1 Section of Hematology/Oncology, Department of Medicine, 2 Cancer Research Center, 3 Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL; 4 Pfizer Inc., Ann Arbor, MI, USA
* Correspondence to: Dr H. L. Kindler, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637, USA. Tel: +1-773-702-0360; Fax: +1-773-702-0963; Email: hkindler{at}medicine.bsd.uchicago.edu
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Abstract |
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Patients and methods: Fifty-four patients were treated according to three different dosing schemes in which the capecitabine dose was fixed and the CI-994 dose was escalated. Capecitabine was administered in twice daily divided doses, and CI-994 was given as a single daily dose. In schedule A, 26 patients were treated with capecitabine 1650 mg/m2/day and CI-994 for 2 weeks of a 3-week cycle. In schedule B, six patients received capecitabine 1650 mg/m2/day for two 3-week cycles and CI-994 for 5 of 6 weeks. In schedule C, 22 patients were treated with capecitabine 2000 mg/m2/day and CI-994 for 2 of 3 weeks.
Results: At the MTD, the principal dose-limiting toxicity was thrombocytopenia. The pharmacokinetics of CI-994 were unaltered by capecitabine, and there was no correlation between body surface area and major pharmacokinetic parameters. Platelet count nadir was best predicted by the observed maximal concentration (Cmax) of CI-994.
Conclusions: The recommended phase II dose is 6 mg/m2 (or 10 mg) of CI-994 in combination with capecitabine 2000 mg/m2/day for 2 weeks of a 3-week cycle.
Key words: capecitabine, CI-994, dose-limiting toxicity, histone deacetylase inhibitor, pharmacokinetics, phase I study
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Introduction |
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Prakash et al. [10] performed a phase I study of single-agent CI-994 using a dose-escalation scheme that increased both the daily dose and the duration of treatment. When given for 8 weeks followed by a 2-week rest period, the maximum tolerated dose (MTD) of CI-994 was 8 mg/m2. The dose limiting toxicities (DLTs) observed were thrombocytopenia and neutropenia, though not occurring concurrently. Stable disease was documented in one patient each with colorectal, non-small-cell lung and renal carcinomas. Furthermore, a partial response lasting over 26 months was seen in a heavily pretreated patient with adenocarcinoma of the lung. In a second phase I study combining gemcitabine with CI-994 given daily for 21 days of a 28-day treatment cycle, thrombocytopenia was again the DLT [11
]. Pharmacokinetic analyses of CI-994 from both studies suggested linear kinetics and rapid absorption after oral administration. Gemcitabine did not alter the pharmacokinetics of CI-994.
Capecitabine is currently approved in the USA for the treatment of breast and colorectal cancer and has been shown to have activity, both alone and in combination with other chemotherapeutic agents, in a variety of other tumors including gastric, head and neck and renal cell carcinoma [1214
]. Toxicities commonly associated with capecitabine monotherapy include anemia, fatigue, gastrointestinal (diarrhea, nausea, vomiting and stomatitis), handfoot syndrome and lymphopenia [15
18
].
Both capecitabine and CI-994 demonstrate activity in solid tumors. They have distinct mechanisms of action with non-overlapping toxicities; in an in vivo murine colon tumor model, they have an additive antitumor effect when administered together. Furthermore, together they provide a convenient oral antitumor regimen. For these reasons, we conducted a phase I study of the combination of CI-994 and capecitabine in patients with advanced solid tumors.
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Patients and methods |
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Pretreatment and follow-up evaluation
Complete history, physical examination, assessment of performance status, electrocardiogram, complete blood count (CBC) with differential, serum chemistry profile and serum pregnancy test, if applicable, were conducted prior to the first treatment. Thereafter, physical examination, assessment of adverse effects and performance status, serum chemistry profile and CBC with differential were performed weekly. Additional CBCs were drawn on days 11 and 18 of the first cycle. Electrocardiograms were obtained on the first day of each cycle and on day 22 for patients on the 6-week dosing schedule. Objective tumor assessment by computed tomography or magnetic resonance imaging was performed prior to starting therapy and every 6 weeks thereafter while the patient was in the study.
Treatment protocol
Three dosing schemes were explored in this study. In the first scheme (schedule A), a 3-week treatment cycle was used in which both agents were administered for 2 weeks followed by a 1-week rest period. The starting dose of capecitabine was 1650 mg/m2/day in twice-daily divided doses, which is 66% of the recommended dose when given as monotherapy in solid tumors. The starting CI-994 dose was 4 mg/m2 as a single daily dose, which is 50% of the phase II recommended single agent dose when administered for 8 weeks of a 10-week treatment cycle.
