanced pancreatic cancer. Semin Oncol 32:Suppl 9, S33–S36.[Web of Science][Medline]
10. Rodney A, Dieringer P, Mathew P, et al. (2006) Phase II study of capecitabine combined with gemcitabine in the treatment of androgen-independent prostate cancer previously treated with taxanes. Cancer 106:2143–2147.[CrossRef][Web of Science][Medline]
11. Cunningham D, Chau I, Stocken D, et al. (2005) Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer Suppl 3:4 (European Cancer Conference Organization).
12. Rini BI, Weinberg V, Small EJ. (2005) A phase I trial of fixed dose rate gemcitabine and capecitabine in metastatic renal cell carcinoma. Cancer 103:553–558.[CrossRef][Web of Science][Medline]
13. Schilsky RL, Bertucci D, Vogelzang NJ, et al. (2002) Dose-escalating study of capecitabine plus gemcitabine combination therapy in patients with advanced cancer. J Clin Oncol 20:582–587.
14. NCI CTC Toxicity scale Version 2.0. www.eortc.be/Services/Doc/ctc/CTCvs2.doc (2000).
15. Therasse P. (2002) Measuring the clinical response. What does it mean? Eur J Cancer 18:17–23.[Medline]
16. Rini BI, Vogelzang NJ, Dumas MC, et al. (2000) Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer. J Clin Oncol 18:2419–2426.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||