The single agent phase I study demonstrated that chronic dosing up to eight consecutive weeks is feasible [10]. Because non-clinical studies of CI-994 demonstrated that the degree of tumor growth inhibition is directly related to the duration of drug exposure [19
], it was postulated that prolonged, chronic dosing would be more effective than intermittent administration. For this reason a longer 6-week dosing schedule was studied in the second dosing scheme (schedule B). Capecitabine was administered as before (2 weeks of treatment followed by a 1-week rest period, then repeated), but CI-994 was administered for five consecutive weeks followed by a 1-week drug-free period. The capecitabine dose for this second schedule was again 1650 mg/m2/day, and the starting CI-994 dose level was two dose levels below the MTD of schedule A.
After the establishment of the schedule B MTD, a third dosing scheme (schedule C) was added to increase the administered capecitabine to a dose closer to the recommended single-agent dose. Schedule C returned to the original 3-week treatment cycle but with a capecitabine dose of 2000 mg/m2/day, which was a 25% increase over the initial capecitabine dose and 80% of the recommended single-agent dose in solid tumors. The CI-994 starting dose was again 4 mg/m2.
In all three dosing schemes, the capecitabine dose remained fixed at the initial dose of either 1650 or 2000 mg/m2/day for all subsequent dose levels, while the CI-994 dose increased by a fixed increment of 2 mg/m2 until establishment of the MTD. Initially, three-patient cohorts were used. When a DLT was observed, cohorts were expanded to six patients. The MTD was established when two or more patients at the same dose level experienced similar DLTs. Dose escalation to a new cohort was not permitted until all patients in the previous cohort had completed the initial 3- or 6-week treatment course. Intrapatient dose escalations were not permitted. Capecitabine dose was reduced by 25% for the second occurrence of grade 2 or first occurrence of grade 3 toxicity. CI-994 dose was decreased by 2 mg/m2 for toxicity grade 3.
Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. DLT was defined as any of the following occurring in the first treatment cycle: platelet nadir <25 000/µl; absolute neutrophil count <500/µl for 5 days or more or associated with infection or fever; grade 2 treatment-related central nervous system toxicities lasting for
24 h; grade
3 non-hematologic toxicity of any type; failure to recover from treatment-related toxicity with 21 days of discontinuation of therapy; or a terminated or non-compliant treatment cycle with <80% of planned capecitabine or CI-994 doses administered due to treatment-related toxicity.
Drug administration
CI-994 was supplied by Parke-Davis Pharmaceutical Research Division (Ann Arbor, MI, USA) as 2.5, 5 and 10 mg gelatin capsules. Capecitabine was commercially available as film-coated tablets in strengths of 150 and 500 mg. Doses of both agents were calculated based on body surface area (BSA) and rounded to the closest available tablet or capsule strength. Patients were instructed to take the CI-994 with the morning capecitabine dose and to swallow the capsules and tablets intact.
Pharmacokinetic studies
Samples for pharmacokinetic analysis were only obtained from patients who were treated on schedule A. Venous blood samples were collected prior to and at 0.5, 1, 2 and 4 h after CI-994 and capecitabine dosing on days 1 and 8 of the first cycle. Blood was collected in evacuated tubes containing 72 USP units of sodium heparin and placed on ice for a maximum of 20 min. Plasma was isolated by centrifugation at 4°C and stored at 20°C until analyzed.
Concentrations of CI-994 in plasma were determined using a previously validated high performance liquid chromatography (HPLC)/mass spectrometry method [20]. Briefly, heparinized human plasma samples (0.5 ml) were mixed with an aqueous internal standard solution and passed through a C18 solid-phase extraction sorbent. The compound of interest was eluted using a mixture of equal parts methanol and acetonitrile, evaporated to dryness under N2, reconstituted in mobile phase, and separated on a reverse-phase HPLC column with mass spectrometry/mass spectrometry detection.
Concentrationtime profiles were analyzed using conventional population pharmacokinetic methods [21]. Both one- and two-compartment models were evaluated and parameterized in terms of oral clearance (CL/F) and volume of distribution Vd/F. The absorption rate (Ka) was modeled as a first order process. Interindividual variability in pharmacokinetic parameters was expressed as log normally distributed. Residual (intra-subject) error was modeled as proportional to concentration.
Response evaluation
Only those patients who underwent appropriate radiological tumor evaluation after at least one cycle of treatment were considered assessable for response. Partial response required a 50% decrease in the sum of the products of the longest perpendicular diameters of all measured lesions for a minimum of 4 weeks. Progressive disease was defined as an increase of
25% in the sum of the products of the longest perpendicular diameters of all measured lesions or the appearance of new lesions. Patients were considered to have stable disease when the criteria for complete response, partial response or progressive disease were not met during the first 6 weeks of treatment.
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Results |
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Dose escalation and MTDs
Table 2 details the dose escalation schema. A total of 162 cycles were administered to the 52 patients who were assessable for toxicity. Thirty-seven per cent of patients required dose reduction of CI-994 and/or capecitabine for toxicity. The MTD of CI-994 in combination with capecitabine 1650 mg/m2/day (schedule A) was determined to be 10 mg/m2 after four patients in that dose level developed DLT. Enrolment then switched to the 6-week schedule B. As 50% of the patients treated at the initial dose level experienced DLT, further dose escalation on the 6-week dosing schedule was abandoned; dose escalation of CI-994 proceeded in combination with a fixed capecitabine dose of 2000 mg/m2/day on a 3-week schedule (schedule C). The MTD of this third dosing scheme was determined when both patients enrolled at the 8 mg/m2 dose level experienced DLT.
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Episodes of severe anemia and neutropenia in cycle 1 were limited. In addition to the above-described patient, two patients treated with 4 mg/m2 of CI-994 in schedule C developed grade 3 anemia. A single episode of grade 3 neutropenia in cycle one was observed at the highest dose level of schedule A. However, one patient each treated with 4, 8 and 10 mg/m2 of CI-994 in schedule A required dose reduction in cycles three or four due to grade 3 neutropenia.
Non-hematological toxicity
Table 4 summarizes the incidence of non-hematological toxicity by dose level. There were no grade 4 non-hematological toxicities observed in cycle one. The most common toxicities were gastrointestinal and included anorexia, diarrhea, nausea and vomiting. Fatigue was also commonly reported and was a DLT at the CI-994 8 mg/m2 dose level of schedule A. The non-hemtaological DLTs at the MTD of schedules A, B and C were handfoot syndrome, diarrhea and stomatitis, respectively.
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Discussion |
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However, CI-994 clearance, volume and dose-normalized Cmax did not correlate with BSA. These results, together with the fact that Cmax, the best predictor of toxicity, increased with the actual CI-994 dose administered (i.e. mg/m2 x BSA), lends support to BSA-independent dosing of CI-994. The phase II recommended flat dose of CI-994 is 10 mg when combined with capecitabine. It is also possible that fixed dosing of capecitabine (e.g. 3000 mg/day) could be utilized in future trials of this combination [22].
As was the case in the single-agent study of CI-994, thrombocytopenia was the primary DLT. Although there was only one instance of grade 4 thrombocytopenia, the incidence would likely have been higher had treatment not been withheld per protocol specified guidelines when platelet counts approached unacceptably low levels. When it occurred, thrombocytopenia was usually reversible within 12 weeks of CI-994 withdrawal, and patients most often could resume therapy with a dose reduction. Other hematological toxicity was limited to single instances of grade 3 anemia and neutropenia at the highest CI-994 dose of 10 mg/m2. Non-hematologic toxicities observed were either grade 2 in severity or well-described toxicities of capecitabine.
Concomitant capecitabine administration did not appear to alter the pharmacokinetic disposition of CI-994, as the pharmacokinetic results were comparable to those obtained from the earlier single agent phase I trial (Table 6). While there appears to be a large difference in Ka, this is likely an artifact of the different sampling schemes used. In particular, sampling during the absorption phase was limited in this study as compared with the previous study. Irrespective of the actual Ka, absorption after oral dosing was rapid, with Cmax occurring within 2 h of drug administration in both studies. On the other hand, the effect of CI-994 on the pharmacokinetics of capecitabine and its active metabolite 5-fluorouracil is unknown, as these data were not collected.
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Schedule C was chosen over schedule A as the recommended phase II schedule because the capecitabine dose of schedule C is closer to the recommended single-agent capecitabine dose of 2500 mg/m2/day. The CI-994 dose is the same as the recommended phase II dose in combination with gemcitabine [11]. It should be noted, however, that this CI-994 dose is <50% of the single-agent MTD of 15 mg/m2 [10
]. It cannot be determined from this phase I trial whether 6 mg/m2 is sufficient to cause an antitumor effect.
No phase II trials of the combination of CI-994 and capecitabine are currently planned. However, disease-specific studies would be most appropriate in breast and colorectal cancer, for which capecitabine monotherapy is approved.
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Acknowledgements |
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Received for publication May 7, 2004. Revision received May 27, 2004. Accepted for publication July 2, 2004.
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References |
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